Experts in CMT

Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for CMT2N: dominant heterozygous AARS1 alleles reduce alanyl-tRNA aminoacylation, but loss of one copy alone is insufficient to cause disease, so the mutant enzyme additionally interferes with the wild-type, and added wild-type protein is not predicted to rescue. The ARS-CMT "a gain or a loss?" framework and dominant tRNA-synthetase models keep the loss-versus-interference balance debated, holding confidence at medium.

Rationale: Heterozygous AARS1 alleles reduce alanyl-tRNA aminoacylation, but data suggest that partial loss is insufficient on its own to cause disease. That insufficiency is the supplementation signature of interference rather than an independent gain of function: the mutant enzyme disrupts the wild-type, so a single dominant-negative mechanism accounts for the phenotype. The gain-versus-loss question keeps confidence at medium.

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Mechanistic basis: Mixed

Prediction: The literature predicts a complex mechanism for dHMN-AARS1: heterozygous AARS1 alleles reduce alanyl-tRNA aminoacylation, a partial loss, but functional and modeling data indicate this loss is necessary yet insufficient, requiring an added toxic component in which the mutant subunit interferes with the wild-type synthetase. Because wild-type supplementation is not predicted to fully rescue the toxic component while the residual phenotype tracks with reduced enzymatic activity, the evidence supports a mixed loss-plus-toxic mechanism rather than a single one.

Rationale: Dominant dHMN-AARS1 combines a partial loss of aminoacylation with a superimposed toxic component from the mutant subunit, so a complex mixed mechanism fits better than a clean loss or gain. Whether the toxic element is a neomorphic gain of function or dominant-negative interference is unresolved, holding confidence at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT-ABHD12: recessive ABHD12 nonsense, frameshift, splice, and missense alleles abolish the enzyme's lysophospholipase activity, and the resulting lysophosphatidylserine accumulation drives the disease. Both copies must be inactivated, and restored wild-type enzyme is predicted to rescue, consistent with loss of function rather than a dominant-negative or gain-of-function effect.

Rationale: Recessive ABHD12 alleles abolish lysophospholipase activity, and lysophosphatidylserine accumulates as a consequence, so restored wild-type enzyme is predicted to rescue: a biallelic loss of function rather than a dominant-negative or gain-of-function effect.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a loss-of-function mechanism for CMTX4: X-linked recessive AIFM1 missense variants destabilize apoptosis-inducing factor and impair its redox and mitochondrial-import interaction with CHCHD4, reducing oxidative phosphorylation in peripheral nerve. This is a hypomorphic loss in the single functional copy, and restored wild-type AIF is predicted to rescue rather than the mutant disrupting the wild-type protein.

Rationale: Hemizygous hypomorphic AIFM1 missense variants partially lose AIF redox and CHCHD4-import function in the single X-linked copy, a recessive-class loss that restored wild-type AIF is predicted to rescue. AIF's multiple mitochondrial roles hold confidence at medium.

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Mechanistic basis: Unresolved

Prediction: The literature does not support a defined mechanism for CMT-ARHGEF10: the association rests on a single large dominant family with the ARHGEF10 Thr109Ile variant of debated causality, and functional evidence is too thin to distinguish a loss of RhoGEF function from a dominant effect, so the mechanism is best predicted as unresolved.

Rationale: The ARHGEF10 CMT association rests on a single dominant family with the Thr109Ile variant of debated causality, and the sparse functional data cannot separate haploinsufficiency from a dominant-negative effect, so the mechanism remains unresolved at low confidence.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for HSN-1D: heterozygous ATL1 missense alleles produce mutant atlastin-1 subunits that incorporate into the GTPase oligomer and impair its homotypic ER membrane-fusion activity, disrupting the wild-type protein rather than acting through a simple null. Because the mutant continues to interfere with the wild-type complex, supplementation is not predicted to rescue, and no independent loss-of-function mechanism is established for this subtype.

Rationale: Heterozygous missense atlastin-1 subunits incorporate into the oligomeric GTPase and disrupt homotypic ER fusion, so wild-type supplementation is not predicted to rescue: the signature of a dominant-negative effect. A partial haploinsufficiency contribution remains debated for ATL1, holding confidence at medium.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for HSN-1F: because atlastin-3 acts as a homo-oligomeric ER-fusion GTPase, the dominant ATL3 alleles (Y192C, P338R) incorporate into mixed mutant and wild-type tethering complexes and disrupt fusion, forming stable tethers that fail to complete, so added wild-type protein is not predicted to rescue. That the mutant persists to disrupt the shared complex, rather than acting cell-autonomously, supports dominant-negative over a neomorphic gain of function, holding confidence at medium.

Rationale: The dominant ATL3 alleles Y192C and P338R disrupt mixed mutant and wild-type tethering complexes, producing stable ER tethers that fail to fuse, so wild-type add-back is not predicted to rescue. That non-rescue is the dominant-negative signature rather than evidence of a cell-autonomous gain of function, and the loss-versus-interference question holds confidence at medium.

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Mechanistic basis: Neomorphic

Prediction: The literature predicts a gain-of-function mechanism for CMT2DD: functional work on these dominant ATP1A1 α1 Na/K-ATPase variants (Clausen et al. 2023) concludes that disease requires a malfunctioning product expressed from one allele and is not haploinsufficiency, supporting an aberrant neomorphic activity of the mutant pump rather than simple loss of a copy. The evidence is from limited functional studies, holding confidence at medium.

Rationale: Dominant ATP1A1 CMT2DD missense variants act through a neomorphic gain of function, most plausibly an aberrant cation leak through the mutant Na/K-ATPase rather than disruption of the wild-type pump, consistent with the finding that a malfunctioning product is required and that this is not haploinsufficiency. The leak-versus-interference distinction is unresolved on limited data, holding confidence at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a loss-of-function mechanism for dSMAX-3: the two characterized ATP7A missense alleles (T994I, P1386S) are hypomorphic, impairing copper-ATPase trafficking and regulation rather than abolishing activity as in Menkes disease, and affected hemizygous males carry a single defective copy, so restored wild-type ATP7A is predicted to rescue. This is a recessive, single-copy partial loss of function, and because these are trafficking-defective variants rather than nulls the evidence supports a specialized loss at medium confidence.

Rationale: dSMAX-3 arises from recessive, single-copy hemizygous partial loss of ATP7A via the hypomorphic trafficking-defective alleles T994I and P1386S, with restored wild-type expected to rescue. Whether these copper-transport-retaining alleles act by pure loss or a motor-neuron-specialized effect remains debated, holding confidence at medium.

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Mechanistic basis: Neomorphic

Prediction: The literature predicts a gain-of-function, neomorphic mechanism for CMT2JJ: the recurrent dominant BAG3 variant (p.Pro209Leu, in the IPV/HSPB8-binding motif) confers a novel proteotoxic activity, producing an aggregation-prone co-chaperone that sequesters HSPB8 and client proteins into toxic aggregates rather than losing normal function. Because the toxicity arises from a new aggregation property, added wild-type BAG3 is not predicted to rescue, distinguishing it from simple haploinsufficiency.

Rationale: The recurrent dominant BAG3 p.Pro209Leu allele acquires an aggregation property and sequesters HSPB8 and CASA clients into proteotoxic aggregates, so wild-type add-back is not predicted to rescue: a toxic gain of function. Because that sequestration blurs into interference with pathway partners, a dominant-negative contribution cannot be excluded, holding confidence at medium.

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Mechanistic basis: Overactivity

Prediction: The literature predicts a gain-of-function mechanism for SMA-LEP-2A: dominant BICD2 variants relieve autoinhibition of the cargo adaptor, enhancing its recruitment and activation of the dynein-dynactin motor and increasing microtubule stability, thereby dysregulating axonal transport. This overactivity model rather than haploinsufficiency is supported by functional studies of the recurrent heterozygous missense alleles, though mechanistic detail remains ongoing, holding confidence at medium.

Rationale: Recurrent heterozygous BICD2 missense alleles relieve adaptor autoinhibition and hyperactivate dynein-dynactin recruitment on their own, a gain-of-function overactivity rather than dominant-negative interference. Ongoing mechanistic debate and allele heterogeneity hold confidence at medium.

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Mechanistic basis: Overactivity

Prediction: The literature predicts a gain-of-function mechanism for SMA-LEP-2B: dominant BICD2 alleles enhance recruitment and activation of the dynein-dynactin motor, producing motor hyperactivity and an altered interactome that dysregulates axonal transport rather than causing haploinsufficiency. Because the mutant is intrinsically overactive, added wild-type protein is not predicted to correct the excess activity, supporting overactive gain of function over loss or dominant-negative.

Rationale: Dominant BICD2 alleles release autoinhibition to hyperactivate dynein-dynactin recruitment as an intrinsic overactive gain of function, not dominant-negative interference. The loss-versus-gain debate holds confidence at medium.

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Mechanistic basis: Neomorphic

Prediction: The literature predicts a toxic gain-of-function mechanism for dHMN-5C: the dominant BSCL2 alleles N88S and S90L abolish an N-glycosylation site in seipin, causing misfolding, ER retention, aggregation, and ER stress that is cytotoxic to motor neurons. This is distinct from the biallelic loss-of-function BSCL2 that causes Berardinelli-Seip lipodystrophy, and added wild-type seipin is not predicted to rescue the aggregate-driven toxicity.

Rationale: The dominant N88S and S90L alleles lose the seipin N-glycosylation site and drive misfolding, ER retention, aggregation, and ER-stress toxicity that wild-type seipin is not predicted to rescue: a neomorphic gain of function, distinct from the biallelic loss-of-function lipodystrophy.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT-C19orf12: recessive homozygous or compound-heterozygous null or hypomorphic C19orf12 alleles reduce or abolish the mitochondrial membrane protein's function. Two defective copies are required, and restored wild-type protein is predicted to rescue, consistent with loss of function rather than a dominant-negative or gain-of-function effect.

Rationale: Recessive C19orf12 alleles require two null or hypomorphic copies to reduce the mitochondrial membrane protein's function, and restored wild-type is predicted to rescue: a biallelic loss of function, not dominant-negative or gain of function.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for CMT2FF: the recurrent heterozygous CADM3 p.Tyr172Cys variant forms an aberrant disulfide bond, is retained in the ER, and disrupts the CADM3–CADM4 axon-glia adhesion complex, so the mutant interferes with the wild-type complex rather than simply reducing dosage, and supplementation is not predicted to rescue. No recessive, null, or haploinsufficiency CADM3-associated CMT has been reported, and the mutant acquires no independent overactive function, supporting dominant-negative over loss or gain of function; the evidence rests on a single recurrent allele and one group's functional work, holding confidence at medium.

Rationale: The recurrent CADM3 p.Tyr172Cys allele forms an aberrant disulfide bond, is ER-retained, and disrupts the wild-type CADM3–CADM4 axon-glia adhesion complex rather than halving dosage, so supplementation is not predicted to rescue: a dominant-negative effect. Resting on a single recurrent allele and one group's functional work holds confidence at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for HSN with spastic paraplegia: the recessive homozygous CCT5 His147Arg substitution impairs the CCT/TRiC chaperonin, so two defective copies reduce chaperonin protein-folding activity, and restored wild-type CCT5 is predicted to rescue, consistent with recessive loss rather than a dominant effect.

Rationale: The recessive homozygous CCT5 His147Arg substitution impairs CCT/TRiC chaperonin activity, and unaffected heterozygous carriers argue against a dominant effect, so restored wild-type is predicted to rescue: a biallelic loss of function. The mutant subunit's exact functional consequence is only partly characterized, holding confidence at medium.

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Mechanistic basis: Mixed

Prediction: The literature predicts a complex mechanism for CMT-CFAP276: this single dominant subtype's own allelic series carries two mechanisms, a partial loss-of-function allele (K28I, supported by a heterozygous-knockout mouse that recapitulates dominant CMT and by AAV gene-addition rescue) alongside a gain-of-function aggregating allele (I122N). Because the subtype's alleles independently carry loss and gain, the evidence supports a mixed mechanism, holding confidence at medium.

Rationale: CFAP276 (alias C1orf194) carries a mixed mechanism: a partial loss-of-function, haploinsufficient allele (K28I, backed by a heterozygous-knockout mouse recapitulating dominant CMT and AAV gene-addition rescue) alongside a gain-of-function aggregating allele (I122N), so a complex call fits better than an unresolved one, holding confidence at medium.

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Mechanistic basis: Neomorphic

Prediction: The literature predicts a toxic gain-of-function mechanism for CMT-CHCHD10: Chchd10-knockout mice are healthy, arguing against haploinsufficiency, while mutations such as S59L and R15S drive misfolding and aggregation of CHCHD10 and co-sequestration of its paralog CHCHD2, consistent with a novel toxic species rather than loss. Because some studies frame the CHCHD2 co-aggregation as a dominant-negative component, the mechanism remains partly debated, holding confidence at medium.

Rationale: Dominant CHCHD10 alleles S59L and R15S misfold into a novel toxic aggregate, and Chchd10-null mice stay healthy, ruling out haploinsufficiency, so this is chiefly a neomorphic gain of function. Co-sequestration of the paralog CHCHD2 keeps a dominant-negative contribution debated, holding confidence at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT-CNTNAP1: recessive nonsense, frameshift, and missense variants abolish or impair Caspr at the paranodal junction, disrupting axo-glial adhesion and node organization. Both copies must be lost, and the phenotype is consistent with absent protein rather than interference, so restored wild-type is predicted to rescue.

Rationale: Recessive CNTNAP1 variants abolish or impair Caspr at the paranode, and restoring a wild-type copy is predicted to rescue: a biallelic loss of function rather than dominant-negative or gain of function.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT-COA7: recessive homozygous or compound-heterozygous COA7 variants reduce or abolish its function as a cytochrome c oxidase assembly factor, impairing complex I and IV assembly and energy production. Restored wild-type COA7 is predicted to rescue, consistent with loss rather than a dominant-negative or gain-of-function effect.

Rationale: Biallelic COA7 variants reduce cytochrome c oxidase assembly-factor function, impairing complex I and IV assembly, so restored wild-type is predicted to rescue: a recessive loss of function.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for dHMN-COQ7: recessive hypomorphic COQ7 alleles reduce the hydroxylase activity needed for coenzyme Q10 biosynthesis, causing a CoQ10 deficiency that impairs mitochondrial energy metabolism in motor axons. Both copies must be impaired, and restored wild-type COQ7 or CoQ10 intermediate supplementation is predicted to rescue, consistent with loss of function.

Rationale: Biallelic hypomorphic COQ7 alleles lower Q7-hydroxylase activity and CoQ10 output, so restoring wild-type enzyme or supplying CoQ10 intermediates is predicted to rescue: a recessive loss of function with no dominant-negative or gain-of-function contribution.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMTRID: COX6A1 encodes a nuclear-encoded subunit of cytochrome c oxidase, and recessive splice-region and loss variants reduce or abolish functional subunit, causing complex IV assembly deficiency and reduced activity in patient fibroblasts. Because both alleles must be impaired and restored wild-type COX6A1 is predicted to restore complex IV, this is a recessive loss of function rather than a dominant-negative or gain-of-function effect.

Rationale: Recessive COX6A1 splice and loss variants deplete a nuclear-encoded complex IV subunit, so restored wild-type is predicted to restore cytochrome c oxidase assembly and activity: a biallelic loss of function, with no dominant-negative or gain-of-function contribution.

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Mechanistic basis: Mixed

Prediction: The literature predicts a complex mechanism for CMT-CRYAB: αB-crystallin is an obligate oligomeric chaperone, so the dominant alleles are predicted to both co-assemble into and disrupt wild-type αB and αA-crystallin complexes (a dominant-negative effect) and lose chaperone activity (a partial loss), alongside any neomorphic aggregation. Because the widely cited Arg120Gly toxic-aggregation account is drawn from dominant myofibrillar myopathy rather than this subtype's own alleles, confidence stays low until CMT-CRYAB-specific variants are characterized.

Rationale: Because αB-crystallin assembles as an obligate oligomer, mutant subunits are predicted to co-assemble into and disrupt wild-type αB and αA-crystallin complexes and to lose chaperone activity, a mixed dominant-negative and partial-loss picture alongside any neomorphic aggregation. The toxic-aggregation account is imported from dominant myofibrillar myopathy rather than characterized from this subtype's own alleles, so confidence stays low.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT-CTDP1: the founder intronic retrotransposon insertion (IVS6+389C>T) causes partial mis-splicing of CTDP1 that lowers functional FCP1 phosphatase across both alleles, a hypomorphic reduction rather than a toxic product. Restored wild-type is predicted to rescue, consistent with recessive loss of function.

Rationale: The founder intronic insertion IVS6+389C>T partially mis-splices CTDP1 to lower functional FCP1 phosphatase on both alleles, a hypomorphic depletion that restored wild-type is predicted to rescue rather than a toxic or interfering allele: a biallelic loss of function.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT-DARS2: recessive, typically compound-heterozygous hypomorphic DARS2 variants partially reduce mitochondrial aspartyl-tRNA synthetase activity, impairing mitochondrial translation in peripheral nerve. Because these are partial-loss variants that restored wild-type enzyme is predicted to rescue, the evidence supports biallelic loss rather than a dominant-negative or gain-of-function effect.

Rationale: Biallelic hypomorphic DARS2 variants, classically a leaky intron-2 splice allele paired with a more severe allele, preserve residual mitochondrial aspartyl-tRNA synthetase activity, so restored wild-type is predicted to rescue: a recessive loss of function.

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Mechanistic basis: Unresolved

Prediction: The literature does not resolve a mechanism for GAN-2: dominant heterozygous DCAF8 missense variants from a single family cause giant axonal neuropathy, but with no functional data the split between haploinsufficiency and a dominant-negative effect on the CRL4 ubiquitin-ligase complex is undetermined, so the mechanism is best predicted as unresolved.

Rationale: Dominant DCAF8 missense variants from a single family cause giant axonal neuropathy, but no functional data separate haploinsufficiency from dominant-negative interference with the CRL4 ligase complex, so the mechanism remains unresolved at low confidence. This is distinct from the recessive gigaxonin subtype GAN-1.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for dHMN-7B: the heterozygous DCTN1 CAP-Gly domain variant (p.G59S) impairs microtubule binding, incorporates into the dynactin complex, and forms cytoplasmic aggregates that sequester wild-type dynactin, so the mutant disrupts the shared complex rather than being absent, and supplementation is not predicted to rescue. No recessive or biallelic loss-of-function DCTN1-associated CMT supports a haploinsufficiency alternative, though a toxic-aggregation gain-of-function contribution keeps confidence at medium.

Rationale: The heterozygous DCTN1 G59S CAP-Gly mutant folds poorly, incorporates into dynactin, and sequesters wild-type subunits, so supplementation is not predicted to rescue: a dominant-negative effect. A co-invoked toxic-aggregation gain of function keeps the mechanism debated, holding confidence at medium.

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Mechanistic basis: Unresolved

Prediction: The literature does not support a defined mechanism for CMT-DGAT2: it rests on a single autosomal dominant family with early-onset CMT (Hong et al. 2016), and while the DGAT2 variant perturbs lipid and triglyceride handling, the evidence does not resolve haploinsufficiency, a dominant-negative effect, or a toxic gain of function, so the mechanism is unresolved.

Rationale: CMT-DGAT2 acts through a dominant perturbation of DGAT2-mediated lipid handling, but the single family and absence of dosage or rescue data leave the mechanism unresolved among haploinsufficiency, dominant-negative, and toxic gain of function at low confidence.

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Mechanistic basis: Haploinsufficiency

Prediction: The literature predicts a loss-of-function mechanism acting through haploinsufficiency for CMT2Q: the reported heterozygous DHTKD1 nonsense allele (p.Y486*, Xu et al. 2012) lowers DHTKD1 transcript and protein, with reduced ATP production and elevated ROS, consistent with a single reduced copy of this 2-oxoadipate dehydrogenase being insufficient. Because the allele reduces dosage rather than yielding a toxic product, added wild-type protein is predicted to rescue, supporting haploinsufficiency over a dominant-negative or gain-of-function mechanism. The evidence rests largely on a single dominant family, holding confidence at medium.

Rationale: The p.Y486* nonsense allele is expected to trigger nonsense-mediated decay and lower DHTKD1 dosage, reducing ATP and raising ROS, rather than yielding a truncated product that disrupts the wild-type enzyme: this points to haploinsufficiency loss of function. Confidence holds at medium because the call rests on a single dominant family and because complete biallelic DHTKD1 loss causes a separate recessive disease, 2-aminoadipic 2-oxoadipic aciduria (AMOXAD), leaving it uncertain that loss of a single copy causes dominant CMT.

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Mechanistic basis: Unresolved

Prediction: The literature does not resolve a mechanism for CMT-DHX9: dominant monoallelic missense variants in the DHX9 helicase cause the disease, but the limited functional evidence from the original cohort does not distinguish haploinsufficiency from a dominant-negative or gain-of-function effect, so the CMT-specific mechanism is unresolved.

Rationale: Dominant DHX9 helicase-domain missense alleles could act by a dominant-negative or gain-of-function effect, suggested by the missense-versus-loss genotype split, but the single 2023 cohort's data cannot exclude haploinsufficiency, so the mechanism remains unresolved at low confidence.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for dSMA-5: DNAJB2 (HSJ1) is an Hsp40 co-chaperone that partners with Hsp70 to clear misfolded proteins, and the recessive splice, truncating, and destabilizing missense alleles deplete functional co-chaperone activity on both copies. Because the mutant loses function rather than interfering with the wild-type, restored wild-type DNAJB2 is predicted to rescue.

Rationale: Recessive DNAJB2/HSJ1 truncating and splice alleles deplete Hsp70-partner co-chaperone activity on both copies, so restored wild-type is predicted to rescue: a biallelic loss of function rather than a dominant-negative effect.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for CMT2M: heterozygous PH-domain DNM2 alleles co-assemble into shared dynamin-2 oligomers and impair lipid binding and membrane fission, disrupting the wild-type rather than acting autonomously, so added wild-type protein is not predicted to rescue. Because the enhanced-assembly gain-of-function picture is drawn from centronuclear-myopathy alleles rather than these, the mechanism is debated, holding confidence at medium.

Rationale: PH-domain DNM2 alleles co-assemble into shared oligomers and disrupt lipid binding and membrane fission, interfering with the wild-type rather than acting on their own, so wild-type add-back is not predicted to rescue: a dominant-negative effect. Because the enhanced-assembly account is drawn from centronuclear myopathy, the mechanism stays debated, holding confidence at medium.

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Mechanistic basis: Overactivity

Prediction: The literature predicts a gain-of-function mechanism for CMTDIB: heterozygous PH-domain DNM2 alleles produce dynamin-2 with enhanced self-assembly and GTPase-dependent fission activity that dysregulates endocytic membrane trafficking on its own, rather than haploinsufficiency, since a heterozygous null does not phenocopy. Because gain of function versus dominant-negative remains debated, confidence holds at medium.

Rationale: PH-domain DNM2 alleles produce dynamin-2 with enhanced self-assembly and fission activity that dysregulates endocytic trafficking on its own, an overactive gain of function rather than dominant-negative interference. Because gain of function versus dominant-negative remains debated, confidence holds at medium.

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Mechanistic basis: Mixed

Prediction: The literature predicts a complex mechanism for HSN-1E: the dominant DNMT1 RFTS-domain alleles both cause misfolding, premature degradation, and reduced maintenance methyltransferase activity, a partial loss producing a globally hypomethylated methylome, and generate mislocalized, aggregating mutant protein contributing a toxic gain. Because a single dominant allele class carries both, the evidence supports a mixed mechanism rather than pure haploinsufficiency, consistent with heterozygous nulls not reproducing the disease.

Rationale: The same dominant DNMT1 RFTS-domain alleles both partially lose maintenance-methylation activity, producing global hypomethylation, and add an independent toxic gain through mislocalization and aggregation, so a complex mixed mechanism fits, consistent with heterozygous nulls not reproducing the disease. The toxic-gain arm is less firmly established, holding confidence at medium.

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Mechanistic basis: Haploinsufficiency

Prediction: The literature predicts a loss-of-function mechanism for CMT-DRP2: the reported X-linked hemizygous nonsense variant abolishes DRP2, disrupting the periaxin-DRP2-dystroglycan complex and Cajal bands in Schwann cells. Because restored wild-type DRP2 is predicted to rescue the complex and a single absent copy suffices in this dosage-sensitive X-linked setting, the evidence supports loss of function rather than a dominant-negative or gain-of-function effect, on limited data.

Rationale: The X-linked nonsense allele abolishes DRP2 and disrupts the periaxin-DRP2-dystroglycan complex through simple loss that restored wild-type is predicted to rescue. The haploinsufficiency label is a slight stretch for a hemizygous null and rests on limited data, holding confidence at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT-DST: recessive compound-heterozygous or null DST variants cause isoform-specific loss of dystonin, a cytoskeletal linker (Motley et al. 2020; the dystonia musculorum null mouse), so both copies must be lost and restored wild-type is predicted to rescue.

Rationale: Recessive biallelic null or compound-heterozygous DST variants cause isoform-specific loss of dystonin, with unaffected heterozygous carriers, so restored wild-type is predicted to rescue: a biallelic loss of function, not dominant-negative or gain of function.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for HSAN-6: recessive DST truncating and null variants abolish dystonin, and the parallel Dst-null (dystonia musculorum) mouse recapitulates the sensory neurodegeneration, so two lost copies remove function while one wild-type copy suffices. Restored wild-type dystonin is predicted to rescue, consistent with loss rather than a dominant-negative effect.

Rationale: Biallelic DST truncating or null alleles abolish dystonin, so a single wild-type copy should suffice and restored wild-type is predicted to rescue: a recessive loss of function, supported by the Dst-null dystonia musculorum mouse with no gain-of-function contribution.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for CMT2O: heterozygous DYNC1H1 missense mutations produce a heavy chain that incorporates into the multi-subunit dynein motor and impairs retrograde transport, disrupting the wild-type complex rather than reducing dosage, so added wild-type is not predicted to rescue. DYNC1H1 haploinsufficiency tends to cause a neurodevelopmental phenotype rather than this CMT, and the exact mechanism remains debated, holding confidence at medium.

Rationale: Heterozygous DYNC1H1 missense subunits incorporate into the cytoplasmic dynein motor and disrupt its retrograde-transport activity rather than merely halving dosage, so wild-type add-back is not predicted to rescue: a dominant-negative effect. The dominant-negative-versus-motor-gain question keeps confidence at medium.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for SMA-LEP-1: heterozygous DYNC1H1 tail- and motor-domain missense variants produce a mutant heavy chain that still incorporates into the homodimeric cytoplasmic dynein-1 complex and disrupts its cargo transport, so added wild-type is not predicted to rescue. This is distinct from DYNC1H1 haploinsufficiency, which causes a neurodevelopmental phenotype, and the loss-versus-interference distinction remains debated, holding confidence at medium.

Rationale: Drawn from this subtype's own dominant lower-extremity phenotype and its heterozygous DYNC1H1 tail and motor missense alleles, a mutant heavy chain that still dimerizes into cytoplasmic dynein-1 disrupts the complex so wild-type add-back is not predicted to rescue: a dominant-negative effect. The loss-versus-interference distinction holds confidence at medium.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for CMT1D: heterozygous EGR2 mutations, mostly in the zinc-finger DNA-binding domain and the R1/NAB-interaction domain, produce a mutant transcription factor that fails to activate myelination genes yet interferes with the wild-type protein. Zinc-finger mutants reduce DNA binding and act dominant-negatively, while R1-domain mutants disrupt the NAB corepressor interaction. Functional studies showing impaired transactivation with dominant suppression of wild-type EGR2 activity indicate that added wild-type protein is not predicted to rescue, arguing against simple haploinsufficiency.

Rationale: Heterozygous zinc-finger EGR2 mutants lose DNA binding yet disrupt wild-type Krox20 transactivation, which points to a dominant-negative effect rather than simple loss of function. The R1-domain/NAB-disruption alleles carry a gain-of-function-like deregulation that keeps the overall mechanism partly debated, holding confidence at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT4E: EGR2/Krox20 is a master transcription factor driving Schwann cell myelination, and the recessive alleles (for example the I268N substitution in the R1 domain) impair EGR2 transcriptional activity so that two defective copies are required. Restored wild-type is predicted to rescue, distinct from the dominant zinc-finger EGR2 subtype CMT1D, which acts dominant-negatively.

Rationale: Recessive CMT4E alleles such as I268N impair EGR2 transcriptional activity, with disease requiring two defective copies and a single wild-type allele predicted to rescue: a biallelic loss of function, distinct from the dominant-negative zinc-finger subtype CMT1D.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for HSAN-3 (familial dysautonomia): the near-universal founder ELP1 splice variant (c.2204+6T>C) causes tissue-specific skipping of exon 20 and a truncated, unstable transcript, reducing functional Elongator ELP1, with a second loss-of-function allele in trans. Because residual or wild-type ELP1 restores function, this is loss rather than a dominant-negative effect, and restored wild-type is predicted to rescue.

Rationale: The founder ELP1 c.2204+6T>C splice variant reduces functional Elongator ELP1 via tissue-specific exon 20 skipping, so restoring correct splicing or wild-type protein is predicted to rescue: a biallelic loss of function rather than a mutant that disrupts the wild-type.

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Mechanistic basis: Unresolved

Prediction: The literature does not resolve the mechanism for CMT1H: the recurrent dominant missense variant in the ECM protein fibulin-5 could act through haploinsufficiency or a dominant-negative effect on the extracellular matrix, and no functional data yet distinguish these for this subtype.

Rationale: The recurrent dominant FBLN5 missense allele could act by dominant-negative disruption of elastic-fiber assembly given fibulin-5's secreted, self-multimerizing biology, but with no functional data separating that from haploinsufficiency the mechanism remains unresolved at low confidence.

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Mechanistic basis: Haploinsufficiency

Prediction: The literature predicts a loss-of-function, haploinsufficiency mechanism for dHMN-2D: the recurrent heterozygous FBXO38 missense variant (p.Cys206Arg, Sumner et al.) impairs FBXO38's function as the SCF substrate-recognition subunit that drives KLF7-dependent transcription, reducing rather than disrupting activity, so restored wild-type is predicted to rescue and the dominant phenotype reflects dosage sensitivity.

Rationale: The FBXO38 p.Cys206Arg variant reduces KLF7 coactivation, most consistent with a loss-of-function, haploinsufficiency mechanism that restored wild-type is predicted to rescue. Because a single recurrent missense in an SCF substrate-recognition subunit could instead disrupt the complex, a dominant-negative alternative cannot be excluded, holding confidence at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT4H: recessive FGD4 nonsense, frameshift, splice, and missense variants affecting the FYVE, DH, and PH domains abolish frabin's Cdc42 guanine-nucleotide-exchange activity and its role in myelination, so both copies must be lost. Restored wild-type frabin is predicted to rescue, consistent with loss rather than a dominant-negative or toxic gain of function.

Rationale: Recessive FGD4 alleles abolish frabin's Cdc42-GEF function in Schwann-cell myelination, so restored wild-type is predicted to rescue: a biallelic loss of function, not dominant-negative or gain of function.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT4J: patients are typically compound heterozygous for a hypomorphic missense allele (most commonly I41T, which destabilizes FIG4 within the VAC14–PIKFYVE complex) in trans with a null allele, reducing PI(3,5)P2 regulatory activity. The pale tremor mouse and complementation data show residual FIG4 determines severity and restored wild-type is predicted to rescue, consistent with recessive loss.

Rationale: CMT4J arises from a hypomorphic FIG4 allele such as I41T in trans with a null allele, reducing PI(3,5)P2 regulatory activity, with wild-type restoring function in complementation and pale-tremor-mouse rescue: a biallelic loss of function rather than dominant-negative or gain of function.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for HSN-FLVCR1: recessive homozygous or compound-heterozygous variants impair FLVCR1 choline and heme transporter activity, so both copies must be lost to compromise sensory neuron survival. Restored wild-type FLVCR1 is predicted to rescue, consistent with loss rather than a dominant-negative or gain-of-function effect.

Rationale: Biallelic FLVCR1 variants lose heme and choline transporter function, so restored wild-type is predicted to rescue: a simple recessive loss rather than a dominant-negative or gain-of-function effect.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for GAN-1: recessive GAN mutations abolish or destabilize gigaxonin, a Cul3-based E3 ubiquitin-ligase adaptor that targets intermediate filaments for degradation, so both copies must be lost and disease results from failed intermediate-filament turnover and toxic accumulation. Restored wild-type gigaxonin rescues the phenotype, the basis of gene-replacement therapy, consistent with pure loss rather than a dominant-negative or gain-of-function effect.

Rationale: Recessive GAN alleles abolish or destabilize gigaxonin, so intermediate filaments accumulate, and wild-type gene replacement is predicted to rescue: a biallelic loss of function with no dominant-negative or gain-of-function contribution.

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Mechanistic basis: Neomorphic

Prediction: The literature predicts a toxic gain-of-function mechanism for CMT2D: dominant GARS1 mutations open the enzyme's conformation and expose aberrant surfaces, driving neomorphic interactions such as inappropriate binding to Nrp1 and Trk receptors and mislocalization, rather than reducing aminoacylation. Evidence against haploinsufficiency is strong, since heterozygous null mice do not develop CMT and knockout is recessive-lethal, so added wild-type is not predicted to rescue. Whether the gained activity is neomorphic surface binding or tRNA-Gly sequestration is debated, holding confidence at medium.

Rationale: Dominant GARS1 alleles acquire an aberrant open conformation with new Nrp1 and Trk binding rather than disrupting wild-type GARS1, and null carriers are healthy while wild-type overexpression fails to rescue, pointing to a toxic gain of function. Whether the gain is neomorphic surface binding or tRNA-Gly sequestration is debated, holding confidence at medium.

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Mechanistic basis: Neomorphic

Prediction: The literature predicts a neomorphic toxic gain-of-function mechanism for dHMN-5A: dominant GARS1 mutations induce an aberrant open conformation that exposes a novel surface, causing aberrant binding to Nrp1 (antagonizing VEGF/Nrp1 signaling) and to Trk receptors and axonal mislocalization, rather than simple loss of aminoacylation. Null and loss-of-function GARS1 alleles do not cause the dominant phenotype and severity does not track residual activity, arguing against haploinsufficiency, so added wild-type is not predicted to rescue; a partial loss-of-aminoacylation contribution remains debated, holding confidence at medium.

Rationale: Dominant GARS1 alleles acquire an aberrant open conformation with new Nrp1 and Trk binding on their own, with nulls unaffected and severity decoupled from enzyme activity, pointing to a neomorphic gain of function rather than disruption of wild-type GARS1. A partial loss-of-aminoacylation contribution remains debated, holding confidence at medium.

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Mechanistic basis: Unresolved

Prediction: The literature does not resolve a mechanism for CMT2GG: ultra-rare dominant and de novo GBF1 missense variants cause CMT via Golgi fragmentation, but the data do not distinguish haploinsufficiency from a dominant-negative effect, so no specific mechanism is supported.

Rationale: Ultra-rare dominant and de novo GBF1 missense variants cause CMT through Golgi fragmentation, but with no data separating haploinsufficiency from a dominant-negative effect the mechanism remains unresolved at low confidence.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT2B3: recessive GDAP1 disease arises from two null or hypomorphic alleles that reduce or abolish GDAP1's mitochondrial function, supported by the Gdap1 knockout mouse, so restored wild-type is predicted to rescue. This recessive subtype is distinct from the dominant GDAP1 subtype CMT2K, which carries a dominant-negative component.

Rationale: Recessive CMT2B3 arises from two null or hypomorphic GDAP1 alleles that abolish mitochondrial function, so restored wild-type is predicted to rescue: a biallelic loss of function, with the dominant-negative component confined to the separate dominant subtype CMT2K.

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Mechanistic basis: Mixed

Prediction: The literature predicts a complex mechanism for CMT2K, because its own alleles split by inheritance: the recessive alleles are biallelic loss-of-function or null (supported by the Gdap1 knockout mouse, where restored wild-type rescues), while the dominant GST-domain alleles act through a milder dominant-negative effect on GDAP1-mediated mitochondrial fission. Because this subtype independently carries both a biallelic loss and a dominant-negative component, the evidence supports a mixed mechanism.

Rationale: CMT2K carries both its own recessive biallelic loss-of-function alleles and dominant GST-domain alleles, so a mixed mechanism fits. Whether the dominant alleles act by true dominant-negative interference on mitochondrial fission or by haploinsufficiency remains debated, and only the dominant-negative reading keeps this from collapsing to plain loss, holding confidence at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT4A: recessive GDAP1 nonsense, frameshift, and missense alleles reduce or abolish GDAP1's role in mitochondrial fission, with disease requiring loss of both copies and heterozygous carriers unaffected. Restored wild-type GDAP1 is predicted to rescue, consistent with simple loss rather than the dominant-negative or gain-of-function effect reserved for the separate dominant subtype CMT2K.

Rationale: Recessive GDAP1 alleles reduce mitochondrial-fission activity, so restored wild-type is predicted to rescue: a biallelic loss of function, with any dominant-negative behavior belonging to the separate dominant subtype CMT2K, not this one.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMTRIA: recessive GDAP1 alleles reduce or abolish GDAP1's mitochondrial-dynamics and antioxidant function, with disease requiring loss of both copies. The mutants lose activity rather than disrupting the wild-type, so restored wild-type GDAP1 is predicted to rescue, consistent with recessive loss.

Rationale: Recessive GDAP1 alleles abolish mitochondrial-dynamics and antioxidant activity, so restored wild-type is predicted to rescue: the recessive-loss side of this split gene, distinct from the dominant-negative dominant subtype CMT2K.

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Mechanistic basis: Haploinsufficiency

Prediction: The literature predicts a loss-of-function mechanism for CMTX1: GJB1 mutations disrupt connexin-32 gap junctions in Schwann cells through impaired trafficking, ER/Golgi retention, or failure to form functional channels, and whole-gene deletions and null alleles produce the same typical phenotype, arguing against a requirement for a dominant-negative or toxic gain. Affected hemizygous males lack a wild-type copy, so restored connexin-32 is predicted to rescue, consistent with dosage-sensitive loss, with variable female severity reflecting X-inactivation.

Rationale: GJB1 null alleles and whole-gene deletions reproduce the typical CMTX1 phenotype and hemizygous males have no wild-type copy, so restored connexin-32 is predicted to rescue: a loss of function.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for CMTDIF: the dominant GNB4 missense alleles (K89E, G77R; Soong et al. 2013) produce a mutant Gβ4 subunit that disrupts wild-type heterotrimeric G-protein signaling rather than reducing dosage, so supplementation is not predicted to rescue.

Rationale: The dominant GNB4 alleles K89E and G77R produce a mutant Gβ4 subunit that disrupts wild-type heterotrimeric G-protein signaling rather than merely halving dosage, so supplementation is not predicted to rescue: a dominant-negative effect, on one group's functional work, holding confidence at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT-HADHB: HADHB encodes the β subunit of the mitochondrial trifunctional protein, and recessive variants reduce or abolish long-chain fatty-acid β-oxidation activity, so two defective copies are required. Restored wild-type protein is predicted to rescue, consistent with a recessive enzyme deficiency rather than a dominant-negative or gain-of-function effect.

Rationale: HADHB-related CMT reflects a recessive mitochondrial trifunctional protein deficiency in which two defective alleles reduce long-chain fatty-acid β-oxidation, so restored wild-type is predicted to rescue: a biallelic loss of function, not dominant-negative or gain of function.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for CMT2W: heterozygous HARS1 missense variants impair histidyl-tRNA synthetase aminoacylation, and because the enzyme is a homodimer the mutant subunit disrupts the wild-type-containing dimer, so added wild-type is not predicted to fully rescue. The aaRS-CMT field remains debated between this dominant-negative loss model and a toxic gain-of-function model, holding confidence at medium.

Rationale: Heterozygous HARS1 missense subunits disrupt the wild-type-containing homodimer, so added wild-type is not predicted to fully rescue: a dominant-negative effect. An unresolved toxic gain-of-function alternative in the aaRS field holds confidence at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT-HINT1: recessive missense and truncating HINT1 variants disrupt histidine-triad nucleotide hydrolase activity and protein stability, with disease requiring loss of both copies. Single-allele carriers are unaffected, so restored wild-type is predicted to rescue, consistent with recessive loss rather than a dominant-negative or gain-of-function effect.

Rationale: Recessive HINT1 variants abolish histidine-triad hydrolase activity and stability, with single-allele carriers unaffected, so restored wild-type is predicted to rescue: a biallelic loss of function.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT4G (Russe type): the recessive HK1 mutations, classically a homozygous variant in an alternative 5' untranslated exon, reduce HK1 expression in peripheral nerve, so two defective copies are required. Restored wild-type HK1 is predicted to rescue, consistent with loss rather than a dominant-negative or gain-of-function effect.

Rationale: Recessive HK1 5'UTR variants reduce nerve HK1 expression, so two defective copies are needed and restored wild-type is predicted to rescue: a biallelic loss of function.

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Mechanistic basis: Neomorphic

Prediction: The literature predicts a toxic gain-of-function mechanism for CMT2F: dominant HSPB1/HSP27 missense mutations confer aberrant new activities, abnormally increased binding to tubulin, microtubules, and neurofilaments that impairs axonal transport, plus a tendency to aggregate, rather than losing chaperone activity. The near-normal Hspb1-null mouse argues against haploinsufficiency, and the toxic component means added wild-type is not predicted to rescue, though a dominant-negative effect on the chaperone oligomer keeps confidence at medium.

Rationale: Dominant HSPB1/HSP27 missense alleles acquire aberrant, hyperactive binding to tubulin and neurofilaments and a tendency to aggregate, impairing axonal transport on their own, and the near-normal Hspb1-null mouse argues against haploinsufficiency, pointing to a toxic gain of function. A secondary dominant-negative effect on the chaperone oligomer keeps confidence at medium.

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Mechanistic basis: Neomorphic

Prediction: The literature predicts a toxic gain-of-function mechanism for dHMN-2B: dominant HSPB1 mutations confer aberrant, gained interactions, with increased binding to tubulin and HDAC6 and reduced tubulin acetylation, disrupted neurofilament assembly, impaired axonal transport, and a tendency to aggregate, rather than simple loss. Functional work supports a neomorphic toxic activity that HDAC6 inhibition can rescue, so added wild-type is not predicted to rescue, though a dominant-negative contribution to the chaperone oligomer keeps confidence at medium.

Rationale: Dominant HSPB1 alleles acquire aberrant tubulin and HDAC6 binding, tubulin hypo-acetylation, and impaired axonal transport that HDAC6 inhibition may rescue, a neomorphic toxic gain. A still-debated dominant-negative pull on the chaperone oligomer keeps confidence at medium.

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Mechanistic basis: Unresolved

Prediction: The literature does not resolve a mechanism for dHMN-2C: HSPB3 dHMN-2C is an ultra-rare, essentially single-family dominant subtype (Kolb et al. 2010, R7S) with no functional studies distinguishing loss of function from a toxic gain or dominant-negative effect, so the mechanism is unresolved.

