Is ARHGAP31 p.Leu496Pro (c.1487T>C) pathogenic?

ARHGAP31 p.Leu496Pro (c.1487T>C) is classified Uncertain significance in ARHGAP31 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-10-15). AlphaMissense: likely pathogenic (0.9726); Very rare (popmax 0.00381%, nfe); Associated with Adams-Oliver syndrome 1.

What condition is associated with ARHGAP31 p.Leu496Pro (c.1487T>C)?

ARHGAP31 p.Leu496Pro (c.1487T>C) is associated with Adams-Oliver syndrome 1 (ClinVar).

How common is ARHGAP31 p.Leu496Pro (c.1487T>C) in the general population?

ARHGAP31 p.Leu496Pro (c.1487T>C) is very rare (popmax 0.00381%, nfe) (gnomAD).

What do computational predictors say about ARHGAP31 p.Leu496Pro (c.1487T>C)?

AlphaMissense predicts likely pathogenic (score 0.9726) — an in-silico prediction, not a clinical call.

ARHGAP31 p.Leu496Pro

c.1487T>C · rs1242925466 · VCV1806036

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9726 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00381%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Adams-Oliver syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9726	likely pathogenic · top 5% in ARHGAP31
REVEL	0.263	benign-leaning
SaProt	LLR -5.96	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 121 kb · p 1.9e-07 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00381% European (non-Finnish) · 45/1,180,038 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00322% 47/1,461,874 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00381%	26,223
Remaining individualsnot grpmax-eligible	0.0032%	31,255

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ARHGAP31
Protein: p.Leu496Pro
Coding: c.1487T>C
MANE Select: NM_020754
dbSNP: rs1242925466
Type: single nucleotide variant
Location: chr3:119402239 (GRCh38)
Gene constraint: LOEUF 0.38 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 43.32

Full ARHGAP31 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Adams-Oliver syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ARHGAP31 p.Arg426Gly Uncertain significance ★★ ⚠ same condition
ARHGAP31 p.Gln1233Leu Uncertain significance ★★ ⚠ same condition
ARHGAP31 p.His48Tyr Uncertain significance ★★ ⚠ same condition
ARHGAP31 p.Lys449Glu Uncertain significance ★★ ⚠ same condition
ARHGAP31 p.Trp304Ter Uncertain significance ★★ same condition
ARHGAP31 c.100+77A>T Benign ★★ same condition
ARHGAP31 c.1070-92G>C Benign ★★ same condition
ARHGAP31 c.1926+11T>C Benign ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/arhgap31-p-leu496pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown