Name: CMT-ARHGEF10
Published: 2026-07-18

Clinical Basics

Genetic Context

HGNC-Approved Gene Symbol: ARHGEF10
Gene Full Name: Rho guanine nucleotide exchange factor 10
Chromosome: 8p23.3
Zygosity of Responsible Variant: Heterozygous
Variant Mechanism: Toxic Gain of Function (GoF)

Details

Mechanistic basis:
Overactivity

Confidence:
Medium

Prediction:
The literature predicts a gain-of-function mechanism for CMT-ARHGEF10: the heterozygous Thr109Ile allele, written Thr332Ile on the longer reading frame (c.995C>T), sits at the edge of an autoinhibitory N-terminal region of this RhoA guanine-nucleotide exchange factor. Deleting that region raises exchange activity, and the disease allele does the same, loading more GTP onto RhoA and driving Rho-dependent transcription and ROCK-dependent contraction.

Rationale:
Rho-ROCK signaling restrains Schwann cell process extension, so an exchange factor released from its own brake shortens the processes a Schwann cell needs in order to wrap, which is what thin sheaths with uniformly slowed conduction and no axon loss look like. Heterozygous loss of ARHGEF10 is tolerated in population constraint data, so a missing copy is not the lesion. The overactivity rests on a single functional study, holding confidence at medium.
ClinVar Pathogenic Variants: View ARHGEF10 ClinVar Variants
ClinGen Curation: View ARHGEF10 ClinGen Curation
CMT-ARHGEF10 OMIM Entry: CMT-ARHGEF10 OMIM
ARHGEF10 OMIM Entry: ARHGEF10 OMIM

Publication Title: Slowed Conduction and Thin Myelination of Peripheral Nerves Associated with Mutant Rho Guanine-Nucleotide Exchange Factor 10.
Authors: Verhoeven, K., De Jonghe, P., Van de Putte, T., Nelis, E., Zwijsen, A., Verpoorten, N., De Vriendt, E., Jacobs, A., Van Gerwen, V., Francis, A., Ceuterick, C., Huylebroeck, D., & Timmerman, V.
Publication Date: October 1, 2003
DOI: 10.1086/378159