Rationale: HSPB3 dHMN-2C could act through a toxic or dominant-negative small-heat-shock-protein mechanism, but no HSPB3-specific study distinguishes loss of function from a dominant effect for its single dominant missense allele, so the mechanism remains unresolved at low confidence.

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Mechanistic basis: Neomorphic

Prediction: The literature predicts a toxic gain-of-function mechanism for CMT2L: heterozygous HSPB8 variants, notably in the α-crystallin domain (K141N/E), render the small heat-shock chaperone aggregation-prone, promoting insoluble aggregates and impaired protein quality control and autophagy rather than losing chaperone activity. A knock-in mouse reproducing the disease supports a novel toxic gain rather than haploinsufficiency, and added wild-type HSPB8 is not predicted to rescue the aggregation-driven toxicity, though sequestration of partner chaperones keeps confidence at medium.

Rationale: The α-crystallin-domain HSPB8 alleles (K141N/E) render the chaperone aggregation-prone and form toxic insoluble inclusions on their own, and knock-in mice are affected while knockouts are spared, arguing against haploinsufficiency, so added wild-type is not predicted to rescue: a toxic gain of function. Because mutant HSPB8 also sequesters HSPB1 and wild-type, a dominant-negative contribution keeps confidence at medium.

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Mechanistic basis: Neomorphic

Prediction: The literature predicts a toxic gain-of-function mechanism for dHMN-2A: heterozygous HSPB8 variants (K141N/K141E) confer a novel aggregation-prone activity that impairs protein quality control, as shown in knock-in mice. Added wild-type HSPB8 is not predicted to rescue, and the recurrent missense alleles argue against haploinsufficiency, pointing to a neomorphic gain, though sequestration of partner chaperones keeps confidence at medium.

Rationale: Recurrent HSPB8 K141N/K141E alleles acquire an aggregation-prone activity that impairs protein quality control, with knock-in mice affected and knockouts spared, so added wild-type is not predicted to rescue: a toxic gain of function. A dominant-negative contribution via sequestration of HSPB1 and BAG3 keeps confidence at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT2S: recessive IGHMBP2 mutations reduce the protein's helicase and ATPase activity, and residual activity correlates with the milder CMT2S phenotype versus near-complete loss in the allelic subtype dHMN-6 (SMARD1). Two hypomorphic or null alleles are required, and restored wild-type is predicted to rescue, consistent with loss rather than a dominant-negative or gain-of-function effect.

Rationale: Two hypomorphic or null IGHMBP2 alleles partially lose helicase and ATPase activity, with residual function sparing CMT2S from the severe near-null phenotype of the allelic subtype dHMN-6 (SMARD1), so restored wild-type is predicted to rescue: a biallelic loss of function.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for dHMN-6 (SMARD1): pathogenic IGHMBP2 variants reduce or abolish ATPase and helicase activity, with disease requiring two defective copies and residual activity correlating with milder phenotypes. Restored wild-type IGHMBP2 is predicted to rescue, consistent with recessive loss rather than a dominant-negative effect.

Rationale: Biallelic IGHMBP2 alleles lose ATPase and helicase activity, with residual function tracking milder disease, so restored wild-type is predicted to rescue: a recessive loss of function.

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Mechanistic basis: Overactivity

Prediction: The literature predicts a gain-of-function mechanism for CMTDIE: the dominant missense variants cluster in the N-terminal diaphanous-inhibitory domain and disrupt the intramolecular DID-DAD interaction that keeps INF2 autoinhibited, releasing the formin into dysregulated constitutive actin polymerization. Because the mutant does more of INF2's normal activity on its own rather than disrupting the wild-type, the evidence supports overactivity over haploinsufficiency or a dominant-negative effect, at medium confidence on limited mechanistic data.

Rationale: Dominant N-terminal DID missense alleles disrupt the intramolecular DID-DAD autoinhibitory clamp and release INF2 to over-do its normal actin-polymerizing activity rather than disrupting the wild-type, a gain-of-function overactivity. Because a dominant-negative or interference effect on dimers is not fully excluded, confidence holds at medium.

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Mechanistic basis: Unresolved

Prediction: The literature does not resolve a mechanism for CMT-INSC: the single dominant INSC missense reported (p.Met70Arg) is hypofunctional at LGN yet gains PAR3 binding, so a dominant-negative or sequestration effect is at least as consistent with the data as haploinsufficiency, and the cross-species fly rescue does not settle dosage-based loss. The mechanism is best predicted as unresolved.

Rationale: The single p.Met70Arg allele is hypofunctional at LGN yet gains PAR3 binding, so a dominant-negative or sequestration effect is at least as consistent with the data as haploinsufficiency, and the Drosophila rescue does not settle dosage loss in patients, leaving the mechanism unresolved at low confidence.

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Mechanistic basis: Unresolved

Prediction: The literature does not resolve a mechanism for CMT1J: recurrent heterozygous missense variants in ITPR3, a subunit of the homotetrameric IP3-receptor calcium-release channel, suggest a dominant effect, possibly dominant-negative interference with the tetramer or a channel gain of function, but no functional study has settled it, so the mechanism is unresolved.

Rationale: The recurrent heterozygous missense variants in the homotetrameric ITPR3 channel act through a dominant mechanism, but whether that is dominant-negative interference with the tetramer or a channel gain of function is undetermined without functional data, so the call is unresolved at low confidence.

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Mechanistic basis: Unresolved

Prediction: The literature does not cleanly resolve the mechanism for CMT2HH: the dominant JAG1 missense variants reduce but do not abolish surface Jagged-1 and alter dosage-sensitive Notch signaling in a way distinct from the JAG1 haploinsufficiency that causes Alagille syndrome, without establishing a definitive loss, gain, or dominant-negative mechanism for this subtype.

Rationale: CMT2HH JAG1 missense variants reduce surface Jagged-1 while altering tissue-specific Notch signaling, a mechanism the primary study leaves unresolved and explicitly distinct from Alagille haploinsufficiency, so the call is unresolved at low confidence.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMTRIE: recessive KCTD11 truncating and missense variants reduce the protein via autophagic degradation, and a Kctd11-knockout mouse phenocopies the myelin defect, so two defective copies impair KCTD11's Cullin3 E3-ubiquitin-ligase adaptor function. Restored wild-type is predicted to rescue, consistent with loss of function.

Rationale: Recessive KCTD11 variants reduce mutant protein via autophagic degradation, and a Kctd11-knockout mouse phenocopies the myelin defect, so restored wild-type is predicted to rescue: a biallelic loss of function.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for HSN-2C: two truncating or null KIF1A alleles reduce or abolish the kinesin-3 anterograde axonal motor, consistent with recessive inheritance where a single wild-type copy suffices, so restored wild-type is predicted to rescue. This recessive subtype is distinct from the dominant KIF1A missense disorders that act through overactivity or a dominant-negative effect.

Rationale: Recessive HSN-2C reflects biallelic loss of KIF1A kinesin-3 motor function where a single wild-type allele suffices, so restored wild-type is predicted to rescue. Because some recessive alleles are hypomorphic missense rather than clean nulls, confidence holds at medium.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for CMT-KIF5A: because KIF5A is an obligate homodimeric kinesin-1 motor, the dominant N-terminal motor-domain missense alleles produce a mutant that disrupts the mixed mutant and wild-type dimer rather than acting through simple haploinsufficiency, so added wild-type is not predicted to rescue. The cited large-deletion dosage evidence is weak for this subtype, so the mechanism is debated at low confidence.

Rationale: As an obligate homodimeric kinesin-1 motor, the dominant N-terminal motor-domain KIF5A alleles disrupt the mixed mutant and wild-type dimer, a dominant-negative effect that wild-type add-back is not predicted to rescue, rather than simple haploinsufficiency, and the dosage evidence is weak for this subtype, so the mechanism is debated at low confidence.

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Mechanistic basis: Neomorphic

Prediction: The literature predicts a toxic gain-of-function mechanism for CMT1C: dominant LITAF/SIMPLE missense mutations in the conserved C-terminal domain cause misfolding, mislocalization from endosomes, and cytoplasmic aggregates that disrupt endosome-to-lysosome trafficking. Because Litaf-null mice do not develop CMT, haploinsufficiency is disfavored, and the acquired toxic aggregation means added wild-type is not predicted to fully rescue, though a dominant-negative sequestration of wild-type SIMPLE keeps confidence at medium.

Rationale: Dominant LITAF/SIMPLE C-terminal missense mutants misfold and aggregate to disrupt endosomal trafficking on their own, and the disease-free Litaf-null mouse disfavors haploinsufficiency, pointing to a neomorphic toxic gain. A possible dominant-negative sequestration of wild-type SIMPLE keeps confidence at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT2B1: the recessive inheritance (classically homozygous LMNA p.R298C) and unaffected heterozygous carriers indicate that two defective copies are needed to reduce functional lamin A/C below a peripheral-nerve threshold, so restored wild-type is predicted to rescue rather than a dominant-negative effect, which characterizes the distinct dominant laminopathies.

Rationale: CMT2B1's own genetics, recessive inheritance, the classic homozygous LMNA p.R298C, and unaffected heterozygous carriers, point to a biallelic loss of functional lamin A/C that restored wild-type is predicted to rescue rather than a dominant interference. The missense nature of R298C holds confidence at medium.

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Mechanistic basis: Repeat expansion

Prediction: The literature predicts a toxic gain-of-function mechanism for CMT-LRP12: a heterozygous noncoding CGG repeat expansion in the 5' region of LRP12 undergoes RAN translation into an aggregation-prone polyglycine protein that forms toxic intranuclear and cytoplasmic inclusions, rather than reducing normal LRP12 activity. This mirrors the repeat-expansion toxicity of LRP12 in oculopharyngodistal myopathy, so added wild-type is not predicted to rescue, and the toxic-species model, debated against RNA toxicity, holds confidence at medium.

Rationale: A heterozygous noncoding CGG expansion in LRP12 is RAN-translated into a polyglycine product that forms toxic aggregates, a neomorphic gain of function, so added wild-type is not predicted to rescue. The toxic-species model remains debated against RNA toxicity, holding confidence at medium.

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Mechanistic basis: Mixed

Prediction: The literature predicts a loss-of-function mechanism for CMT2P: both the dominant (RING-domain truncating, acting by haploinsufficiency) and recessive (biallelic) LRSAM1 alleles reduce or abolish the protein's E3 ubiquitin-ligase activity, so restored wild-type is predicted to rescue rather than the mutant disrupting the wild-type. Because the dominant frameshifts truncate the RING domain yet retain the self-association domains, a dominant-negative contribution to the dominant form cannot be dismissed, holding confidence at low.

Rationale: CMT2P converges on loss of LRSAM1 E3-ligase function, with recessive biallelic loss and dominant RING-domain truncations, so restored wild-type is predicted to rescue. Because the dominant frameshifts retain the self-association domains, a dominant-negative contribution remains debated, giving a mixed picture at low confidence.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT-MCM3AP: recessive hypomorphic or null MCM3AP variants reduce the activity of GANP, required for nuclear mRNA export, and both copies must be impaired. Because the alleles reduce rather than disrupt protein function, restored wild-type GANP is predicted to rescue, a loss-of-function signature.

Rationale: Biallelic hypomorphic or null MCM3AP alleles reduce GANP-mediated mRNA nuclear export, so restored wild-type is predicted to rescue rather than leaving a disrupted complex: a recessive loss of function.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for CMT2A: mutant MFN2, a mitochondrial outer-membrane GTPase that drives fusion, does not simply lose activity but interferes with the wild-type protein, disrupting MFN1/MFN2-mediated mitochondrial fusion, transport, and tethering within the complex. Because the mutant remains incorporated in the shared complex, added wild-type protein is not predicted to fully rescue, and haploinsufficient loss of function alone does not explain the dominant, often severe phenotype, consistent with a dominant-negative rather than a pure loss-of-function mechanism.

Rationale: Heterozygous MFN2 mutants disrupt wild-type MFN2/MFN1 fusion complexes rather than simply losing activity, indicating a dominant-negative rather than a loss-of-function effect. Because MFN1 can complement some MFN2 mutants in trans and haploinsufficiency remains a competing explanation, the mechanism is genuinely debated, holding confidence at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT2A2B: as the autosomal recessive form of MFN2-related CMT, disease requires two defective MFN2 copies, and restored wild-type mitofusin-2 is predicted to restore mitochondrial fusion, distinct from the dominant-negative dominant subtype CMT2A.

Rationale: CMT2A2B is recessive and requires two defective MFN2 alleles, so restored mitofusin-2 is predicted to restore mitochondrial fusion: a biallelic loss of function, unlike the dominant-negative subtype CMT2A.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT2B4: the recessive MFN2 alleles reduce or abolish mitofusin-2 activity, and disease manifests only when both copies are compromised, so restored wild-type MFN2 is predicted to restore mitochondrial fusion. This contrasts with the dominant MFN2 subtypes such as CMT2A, where single alleles act through a dominant-negative mechanism.

Rationale: The recessive, biallelic requirement means both MFN2 copies must be compromised and restored wild-type is predicted to restore fusion: a biallelic loss of function, distinct from the dominant-negative dominant subtypes such as CMT2A.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for HMSN-6A: MFN2 is a mitochondrial outer-membrane fusion GTPase that oligomerizes and works in trans, so mutant subunits incorporate into fusion complexes and disrupt wild-type MFN2 and MFN1, impairing fusion and axonal transport. Because the mutant interferes with the wild-type rather than being absent, added wild-type is not predicted to rescue; recessive MFN2 alleles are handled as a separate loss-of-function subtype. Because MFN1 co-expression rescues several mutants, the mechanism remains debated, holding confidence at medium.

Rationale: Mutant MFN2 oligomerizes and disrupts wild-type fusion complexes from this subtype's own dominant alleles, so added wild-type is not predicted to rescue: a dominant-negative effect. Because MFN1 co-expression rescues several mutant alleles, the mechanism remains debated, holding confidence at medium.

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Mechanistic basis: Mixed

Prediction: The literature predicts a loss-of-function mechanism for CMT2T: both the recessive biallelic null or hypomorphic alleles and the later dominant late-onset alleles converge on reduced neprilysin/MME peptidase activity, with the dominant form supported as dosage-sensitive haploinsufficiency. Because restored neprilysin is predicted to restore peptidase activity rather than the mutant disrupting wild-type, the evidence favors loss over a dominant-negative or gain-of-function mechanism, though single heterozygous pathogenicity is only moderately established, holding confidence at medium.

