ARHGAP31

Chr 3AD

Rho GTPase activating protein 31

Also known as: AOS, AOS1, CDGAP

NCBI Gene: 57514 ENSG00000031081 UniProt: Q2M1Z3 OMIM: 610911

The protein functions as a GTPase-activating protein that regulates RAC1 and CDC42, controlling cell spreading, lamellipodia formation, and cell migration. Mutations cause Adams-Oliver syndrome 1, characterized by congenital scalp defects and limb malformations, with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI >0.99), indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a GTPase-activating protein (GAP). A variety of cellular processes are regulated by Rho GTPases which cycle between an inactive form bound to GDP and an active form bound to GTP. This cycling between inactive and active forms is regulated by guanine nucleotide exchange factors and GAPs. The encoded protein is a GAP shown to regulate two GTPases involved in protein trafficking and cell growth. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.191 OMIM phenotype

Clinical Summary— ARHGAP31

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

4 unique Pathogenic / Likely Pathogenic· 375 VUS of 665 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.19LOEUF

pLI 1.000

Z-score 6.23

OE 0.09 (0.05–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.80Z-score

OE missense 0.92 (0.86–0.98)

706 obs / 768.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.09 (0.05–0.19)

0≤0.351.4

Missense OE?0.92 (0.86–0.98)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 5 / 54.8Missense obs/exp: 706 / 768.1Syn Z: 1.00

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongARHGAP31-related Adams-Oliver syndromeLOFAD

This gene — mechanism propensity

0.4091th %ile

GOF

0.5465th %ile

LOF

0.71top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.19

GOF1 literature citation

Literature Evidence

GOFMutant transcripts are stable and increase ARHGAP31 activity in vitro through a gain-of-function mechanism.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 21565291 ↗

ClinVar Variant Classifications

665 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic1

VUS375

Likely Benign184

Benign60

Conflicting34

Pathogenic

Likely Pathogenic

375

VUS

184

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	0	0	0	3
Likely Pathogenic	1	0	0	0	1
VUS	16	347	7	5	375
Likely Benign	0	36	54	94	184
Benign	0	7	40	13	60
Conflicting	—				34
Total	20	390	101	112	657

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

14 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap ARHGAP31 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →