Hereditary neuropathy

Gene: ARHGAP19

Green List (high evidence)

Comment on list classification: As reviewed by Shahryar Alavi, there are multiple unrelated families reported with biallelic ARHGAP19 variants and with motor-predominant neuropathy. Hence, this gene has been promoted to green rating on this panel.

Created: 28 Oct 2025, 4:56 p.m. | Last Modified: 28 Oct 2025, 4:56 p.m.

Panel Version: 1.504

PMID:41086021 (2025) reported the identification of 16 different biallelic variants in ARHGAP19 gene in 25 individuals from 20 unrelated families. The variants included missense and nonsense variants both within and outside the functional GAP domain. The patients had a motor-predominant neuropathy with age of onset almost exclusively in the first two decades of life. The clinical phenotype was generally length-dependent but there are some unusual features, including frequent conduction slowing +/- conduction block, prominent asymmetry, subacute deterioration in some individuals, and upper limb onset.

In vitro biochemical and cellular assays showed GAP domain variants cause loss of protein function. Transcriptomic studies showed loss-of-function altered expression of genes linked to 3 cellular pathways, compared to controls. In addition, iPSC-derived motor neurons showed reduced ARHGAP19 expression. In vivo studies from zebrafish and drosophila loss of function models showed movement deficits.

There was no genotype-phenotype correlation observed in LOF variants reported in 'GAP' domain and outside of this domain.

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype (records accessed on 28 October 2025). This gene is rated green on the 'Hereditary Neuropathy_CMT - isolated' panel in PanelApp Australia (https://panelapp-aus.org/panels/3069/gene/ARHGAP19/)

Created: 28 Oct 2025, 4:55 p.m. | Last Modified: 28 Oct 2025, 4:55 p.m.

Panel Version: 1.501

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
motor peripheral neuropathy, MONDO:0002316

Publications

• 41086021

Green List (high evidence)

A comprehensive study on loss of function variants of the ARHGAP19 gene from several unrelated families shows that homozygous mutations cause early-onset motor-predominant neuropathy.
Biochemical assays revealed that GAP domain variants cause loss of protein function. Fruit fly and Zebrafish loss of function models also showed movement deficits.
RNA-Seq analysis confirmed downregulation of ARHGAP19 as well as cell cycle, motor and muscular cytoskeleton pathways in patients compared to controls.
The paper is under review.
Sources: Research

Created: 30 Apr 2025, 11:09 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
neuropathy; Charcot-Marie-Tooth disease

Publications

• https://www.medrxiv.org/content/10.1101/2024.05.10.24306768v1

Mode of pathogenicity
Other