Rationale: Recessive biallelic null or hypomorphic MME alleles and the later dominant late-onset alleles both reduce neprilysin peptidase activity, so restored wild-type is predicted to rescue rather than the mutant disrupting it: a loss of function with a mixed recessive-plus-dominant-haploinsufficiency flavor. Heterozygous pathogenicity is only moderately established, holding confidence at medium.

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Mechanistic basis: Overactivity

Prediction: The literature predicts a gain-of-function mechanism for CMT2Z: dominant MORC2 missense variants cluster in and around the GHKL ATPase module and hyperactivate the protein, driving enhanced HUSH-complex-mediated H3K9me3 silencing rather than reducing MORC2 activity. Structural and cellular studies support constitutive, overactive ATPase and silencing, consistent with overactivity rather than haploinsufficiency or a dominant-negative effect.

Rationale: Dominant MORC2 missense variants relieve autoinhibition and constitutively hyperactivate the ATPase and HUSH-silencing axis, an intrinsic overactivity gain of function rather than haploinsufficiency or dominant-negative interference.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT2EE: MPV17 encodes a mitochondrial inner-membrane protein required for mtDNA maintenance and nucleotide homeostasis, and recessive variants reduce or abolish this function, so both copies must be impaired. Restored wild-type is predicted to rescue, consistent with loss rather than a dominant-negative or gain-of-function effect.

Rationale: Biallelic MPV17 variants impair mtDNA maintenance, so restored wild-type is predicted to rescue: a recessive loss of function. The rarity and sparse subtype-specific literature hold confidence at medium.

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Mechanistic basis: Mixed

Prediction: The literature predicts a complex mechanism for CMT1B: most dominant MPZ missense alleles act through misfolding, ER retention, and chronic UPR activation (for example S63del and R98C) plus disruption of the homophilic P0 adhesion complex, so added wild-type P0 is not predicted to fully rescue, while a distinct subset of MPZ-deficiency haploinsufficiency alleles produces a milder loss-of-function CMT, mirrored by late-onset demyelination in heterozygous-null mice. Because these allele classes carry genuinely different mechanisms within the same subtype, the evidence supports a mixed mechanism.

Rationale: CMT1B's own alleles carry genuinely mixed mechanisms: a toxic gain and UPR arm (for example S63del) plus dominant-negative disruption of P0 adhesion, alongside a less firmly established haploinsufficiency arm, so a complex call fits. The mouse-derived loss-of-function arm holds confidence at medium.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for CMT2I: the dominant heterozygous MPZ missense alleles (for example Thr124Met) produce a mutant P0 that is incorporated into myelin and disrupts the adhesive, oligomeric function of wild-type P0 rather than being absent, so supplementation is not predicted to rescue. The haploinsufficiency seen with MPZ-null deficiency alleles does not drive CMT2I, and a residual toxic-gain interpretation holds confidence at medium.

Rationale: CMT2I's own late-onset MPZ missense alleles such as Thr124Met produce a mutant P0 incorporated into myelin that disrupts wild-type P0 adhesion rather than being merely absent, so supplementation is not predicted to rescue: a dominant-negative effect. A residual toxic-gain interpretation holds confidence at medium.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for CMT2J: MPZ/P0 is a homophilic adhesion glycoprotein of compact myelin that oligomerizes, and the classic CMT2J allele Thr124Met is trafficked into myelin where the mutant P0 disrupts wild-type P0-mediated adhesion rather than being absent, so added wild-type is not predicted to rescue. Because MPZ null or haploinsufficiency produces a milder late-onset phenotype than the point mutation, the evidence favors interference; a gain-of-function interpretation keeps confidence at medium.

Rationale: The Thr124Met P0 is trafficked into myelin and disrupts wild-type P0 homophilic adhesion rather than being absent, so added wild-type is not predicted to rescue: a dominant-negative effect. A gain-of-function interpretation remains debated, holding confidence at medium.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for CMTDID: the heterozygous dominant-intermediate MPZ missense alleles produce a misfolded P0 that disrupts wild-type P0 adhesion in compact myelin, so added wild-type is not predicted to rescue. The loss-of-function haploinsufficiency seen at the broader MPZ locus is not what drives CMTDID, and because dominant-negative versus toxic-gain for these misfolding alleles remains debated, confidence holds at medium.

Rationale: CMTDID's own heterozygous dominant-intermediate MPZ missense alleles produce a misfolded P0 that disrupts wild-type P0 adhesion in compact myelin, so added wild-type is not predicted to rescue: a dominant-negative effect. Because dominant-negative versus toxic-gain for these misfolding alleles remains debated, confidence holds at medium.

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Mechanistic basis: Dosage

Prediction: The literature predicts a loss-of-function mechanism for CMT-ATP6: mitochondrially inherited MT-ATP6 missense variants (for example m.9185T>C) impair proton translocation through the Fo subunit a of ATP synthase, reducing ATP synthesis in peripheral nerve. Pathogenic alleles are typically homoplasmic, and restored wild-type subunit a is predicted to rescue, consistent with loss of function rather than a dominant-negative effect; the flavor reflects mtDNA copy-load dosage rather than nuclear biallelic genetics.

Rationale: Homoplasmic MT-ATP6 subunit-a variants reduce ATP-synthase proton translocation, so restored wild-type is predicted to rescue: a mitochondrial loss of function, better modeled as mtDNA copy-load dosage than nuclear biallelic genetics.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT4B1: MTMR2 encodes a phosphoinositide 3-phosphatase, and the recessive nonsense, frameshift, and catalytic-domain missense mutations abolish phosphatase activity, with the Mtmr2-null mouse recapitulating the myelin-outfolding phenotype. Restored wild-type MTMR2 is predicted to rescue, consistent with loss over a dominant-negative effect.

Rationale: Recessive MTMR2 null and catalytic-domain mutations abolish phosphatase activity, and the Mtmr2-null mouse phenocopies the disease, so restored wild-type is predicted to rescue: a biallelic loss of function.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a recessive biallelic loss-of-function mechanism for CMT-MTRFR: truncating variants in MTRFR (C12orf65), a mitochondrial translation release and recycling factor, abolish protein function so both copies must be lost, impairing mitochondrial translation quality control. Restored wild-type is predicted to rescue, consistent with loss rather than a dominant-negative or gain-of-function process.

Rationale: Biallelic truncating MTRFR/C12orf65 variants abolish a mitochondrial translation release and recycling factor, so restored wild-type is predicted to rescue: a recessive loss of function. The small, heterogeneous patient cohort holds confidence at medium.

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Mechanistic basis: Unresolved

Prediction: The literature identifies dominant missense variants in MYH14 (non-muscle myosin heavy chain IIC) as causative for dHMN-MYH14, but no functional work distinguishes loss of function from a dominant-negative or toxic gain for this subtype, so the mechanism is unresolved.

Rationale: Because non-muscle myosin IIC dimerizes and assembles into bipolar filaments, a dominant-negative filament-disrupting mechanism is favored for dHMN-MYH14, but with no allele-specific data separating it from loss of function or toxic gain, the mechanism remains unresolved at low confidence.

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Mechanistic basis: Unresolved

Prediction: The literature does not yet resolve a mechanism for CMT-MYO9B: this ultra-rare 2023 association links heterozygous MYO9B variants (myosin IXb, a RhoGAP-containing unconventional myosin) to a dominant CMT, with no functional data distinguishing haploinsufficiency, a dominant-negative effect, or gain of function, so the call is unresolved.

Rationale: CMT-MYO9B remains mechanistically unresolved until functional studies distinguish haploinsufficiency from a dominant-negative or gain-of-function effect, so an unresolved call at low confidence is best supported by the ultra-rare 2023 evidence.

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Mechanistic basis: Unresolved

Prediction: The literature does not resolve a mechanism for CMT2V: dominant heterozygous NAGLU missense variants cause CMT (Tetreault et al. 2015), but because obligate heterozygous carriers of biallelic NAGLU-null alleles that cause Sanfilippo B are neurologically unaffected, simple haploinsufficiency is unlikely, and no toxic gain or dominant-negative effect has been demonstrated, so the mechanism is unresolved.

Rationale: Because obligate null carriers who cause the recessive Sanfilippo B disease are unaffected, dosage loss is unlikely for CMT2V, while no dominant-negative or gain-of-function effect of the dominant missense alleles has been demonstrated, leaving the mechanism unresolved at low confidence.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT-NAMPT: recessive homozygous NAMPT variants, in the rate-limiting enzyme of the NAD+ salvage pathway, reduce enzymatic activity and impair NAD+ biosynthesis in neurons. Because both copies must be affected and restored wild-type enzyme is predicted to rescue, this is loss of function, though the ultra-rare 2025 evidence holds confidence at low.

Rationale: Biallelic NAMPT variants lose enzymatic function and reduce NAD+ salvage in axons, so restored wild-type is predicted to rescue: a recessive loss of function. The ultra-rare 2025 evidence holds confidence at low.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for CMT-NARS1: the heterozygous variants are catalytically null or hypomorphic for asparaginyl-tRNA aminoacylation yet cause dominant CMT, and 2025 functional studies show the mutant subunit disrupts the wild-type NARS1 homodimer, so added wild-type is not predicted to rescue. Biallelic true loss instead causes a distinct neurodevelopmental disorder, and a toxic gain-of-function alternative in the aaRS field holds confidence at medium.

Rationale: The dominant CMT-NARS1 variants are catalytically compromised subunits that disrupt the wild-type NARS1 homodimer, directly supported by two 2025 studies, so added wild-type is not predicted to rescue: a dominant-negative effect, distinct from the biallelic neurodevelopmental disorder. A residual aaRS toxic-gain debate holds confidence at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT4D (HMSN-Lom): the recurrent NDRG1 truncating alleles (classically p.Arg148* in the Roma founder population) abolish NDRG1 expression, with absent protein in patient tissue impairing NDRG1's role in Schwann cell myelin maintenance. Because two null copies are required and restored wild-type is predicted to rescue, this is a recessive loss of function rather than a dominant-negative or gain-of-function effect.

Rationale: Recurrent truncating NDRG1 alleles (classically p.Arg148* in the Roma founder population) abolish NDRG1, so restored wild-type is predicted to rescue: a biallelic loss best labeled biallelic since carriers are unaffected, with no dominant-negative or gain-of-function signal.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT-NDUFS6: recessive variants in NDUFS6, a nuclear-encoded core subunit of mitochondrial complex I, reduce or abolish subunit function and impair complex I assembly and activity, so two damaged copies are required. Restored wild-type is predicted to rescue, consistent with loss rather than a dominant-negative effect; the recent 2024 association holds confidence at low.

Rationale: Recessive NDUFS6 variants reduce a core complex I structural subunit whose absence fails to incorporate rather than disrupting the wild-type assembly, so restored wild-type is predicted to rescue: a biallelic loss of function. The recent, limited reports hold confidence at low.

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Mechanistic basis: Neomorphic

Prediction: The literature predicts a neomorphic toxic gain-of-function mechanism for CMT2CC: heterozygous frameshift variants in the NEFH tail domain cause translational read-through into the 3'UTR, exposing a cryptic amyloidogenic element that yields an aggregation-prone neurofilament heavy chain. The aggregates drive axonal toxicity, a novel toxic species rather than simple loss, so added wild-type is not predicted to rescue, though a dominant-negative co-aggregation contribution keeps confidence at medium.

Rationale: CMT2CC's own NEFH tail-domain frameshifts read through into the 3'UTR and expose a cryptic amyloidogenic element, generating a novel aggregation-prone neurofilament species, so the mechanism is a neomorphic toxic gain that added wild-type is not predicted to rescue. Resting largely on one study with a possible dominant-negative co-aggregation, confidence holds at medium.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for CMT1F: heterozygous NEFL missense variants produce a mutant neurofilament light chain that co-assembles with and disrupts the wild-type filament network, impairing neurofilament assembly and axonal transport and forming aggregates, so that added wild-type protein is not predicted to rescue. This is distinct from CMT2B5, the recessive NEFL-null subtype, which is loss of function.

Rationale: Mutant neurofilament light chain from heterozygous NEFL missense variants co-assembles with and disrupts the wild-type filament network, impairing assembly and axonal transport, so wild-type add-back is not predicted to rescue: the signature of a dominant-negative rather than a loss-of-function effect.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT2B5: recessive NEFL null or truncating alleles produce near-complete loss of neurofilament light chain, so two lost copies are required. This contrasts with the dominant-negative missense alleles of the dominant NEFL subtypes CMT2E and CMT1F, and restored wild-type is predicted to rescue.

Rationale: Recessive CMT2B5 arises from biallelic null or truncating NEFL alleles causing near-complete loss of neurofilament light chain, so restored wild-type is predicted to rescue: a biallelic loss of function, distinct from the dominant-negative missense biology of CMT2E and CMT1F.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for CMT2E: dominant missense mutations in NEFL produce a mutant neurofilament light chain that co-assembles with and disrupts the wild-type neurofilament network, impairing assembly, causing perikaryal aggregation, and disrupting axonal transport. Because the mutant continues to interfere with wild-type subunits rather than reducing NEFL activity, added wild-type is not predicted to rescue.

Rationale: CMT2E's dominant missense NEFL alleles co-assemble with and disrupt the wild-type neurofilament network rather than simply reducing activity, so added wild-type is not predicted to rescue: a dominant-negative effect, reinforced by NEFL's separate recessive loss-of-function subtype CMT2B5.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for CMTDIG: the mutant NEFL light chain incorporates into and disrupts the self-assembling neurofilament network, impairing assembly and axonal transport and forming aggregates that sequester wild-type subunits, so added wild-type is not predicted to rescue. This is distinct from the recessive NEFL-null subtype CMT2B5, which is loss of function.

Rationale: Dominant NEFL alleles produce a mutant light chain that co-assembles into and disrupts the self-building neurofilament network and sequesters wild-type protein, so added wild-type is not predicted to rescue: a dominant-negative effect, distinct from the recessive NEFL-null subtype CMT2B5.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for HSAN-5: recessive NGF variants (classically NGFB p.R100W) impair NGF processing, secretion, and TrkA-mediated neurotrophic signaling required for small-fiber nociceptive neurons. With both copies functionally lost and recessive inheritance, restored wild-type NGF is predicted to rescue, consistent with loss rather than a dominant-negative or gain-of-function effect.

Rationale: Recessive NGF alleles such as p.R100W impair NGF processing, secretion, and TrkA-mediated nociceptor support, so restored wild-type is predicted to rescue: a biallelic loss of function, whether a complete null or a selective hypomorph.

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Mechanistic basis: Repeat expansion

Prediction: The literature predicts a toxic gain-of-function repeat-expansion mechanism for CMT-NOTCH2NLC: a heterozygous GGC repeat expansion in the 5'UTR of NOTCH2NLC drives repeat-associated non-AUG translation of a polyglycine protein and RNA and protein toxicity, producing the characteristic eosinophilic intranuclear inclusions. Because the toxicity arises from the expanded allele's novel aggregating species rather than reduced NOTCH2NLC activity, added wild-type is not predicted to rescue, consistent with gain of function.

Rationale: The heterozygous 5'UTR GGC expansion is RAN-translated into a polyglycine product that forms intranuclear inclusions, a novel aggregating species rather than loss or interference, so added wild-type is not predicted to rescue: a toxic gain of function.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for HSAN-4: recessive NTRK1 mutations abolish or reduce TrkA receptor tyrosine kinase activity, disrupting NGF signaling required for nociceptive sensory and sympathetic neurons. Because the mutant receptor loses activity rather than disrupting wild-type, restored functional TrkA is predicted to rescue, consistent with recessive loss of function.

Rationale: Biallelic NTRK1 loss-of-function alleles abolish or reduce TrkA kinase activity and NGF signaling, so restored wild-type TrkA is predicted to rescue rather than the mutant disrupting wild-type: a recessive loss of function.

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Mechanistic basis: Overactivity

Prediction: The literature predicts a gain-of-function mechanism for CMTX6: the PDK3 p.R158H mutation increases the kinase's binding to and activity within the pyruvate dehydrogenase complex, causing hyperphosphorylation and excessive inhibition of pyruvate dehydrogenase and impaired mitochondrial energy metabolism. This is a hyperactive enzyme doing more of its normal inhibitory function rather than a loss, consistent with X-linked dominant inheritance.

Rationale: The CMTX6 PDK3 p.R158H allele hyperactivates the kinase's inhibitory phosphorylation of pyruvate dehydrogenase, a gain-of-function overactivity rather than disruption of a wild-type product. The evidence rests largely on one recurrent mutation, holding confidence at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for HMSN-6C: recessive PDXK variants reduce or abolish pyridoxal kinase activity, lowering pyridoxal 5'-phosphate, the active vitamin B6 cofactor (Chelban et al. 2019). Patients show reduced enzyme activity and partial PLP responsiveness, so restored wild-type activity is predicted to rescue, arguing against a dominant-negative or gain-of-function effect.

Rationale: Biallelic PDXK variants abolish pyridoxal kinase activity and lower PLP, so restoring wild-type enzyme or supplying PLP is predicted to rescue: a recessive loss of function rather than a dominant-negative or gain-of-function effect.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for HMSN-4 (Refsum disease): recessive PHYH mutations abolish phytanoyl-CoA hydroxylase activity, causing toxic phytanic acid accumulation. Because both copies of this peroxisomal enzyme are lost and restoring activity rescues metabolism, the basis of dietary phytanic-acid restriction, the evidence supports a recessive enzyme deficiency rather than a dominant-negative or gain-of-function effect.

Rationale: Recessive PHYH null alleles abolish phytanoyl-CoA hydroxylase activity, so restoring wild-type enzyme is predicted to rescue phytanic-acid metabolism: a biallelic loss of function rather than any mutant disrupting the wild-type product.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMTRIC: recessive PLEKHG5 variants (the founder missense p.Arg204Trp and truncating frameshifts) reduce or abolish this RhoGEF's activity, with disease requiring two defective copies and heterozygous carriers unaffected. Restored wild-type PLEKHG5 is predicted to rescue, supporting loss of function over a dominant-negative action.

Rationale: Recessive PLEKHG5 alleles, the founder p.Arg204Trp plus truncating frameshifts, reduce or abolish RhoGEF activity with unaffected heterozygous carriers, so restored wild-type is predicted to rescue: a biallelic loss of function.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for dSMA-4: PLEKHG5 encodes a Rho guanine-nucleotide exchange factor, and the recessive missense and truncating alleles reduce or abolish GEF activity, with impaired downstream signaling and protein instability, requiring two defective copies. Restored wild-type is predicted to rescue, consistent with loss of function.

Rationale: dSMA-4's own recessive missense and truncating PLEKHG5 alleles reduce GEF activity, requiring two defective copies, so restored wild-type is predicted to rescue: a biallelic loss of function.

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Mechanistic basis: Neomorphic

Prediction: The literature predicts a dominant toxic gain-of-function mechanism for CMT1G: heterozygous PMP2 missense variants (for example I43N, T51P) destabilize the protein and perturb its fatty-acid and lipid binding, so mutant PMP2 in myelin disrupts membrane stacking and compaction. Because Pmp2-null mice are near-normal, arguing against haploinsufficiency, and PMP2 overexpression is itself demyelinating, the evidence favors a neomorphic toxic effect, though limited data hold confidence at low.

Rationale: Because Pmp2-null mice are near-normal, both haploinsufficiency and a dominant-negative effect are disfavored, leaving the destabilized mutant PMP2's aberrant incorporation into myelin as the toxic effect, a neomorphic gain of function. Limited data hold confidence at low.

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Mechanistic basis: Dosage

Prediction: The literature strongly supports a gene-dosage mechanism for CMT1A: the disease is caused in most cases by a 1.5 Mb tandem duplication of chromosome 17p11.2 containing PMP22, so three functional copies overexpress PMP22. This trisomic overdose of otherwise normal protein, rather than loss or disruption of wild-type, disrupts Schwann-cell myelination, consistent with the reciprocal deletion causing HNPP and with dosage-dependent rodent models.

Rationale: CMT1A is driven by overexpression of structurally normal PMP22 from the 17p11.2 duplication, a gene-dosage effect distinct from the haploinsufficiency of the reciprocal deletion in HNPP and from the dominant-negative PMP22 point mutations of CMT1E.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for CMT1E: unlike CMT1A (duplication, dosage) and HNPP (deletion, haploinsufficiency), CMT1E arises from heterozygous PMP22 point mutations (for example Trembler and Trembler-J) that produce a misfolded protein retained in the ER, where it aggregates and sequesters wild-type PMP22 and interacting proteins. Because the mutant disrupts the wild-type product, added wild-type is not predicted to fully rescue, and the more severe, earlier-onset phenotype supports a toxic dominant-negative effect over simple loss.

Rationale: Heterozygous PMP22 missense alleles (Trembler, Trembler-J) misfold, are ER-retained, and sequester wild-type PMP22 and interacting partners, so supplementation is not predicted to rescue: a dominant-negative effect, cleanly distinguished from CMT1A dosage and HNPP haploinsufficiency.

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Mechanistic basis: Haploinsufficiency

Prediction: The literature strongly predicts a loss-of-function, haploinsufficiency mechanism for HNPP: it is caused by deletion of one PMP22 copy (the 1.5 Mb 17p11.2 deletion reciprocal to the CMT1A duplication) or by loss-of-function point or frameshift alleles, so a single reduced-dosage copy produces the phenotype. This is dosage-sensitive and dominant, and restored PMP22 is predicted to rescue, consistent with haploinsufficiency rather than a dominant-negative or toxic effect.

Rationale: HNPP's own alleles, the reciprocal 17p11.2 deletion and PMP22 truncating variants, produce a haploinsufficiency in which a single reduced-dosage copy drives the phenotype and restored PMP22 is predicted to rescue, distinct from the CMT1A duplication.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a recessive biallelic loss-of-function mechanism for CMT2B2: PNKP encodes polynucleotide kinase 3'-phosphatase, and the two hypomorphic or damaging alleles reduce its kinase and phosphatase activity, impairing DNA single- and double-strand break repair in neurons. Restored wild-type is predicted to rescue, consistent with loss rather than a dominant-negative or gain-of-function effect.

Rationale: Two hypomorphic or damaging PNKP alleles reduce its DNA-repair kinase and phosphatase activity, so restored wild-type is predicted to rescue: a recessive biallelic loss of function, with no dominant-negative or gain-of-function contribution.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT-POLG: recessive POLG variants reduce the catalytic activity of mitochondrial DNA polymerase γ, causing mtDNA depletion and instability and secondary respiratory-chain failure in peripheral nerve. Two defective copies are required, and restored wild-type polymerase is predicted to rescue, consistent with loss rather than a dominant-negative effect.

Rationale: Recessive POLG variants reduce mitochondrial polymerase γ catalytic and proofreading activity, causing mtDNA depletion, so restored wild-type is predicted to rescue: a biallelic loss of function. The heterogeneity of hypomorphic POLG alleles holds confidence at medium.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for CMT1I: heterozygous POLR3B variants clustering in the catalytic/assembly region of RNA polymerase III are thought to incorporate into and disrupt the Pol III complex, impairing its function in a way that added wild-type protein is not predicted to rescue. This is mechanistically distinct from the separate biallelic recessive POLR3B loss-of-function that leads to leukodystrophy.

Rationale: Heterozygous POLR3B CMT1I variants are predicted to incorporate into and disrupt the Pol III complex (a dominant-negative effect that wild-type protein is not predicted to rescue), consistent with dominant inheritance where pure loss of function is recessive, though the interference remains inferred rather than functionally demonstrated.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for HSAN-8: recessive PRDM12 mutations (truncating, PR/SET-domain missense, and polyalanine-tract expansions) abolish this transcriptional regulator's activity, required for development and survival of nociceptive sensory neurons. Both copies must be disrupted, and restored wild-type PRDM12 is predicted to rescue, consistent with loss rather than a dominant-negative or gain-of-function effect.

Rationale: HSAN-8 is strictly recessive with unaffected heterozygous carriers, and even the polyalanine-expansion alleles deplete PRDM12 from the nucleus rather than disrupting the wild-type product, so restored wild-type is predicted to rescue: a biallelic loss of function.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a loss-of-function mechanism for CMTX5: PRPS1 missense mutations reduce PRS-I enzyme activity, and residual activity correlates with phenotypic severity across the PRPS1 spectrum. As X-linked recessive, affected hemizygous males lack a compensating copy, so restored PRS-I activity is predicted to rescue, consistent with recessive loss rather than haploinsufficiency or a dominant-negative effect, and distinct from the separate PRPS1 superactivity gain-of-function disorder.

Rationale: Hypomorphic PRPS1 missense alleles partially reduce PRS-I activity, a recessive loss where the hemizygous male's single X copy is knocked out and carrier females are spared, so restored wild-type is predicted to rescue, distinct from the separate PRPS1 superactivity gain-of-function disorder.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT4F: recessive PRX mutations are predominantly nonsense and frameshift truncations that abolish periaxin function, disrupting Schwann cell myelin maintenance and the dystroglycan-DRP2 complex. Because two defective copies are required and restored wild-type periaxin is predicted to rescue, this is a simple recessive loss rather than a dominant-negative or gain-of-function effect.

Rationale: Recessive PRX truncations abolish periaxin, so restored wild-type is predicted to rescue Schwann cell myelin maintenance: a biallelic loss of function, with no dominant-negative or gain-of-function contribution.

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Mechanistic basis: Biallelic

Prediction: The literature supports a loss-of-function mechanism for CMT-PSAT1: biallelic PSAT1 variants impair phosphoserine aminotransferase activity in the serine-biosynthesis pathway, reducing serine available for nerve function. Because restored wild-type enzyme rescues the deficiency, this is a recessive biallelic loss of enzymatic function rather than a dominant-negative or gain-of-function effect.

Rationale: Biallelic PSAT1 variants lose phosphoserine aminotransferase activity in serine biosynthesis, a recessive deficiency expected to respond to restored wild-type or serine supplementation rather than any dominant-negative or gain-of-function effect.

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Mechanistic basis: Overactivity

Prediction: The literature predicts a gain-of-function mechanism for CMT2B: the dominant RAB7A missense mutations (for example L129F, K157N) cluster around the nucleotide-binding pocket and produce a constitutively active Rab7 GTPase with accelerated GDP/GTP exchange and prolonged activation, perturbing late-endosomal and lysosomal trafficking and NGF/TrkA signaling. Functional and genetic evidence converge on overactivity rather than loss, consistent with dominant inheritance.

Rationale: Dominant RAB7A missense alleles drive unregulated nucleotide exchange and constitutive Rab7 hyperactivation that perturbs endolysosomal and NGF/TrkA trafficking, the mutant acting overactively on its own rather than disrupting wild-type: a gain of function.

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Mechanistic basis: Haploinsufficiency

Prediction: The literature predicts a loss-of-function, haploinsufficiency mechanism for dHMN-5B: REEP1 is a dosage-sensitive ER-shaping and microtubule-interacting protein, and its dominant alleles are predominantly truncating variants expected to trigger nonsense-mediated decay, with Reep1-null models recapitulating axonal degeneration, so a single reduced copy suffices and restored wild-type is predicted to rescue. Because some C-terminal alleles escape decay and may add a toxic component, confidence holds at medium.

Rationale: dHMN-5B is driven by REEP1 haploinsufficiency, since its dominant alleles are predominantly decay-prone truncating variants and Reep1-null models degenerate, so restored wild-type is predicted to rescue. Because C-terminal decay-escaping alleles may add a toxic component, confidence holds at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for HSAN-2B: recessive nonsense and frameshift truncating mutations in RETREG1 (FAM134B) abolish the ER-phagy receptor, and loss of its ER membrane-shaping and autophagy function causes sensory neuron degeneration. Because both copies must be lost and restored wild-type is predicted to rescue, this is a recessive loss rather than a dominant-negative or gain-of-function effect.

Rationale: Recessive truncating RETREG1/FAM134B mutations ablate the ER-phagy receptor, so restored wild-type is predicted to rescue: a biallelic loss of function rather than dominant-negative or gain of function.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a recessive loss-of-function mechanism for CMT-RFC1: biallelic intronic pentanucleotide (typically AAGGG) repeat expansions in RFC1 reduce RFC1 expression and function, producing the sensory neuronopathy. Although the lesion is a repeat expansion, the supported disease mechanism is loss of the replication factor's normal activity in two copies rather than a toxic gain, and restored wild-type is predicted to rescue.

Rationale: Biallelic intronic AAGGG repeat expansions in RFC1 act through recessive loss of replication-factor function, so restored wild-type is predicted to rescue. Because reduced-expression loss versus a repeat-driven RNA or toxic component remains debated, confidence holds at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT-SACS: recessive SACS variants, predominantly truncating plus destabilizing missense, abolish or reduce the sacsin chaperone, impairing its HSP70/HSP90 co-chaperone and mitochondrial and cytoskeletal functions. Because two defective copies are required and restored wild-type sacsin is predicted to rescue, this is a simple loss rather than a dominant-negative or gain-of-function effect.

Rationale: Recessive truncating and destabilizing missense SACS variants deplete or inactivate the sacsin chaperone with no sign of the mutant disrupting wild-type, so restored wild-type is predicted to rescue: a biallelic loss of function.

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Mechanistic basis: Unresolved

Prediction: The literature does not resolve a mechanism for CMT-SARS1: this ultra-rare dominant SARS1 (SerRS) subtype is known from a single de novo report (Record et al. 2023) with no functional dissection, and the evidence is debated between loss of aminoacylation and the toxic-gain or dominant-negative component typical of other dominant tRNA-synthetase CMTs, so the mechanism is unresolved.

Rationale: CMT-SARS1's own de novo alleles have no aminoacylation, supplementation, or model data, so the mechanism remains unresolved between haploinsufficiency and a dominant-negative or toxic gain, and it should not be assigned the aaRS family's presumed mechanism by inference, at low confidence.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT4B3: recessive SBF1 (MTMR5) variants abolish or reduce this myotubularin-family pseudophosphatase, whose scaffolding role supports the MTMR2 phosphoinositide-phosphatase complex, consistent with the myelin-outfolding pathology of the CMT4B group. With two null or hypomorphic alleles required and restored wild-type predicted to rescue, this is loss rather than a dominant-negative or gain-of-function mechanism.

Rationale: Recessive SBF1/MTMR5 null or hypomorphic alleles fail to scaffold the MTMR2 phosphatase complex, so restored wild-type is predicted to rescue: a biallelic loss of function rather than dominant-negative or gain of function.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT4B2: recessive SBF2 (MTMR13) mutations are typically truncating or affect the DENN and pseudophosphatase domains, abolishing the protein's ability to regulate the PI(3,5)P2 phosphatase MTMR2 and producing myelin outfoldings. Two defective copies are required, and restored functional SBF2 is predicted to rescue, consistent with simple loss rather than a dominant-negative or gain-of-function effect.

Rationale: Recessive truncating or domain-disrupting SBF2/MTMR13 mutations abolish activation of the MTMR2 phosphatase, so restored wild-type is predicted to rescue: a biallelic loss of function, with no dominant-negative or gain-of-function contribution.

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Mechanistic basis: Overactivity

Prediction: The literature predicts a gain-of-function mechanism for HSAN-7: heterozygous de novo missense variants in SCN11A (classically p.Leu811Pro) render the nociceptor sodium channel Nav1.9 overactive, producing an aberrant persistent sodium current that depolarizes sensory neurons and impairs firing, causing congenital insensitivity to pain. Functional studies show the mutant channel is hyperactive on its own, distinct from SCN11A loss-of-function alleles that cause a different pain phenotype.

Rationale: Heterozygous de novo SCN11A missense alleles such as p.Leu811Pro render Nav1.9 intrinsically overactive, producing an aberrant persistent sodium current that depolarizes and silences nociceptors, a gain of function acting on its own rather than disrupting the wild-type channel.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for HSAN-2D: recessive nonsense, frameshift, and other inactivating SCN9A variants abolish Nav1.7 sodium-channel activity in nociceptive neurons, and both copies non-functional produce the pain-insensitivity phenotype. Restored wild-type Nav1.7 is predicted to rescue, consistent with loss rather than the gain-of-function that drives the separate dominant SCN9A pain disorders.

Rationale: Biallelic loss-of-function SCN9A alleles abolish Nav1.7 activity in nociceptors, so restored wild-type is predicted to rescue: a recessive loss of function, distinct from the dominant gain-of-function SCN9A pain disorders.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT-SCO2: SCO2 encodes a copper metallochaperone required for cytochrome c oxidase (Complex IV) assembly, and the recessive missense and truncating alleles reduce COX assembly and mitochondrial respiratory function, with disease manifesting only when both copies are impaired. Restored wild-type SCO2 is predicted to rescue COX assembly, consistent with loss of function rather than a dominant-negative effect.

Rationale: Recessive SCO2 missense and truncating alleles reduce copper-metallochaperone-dependent Complex IV assembly, and disease appears only when both copies are compromised. Because restored wild-type SCO2 is predicted to rescue assembly, the mechanism is biallelic loss of function, not dominant-negative interference.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT-SCYL1: recessive nonsense, frameshift, and splice SCYL1 mutations abolish the pseudokinase's role in COPI-mediated retrograde Golgi-to-ER trafficking, with the Scyl1-deficient mdf mouse and human null alleles converging on absent function. Because both copies are inactivated and restored wild-type SCYL1 is predicted to rescue, this is a simple loss rather than a dominant-negative or gain-of-function effect.

Rationale: Biallelic truncating and splice SCYL1 alleles eliminate the pseudokinase's COPI-retrograde trafficking function, with the Scyl1-null mdf mouse and human null variants converging on loss, so restored wild-type is predicted to rescue: a recessive loss of function.

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Mechanistic basis: Dosage

Prediction: The literature predicts a gain-of-function (dosage) mechanism for SEPTIN9-associated CMT: intragenic SEPTIN9 duplications increase gene dosage, so disease is driven by an extra normal-sequence copy rather than by loss of one, and added wild-type protein is not predicted to rescue. Clustered N-terminal missense alleles are also reported and could instead disrupt the hetero-oligomeric septin filament, a dominant-negative possibility that holds confidence at medium.

Rationale: Intragenic SEPTIN9 duplications raise gene dosage, and disease from an extra normal-sequence copy cannot arise through simple loss: added wild-type is not predicted to rescue, which points to a gain-of-function dosage effect over haploinsufficiency. The clustered N-terminal missense alleles could instead disrupt the hetero-oligomeric septin filament, a dominant-negative contribution that leaves the mechanism genuinely unresolved and holds confidence at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT-SETX: two SETX null or hypomorphic alleles reduce senataxin, an RNA/DNA helicase involved in transcription termination and R-loop resolution, below a functional threshold, so restored wild-type senataxin is predicted to rescue. This contrasts with the distinct dominant SETX gain-of-function subtype, judged separately.

Rationale: Recessive CMT-SETX arises from two null or hypomorphic SETX alleles dropping senataxin helicase activity below a functional threshold, so restored wild-type is predicted to rescue: a biallelic loss of function, distinct from the separately judged dominant SETX gain-of-function disease.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT-SGPL1: recessive compound-heterozygous or homozygous null or hypomorphic alleles cause sphingosine-1-phosphate lyase deficiency, with reduced or abolished enzyme activity on both copies. Restored functional enzyme is predicted to rescue, consistent with loss rather than a dominant-negative or toxic gain-of-function effect.

Rationale: Biallelic null or hypomorphic SGPL1 alleles cause recessive sphingosine-1-phosphate lyase insufficiency, so restoring functional enzyme is predicted to rescue: a loss of function, with no dominant-negative or gain-of-function contribution.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT4C: recessive SH3TC2 mutations (nonsense, frameshift, splice, and trafficking-disrupting missense) abolish or reduce SH3TC2 function needed for Schwann cell myelination and endosomal recycling, on both alleles, with carriers unaffected. Restored wild-type SH3TC2 is predicted to rescue, consistent with loss rather than a dominant-negative or gain-of-function effect.

Rationale: Recessive SH3TC2 alleles lose function needed for Schwann cell myelination, with unaffected heterozygous carriers, so restored wild-type is predicted to rescue: a biallelic loss of function.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for dHMN2-SIGMAR1: recessive SIGMAR1 mutations destabilize or reduce the sigma-1 receptor and impair its chaperone and ER-mitochondria function, with disease requiring two defective copies. Restored wild-type receptor is predicted to rescue, consistent with recessive loss.

Rationale: Biallelic SIGMAR1 variants reduce or destabilize the sigma-1 receptor and impair its ER-mitochondria chaperone function, so restored wild-type is predicted to rescue: a recessive loss of function.

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Mechanistic basis: Overactivity

Prediction: The literature predicts a gain-of-function mechanism for CMT2II: the dominant SLC12A6 variants (for example the de novo Thr991Ala) disrupt inhibitory C-terminal phosphoregulation of the KCC3 K-Cl cotransporter, rendering it constitutively active. This contrasts with the recessive biallelic loss-of-function of Andermann syndrome, and functional data support a constitutively overactive transporter rather than loss or a dominant-negative effect.

Rationale: The dominant CMT2II allele Thr991Ala abolishes inhibitory C-terminal phosphoregulation and renders KCC3 constitutively overactive on its own, a cell-autonomous gain of function distinct from the recessive biallelic loss-of-function of Andermann syndrome. The limited functional dataset holds confidence at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for HMSN-6B: recessive SLC25A46 variants destabilize or truncate this outer mitochondrial membrane protein, sharply reducing its steady-state levels and disrupting mitochondrial fission and fusion. Because pathogenic alleles act by loss of protein and phenotypes track reduced abundance, restored wild-type SLC25A46 is predicted to rescue, consistent with recessive loss rather than a dominant-negative or gain-of-function effect.

Rationale: Recessive SLC25A46 alleles destabilize or truncate the outer-membrane protein and lower its steady-state abundance, so restored wild-type is predicted to rescue: a biallelic loss of function rather than an allele disrupting the wild-type or acting neomorphically.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for dHMN-7A: the heterozygous C-terminal truncating variants in SLC5A7, encoding the high-affinity choline transporter CHT1, produce mistrafficked, altered transporters that reduce choline uptake below the level of simple haploinsufficiency, consistent with the mutant interfering with the wild-type transporter. This contrasts with biallelic loss-of-function SLC5A7 alleles that cause a recessive congenital myasthenic syndrome, so added wild-type CHT1 is not predicted to fully rescue.

Rationale: The heterozygous C-terminal truncating SLC5A7 alleles produce mistrafficked mutant CHT1 that disrupts the wild-type transporter rather than causing simple haploinsufficiency, as the recessive biallelic-null alleles do in a separate congenital myasthenic syndrome, so co-expressed wild-type is not predicted to fully rescue. The interference remains inferred, holding confidence at medium.

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Mechanistic basis: Biallelic

Prediction: The literature strongly predicts a biallelic loss-of-function mechanism for CMT-SORD: recessive SORD variants (most commonly the frameshift c.757delG) abolish sorbitol dehydrogenase activity, causing sorbitol accumulation in serum and nerve. Both copies must be lost, carriers are unaffected, and restoring SORD activity, genetically or with aldose reductase inhibitors, is predicted to rescue, consistent with pure loss rather than a dominant-negative or toxic gain.

Rationale: Biallelic SORD loss (commonly c.757delG) abolishes sorbitol dehydrogenase and causes toxic sorbitol accumulation, with unaffected carriers, so restoring or bypassing enzyme activity is predicted to rescue: a pure loss of function rather than dominant-negative or gain of function.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT2X: the SPG11 (spatacsin) mutations in this recessive phenotype are predominantly truncating alleles that abolish protein function, so both copies must be lost. Spatacsin is a lysosomal and autophagy-related protein, and restored wild-type is predicted to rescue, with no dominant-negative or gain-of-function component.

Rationale: Recessive SPG11 truncating null alleles require both copies lost to abolish spatacsin function, so restored wild-type is predicted to rescue: a biallelic loss of function, with no dominant-negative or gain-of-function contribution.

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Mechanistic basis: Neomorphic

Prediction: The literature predicts a neomorphic gain-of-function mechanism for HSAN-1A: dominant SPTLC1 missense mutations alter the substrate specificity of serine palmitoyltransferase so it uses alanine and glycine instead of serine, generating toxic 1-deoxysphingolipids that accumulate and damage sensory neurons. Because the mutant acquires a novel toxic biosynthetic activity rather than losing SPT function, added wild-type is not predicted to rescue, consistent with a neomorphic gain rather than haploinsufficiency or a dominant-negative effect.

Rationale: Dominant SPTLC1 missense alleles redirect serine palmitoyltransferase toward alanine and glycine to generate toxic 1-deoxysphingolipids, a novel activity the mutant exerts on its own rather than by disrupting or losing wild-type SPT, so added wild-type is not predicted to rescue: a neomorphic gain of function.

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Mechanistic basis: Neomorphic

Prediction: The literature predicts a neomorphic gain-of-function mechanism for HSN-1A: dominant SPTLC1 missense mutations (for example C133W, V144D) shift the substrate specificity of serine palmitoyltransferase so it condenses alanine and glycine instead of serine, generating neurotoxic 1-deoxysphingolipids. Sptlc1 knockout does not phenocopy the disease and added wild-type does not neutralize the toxic species, arguing against loss or a dominant-negative effect and for an acquired toxic activity.

Rationale: Dominant SPTLC1 missense alleles shift serine palmitoyltransferase substrate specificity toward alanine and glycine, generating neurotoxic 1-deoxysphingolipids that added wild-type does not neutralize and that Sptlc1 knockout does not reproduce: a neomorphic gain of function.

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Mechanistic basis: Neomorphic

Prediction: The literature predicts a neomorphic gain-of-function mechanism for HSAN-1C: dominant SPTLC2 missense mutations alter serine palmitoyltransferase substrate specificity so it uses alanine and glycine instead of serine, generating neurotoxic 1-deoxysphingolipids. This is a novel toxic species rather than loss of enzyme activity, and added wild-type SPT does not clear the toxic metabolites, consistent with acquired toxic activity rather than haploinsufficiency or a dominant-negative effect.

Rationale: Dominant SPTLC2 missense alleles shift SPT substrate specificity toward alanine and glycine, generating neurotoxic 1-deoxysphingolipids that wild-type enzyme cannot clear, consistent with an acquired toxic activity rather than haploinsufficiency or dominant-negative interference: a neomorphic gain of function.

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Mechanistic basis: Neomorphic

Prediction: The literature predicts a neomorphic gain-of-function mechanism for HSN-1C: dominant SPTLC2 missense mutations cause serine palmitoyltransferase to use alanine and glycine instead of serine and produce neurotoxic 1-deoxysphingolipids. Added wild-type SPT does not rescue because the toxicity comes from the aberrant lipid species rather than lost normal activity, supporting a gain of a novel toxic function over haploinsufficiency or a dominant-negative effect.

Rationale: Dominant SPTLC2 missense alleles shift serine palmitoyltransferase substrate specificity toward alanine and glycine and generate neurotoxic 1-deoxysphingolipids on their own, a novel activity that added wild-type does not rescue, distinguishing it from haploinsufficiency or dominant-negative interference: a neomorphic gain of function.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT4K: SURF1 encodes a nuclear assembly factor required for cytochrome c oxidase biogenesis, and the recessive CMT4K alleles (truncating, null, or hypomorphic) abolish or reduce this assembly activity, causing COX deficiency. Two defective copies are required, and restored wild-type SURF1 is predicted to rescue, consistent with loss rather than a dominant-negative or gain-of-function effect.

Rationale: Recessive truncating or hypomorphic SURF1 alleles reduce complex IV assembly, so restored wild-type is predicted to rescue: a biallelic loss of function rather than a dominant-negative or gain-of-function effect.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for CMT-SYT2: heterozygous C2B-domain missense variants in SYT2 (for example p.Pro308Leu, p.Asp307Ala) produce a mutant synaptotagmin-2 that incorporates into the release machinery and interferes with calcium-triggered synaptic vesicle exocytosis, impairing presynaptic neurotransmission. Because the mutant sensor is built into the release machinery, added wild-type protein is not predicted to rescue. Biallelic null alleles instead cause a separate recessive presynaptic myasthenic syndrome, a loss-of-function phenotype distinct from this dominant missense mechanism.

Rationale: Mutant synaptotagmin-2 from the heterozygous C2B-domain missense variants incorporates into the release machinery and disrupts calcium-triggered vesicle exocytosis, which points to a dominant-negative effect rather than loss of function. That biallelic nulls instead cause a separate recessive presynaptic myasthenic syndrome supports the distinction, and because the mutant sensor is built into the release apparatus, wild-type add-back is not predicted to rescue.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for HSAN-9: recessive TECPR2 variants are predominantly truncating or otherwise deleterious changes that abolish TECPR2, required for autophagosome formation and ER-Golgi trafficking, so both copies must be lost. Because a wild-type copy is protective, restored wild-type is predicted to rescue, consistent with loss rather than a dominant-negative or gain-of-function effect.

Rationale: Recessive truncating or deleterious TECPR2 variants abolish this autophagy and trafficking protein, and a single wild-type copy suffices, so restored wild-type is predicted to rescue: a biallelic loss of function, with no dominant-negative or gain-of-function signal.

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Mechanistic basis: Neomorphic

Prediction: The literature predicts a toxic gain-of-function mechanism for HMSN-Okinawa Type: the recurrent dominant TFG p.Pro285Leu variant increases the protein's propensity to self-aggregate into insoluble inclusions and impair the proteasome, a novel toxic species rather than reduced ER-to-Golgi trafficking activity. Because the pathology is driven by acquired aggregation, added wild-type is not predicted to rescue, distinct from haploinsufficiency, though co-aggregation with wild-type keeps confidence at medium.

Rationale: The recurrent dominant TFG p.Pro285Leu acts by toxic aggregation, and the separate recessive biallelic loss-of-function phenotype argues against haploinsufficiency, so added wild-type is not predicted to rescue: a neomorphic gain of function. Because TFG self-assembles, a dominant-negative co-aggregation cannot be excluded, holding confidence at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for CMT2R: the reported TRIM2 variants are homozygous or compound-heterozygous truncating alleles that abolish the E3 ubiquitin-ligase activity of TRIM2, impairing neurofilament light chain turnover, consistent with a recessive requirement for both copies lost. Restored wild-type TRIM2 is predicted to rescue, with no dominant-negative or gain-of-function component.

Rationale: Biallelic truncating TRIM2 alleles abolish the E3 ubiquitin-ligase activity and impair neurofilament turnover, so restored wild-type is predicted to rescue: a recessive loss of function. The small number of reported families holds confidence at medium.

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Mechanistic basis: Overactivity

Prediction: The literature predicts a gain-of-function mechanism for CMT2C: dominant TRPV4 missense mutations clustered in the intracellular ankyrin-repeat domain produce an overactive calcium channel with elevated basal activity and increased intracellular calcium influx toxic to motor and sensory neurons. Functional studies show the mutant channels are hyperactive rather than lost, consistent with channel overactivity rather than haploinsufficiency or a dominant-negative effect.

Rationale: Dominant TRPV4 ankyrin-repeat missense mutations render the calcium channel overactive on its own, with elevated basal activity and calcium influx, rather than acting by haploinsufficiency or disrupting wild-type subunits: a gain of function.

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Mechanistic basis: Overactivity

Prediction: The literature predicts a gain-of-function mechanism for dHMN-8: dominant TRPV4 missense variants clustered in the cytoplasmic ankyrin-repeat domains render the cation channel overactive, with increased basal activity and elevated calcium influx toxic to motor neurons, rather than reducing channel function. Constitutive channel activity, calcium overload, and the fact that Trpv4-null does not phenocopy the disease support overactivity rather than loss or a dominant-negative effect.

Rationale: Dominant TRPV4 ankyrin-repeat missense alleles render the channel constitutively overactive with toxic calcium influx, and Trpv4-null does not phenocopy the disease, so wild-type does not rescue: a gain of function.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for CMT-TUBB3: heterozygous TUBB3 missense variants produce mutant β-tubulin that incorporates into the α/β-heterodimer and the microtubule lattice alongside wild-type, perturbing microtubule dynamics and kinesin interactions and impairing axonal transport, so supplementation is not predicted to rescue. There is no loss-of-function TUBB3 disease and no haploinsufficiency evidence, though some reports frame the altered microtubule behavior as a toxic gain of function, holding confidence at medium.

Rationale: Mutant β-tubulin incorporates into the α/β-heterodimer and microtubule lattice alongside wild-type and disrupts the shared polymer, so wild-type supplementation is not predicted to rescue: a dominant-negative effect. Some reports read the altered kinesin behavior as a toxic gain of function, and that unsettled question holds confidence at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a loss-of-function mechanism for dSMAX-2: X-linked recessive hypomorphic missense and regulatory variants in UBA1 reduce ubiquitin-activating enzyme E1 activity, impairing regulated protein degradation in motor neurons. Affected hemizygous males have a single reduced-function copy, so restored wild-type E1 is predicted to rescue, a partial loss rather than a dominant-negative or gain-of-function effect.

Rationale: Hypomorphic UBA1 missense and regulatory variants lower E1 ubiquitin-activating activity in motor neurons, so restored wild-type is predicted to rescue: a partial loss of function in the affected hemizygous male's single copy, not dominant-negative or gain of function.

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Mechanistic basis: Haploinsufficiency

Prediction: The literature predicts a loss-of-function mechanism for dHMN1-UBE3C: the single reported autosomal dominant case is a UBE3C-intergenic gene fusion (UBE3C-IF) whose transcript lowers levels of full-length wild-type UBE3C, the ubiquitin ligase, in patient iPSC-derived motor neurons. Because the fusion reduces the dosage of wild-type enzyme rather than interfering with the residual protein, restored wild-type UBE3C is predicted to rescue, consistent with haploinsufficiency. Evidence is limited to a single 2023 report, holding confidence at medium.

Rationale: The UBE3C-intergenic fusion lowers levels of full-length wild-type UBE3C in patient iPSC-derived motor neurons, reducing enzyme dosage rather than interfering with the residual protein. Because restoring wild-type UBE3C is predicted to rescue, the mechanism is haploinsufficiency-type loss of function. The single-report basis holds confidence at medium.

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Mechanistic basis: Neomorphic

Prediction: The literature predicts a toxic gain-of-function mechanism for CMT2Y: dominant VCP (p97) missense mutations cluster at the N-domain/D1 interface and confer enhanced ATPase activity with altered cofactor binding, disrupting autophagy and protein clearance and producing TDP-43 aggregation. This is not haploinsufficiency, since heterozygous VCP loss is not disease-causing, and the mechanism is inferred from the shared multisystem proteinopathy alleles, holding confidence at medium.

Rationale: Dominant VCP mutations at the N-D1 interface enhance intrinsic ATPase activity and alter cofactor binding rather than lose function, since heterozygous VCP loss is not disease-causing: a toxic gain of function. Because p97 is an obligate hexamer and subtype-specific data are sparse, a dominant-negative or partial-loss contribution cannot be excluded, holding confidence at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for VRK1-related dSMA: the recessive, typically compound-heterozygous or homozygous missense variants reduce VRK1 serine/threonine kinase activity and impair its roles in Cajal body regulation, nuclear envelope dynamics, and DNA-damage repair, with disease emerging only when both copies are compromised. Restored wild-type VRK1 is predicted to rescue, consistent with loss rather than a dominant-negative or gain-of-function process.

Rationale: Biallelic hypomorphic VRK1 variants reduce serine/threonine kinase activity below a functional threshold, so restored wild-type is predicted to rescue: a recessive loss of function rather than dominant-negative interference or gain of function.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for dHMN-VWA1: recessive truncating variants in VWA1 (notably the founder frameshift c.62_71dup) abolish or severely reduce the secreted extracellular-matrix protein WARP, so both alleles must be lost and restored wild-type is predicted to rescue. Convergent genetic and functional evidence supports simple loss rather than a dominant-negative or gain-of-function effect.

Rationale: Biallelic truncating VWA1 variants (notably the founder c.62_71dup) abolish the secreted WARP protein, so restored wild-type is predicted to rescue: a biallelic loss of function, with no dominant-negative or gain-of-function contribution.

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Mechanistic basis: Dominant-negative

Prediction: The literature predicts a dominant-negative mechanism for dHMN-9: heterozygous WARS1 variants reduce tryptophanyl-tRNA aminoacylation and, from WARS1's own allelic data, the mutant subunit disrupts the wild-type dimer, so added wild-type is not predicted to rescue. Recessive WARS1 disease is a distinct multisystem phenotype that provides no independent loss-of-function evidence, and because the WARS1 mechanism remains debated with no in vivo model, confidence holds at medium.

Rationale: Heterozygous WARS1 alleles reduce aminoacylation and the mutant subunit disrupts the wild-type dimer, so added wild-type is not predicted to rescue: a dominant-negative effect read from WARS1's own alleles rather than the aaRS-family neomorphic narrative. Because the mechanism remains debated with no in vivo model, confidence holds at medium.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for HSAN-2A: recessive truncating variants confined to the nervous-system-specific HSN2 exon of WNK1 abolish the neuronal isoform, and disease requires loss of both copies. Restored wild-type is predicted to rescue, consistent with recessive loss, distinct from the separate WNK1 gain-of-function alleles that cause a hypertension disorder.

Rationale: Recessive truncating variants in the nervous-system-specific HSN2 exon of WNK1 abolish the neuronal isoform, so loss of both copies is required and restored wild-type is predicted to rescue: a biallelic loss of function, distinct from the separate WNK1 gain-of-function hypertension disorder.

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Mechanistic basis: Biallelic

Prediction: The literature predicts a biallelic loss-of-function mechanism for HSN-2A: recessive truncating mutations in the neuron-specific HSN2 exon of WNK1 trigger nonsense-mediated decay or yield a non-functional truncated protein, so both copies of the nervous-system WNK1/HSN2 isoform must be lost. Restored wild-type is predicted to rescue, consistent with loss rather than a dominant-negative or gain-of-function effect.

Rationale: Recessive truncating mutations confined to the neuron-specific HSN2 exon of WNK1 trigger decay or yield non-functional protein, so restored wild-type is predicted to rescue: a biallelic loss of function, distinct from the WNK1 gain-of-function alleles.

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Mechanistic basis: Gene unknown

Prediction: The literature does not attribute CMTX3 to a coding mutation: it arises from a large interchromosomal insertion of chromosome 8q24.3 sequence into Xq27.1 (Brewer et al.), a non-coding structural variant in a gene desert. The predicted mechanism is a position or regulatory effect on a nearby gene, but no causative gene or defined loss or gain mechanism has been established, so the mechanism remains unresolved.

Rationale: CMTX3 arises from a non-coding Xq27.1/8q24.3 insertion thought to exert a position or regulatory effect, but with no causative gene identified the mechanism remains unresolved at low confidence.

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Mechanistic basis: Neomorphic

Prediction: The literature predicts a toxic gain-of-function mechanism for CMTDIC: heterozygous YARS1 variants acquire neomorphic properties, an aberrant conformational opening, axonal mislocalization, and novel interactions demonstrated in Drosophila and yeast models, that damage peripheral axons beyond any loss of aminoacylation. Because loss of catalytic activity is necessary but not sufficient and the toxicity is intrinsic to the mutant, the evidence supports a neomorphic gain rather than haploinsufficiency, holding confidence at medium.

Rationale: Heterozygous YARS1 alleles acquire an aberrant open conformation and novel interactions, with wild-type failing to rescue and toxicity dissociable from aminoacylation loss, pointing to a toxic neomorphic gain rather than disruption of wild-type. Because the precise neomorphic partner and the residual role of catalytic loss remain debated, confidence holds at medium.

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Mechanistic basis: Gene unknown

Prediction: No causative gene is identified for CMTX2: the disease maps to the Xp22.2 locus, distinct from the GJB1 gene of CMTX1, but the responsible gene and its protein product remain unknown, so no molecular mechanism can be assigned pending gene identification.

Rationale: CMTX2 maps only to the Xp22.2 locus with no identified gene or protein product, so no loss-of-function, dominant-negative, or gain-of-function inference can be drawn, and the mechanism remains unknown until the gene is cloned.

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Mechanistic basis: Gene unknown

Prediction: No causative gene is identified for dHMN-1: no single gene has been definitively established for this autosomal dominant subtype, so the literature does not support assigning a molecular mechanism.

Rationale: With no established causative gene for dHMN-1, no molecular mechanism can be predicted, and the call remains unknown until a gene is identified.

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Mechanistic basis: Gene unknown

Prediction: No causative gene is identified for HMSN-5: this historical designation for CMT with pyramidal features is genetically heterogeneous with no single gene assigned, so the literature supports no specific molecular mechanism.

Rationale: HMSN-5 is a genetically heterogeneous CMT-plus-pyramidal designation with no single causative gene or defined allele class, so no mechanism can be predicted and the call remains unknown until a gene is identified.

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Mechanistic basis: Gene unknown

Prediction: No causative gene is identified for HSAN-1B: this autosomal dominant sensory and autonomic subtype is mapped by linkage to chromosome 3p22-p24, but no causative gene is confirmed, so no variant mechanism can be predicted.

Rationale: HSAN-1B is defined only by linkage to 3p22-p24 with no confirmed causative gene, so no alleles exist to reason from and the mechanism remains unknown until a gene is identified.

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Mechanistic basis: Gene unknown

Prediction: No causative gene is identified for HSN-1B: this autosomal dominant sensory subtype maps to chromosome 3p22-p24, but no causative gene has been identified, so the literature supports no specific molecular mechanism.

Rationale: HSN-1B maps to 3p22-p24 with no causative gene cloned, so no molecular mechanism can be predicted until the gene and its alleles are identified.

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