Is ARHGAP31 p.Ala1199Val (c.3596C>T) pathogenic?

ARHGAP31 p.Ala1199Val (c.3596C>T) is classified Conflicting classifications of pathogenicity in ARHGAP31 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-05). AlphaMissense: likely pathogenic (0.6647); Ultra-rare (popmax 0.0233%, amr); Associated with Adams-Oliver syndrome 1.

What condition is associated with ARHGAP31 p.Ala1199Val (c.3596C>T)?

ARHGAP31 p.Ala1199Val (c.3596C>T) is associated with Adams-Oliver syndrome 1 (ClinVar).

How common is ARHGAP31 p.Ala1199Val (c.3596C>T) in the general population?

ARHGAP31 p.Ala1199Val (c.3596C>T) is ultra-rare (popmax 0.0233%, amr) (gnomAD).

What do computational predictors say about ARHGAP31 p.Ala1199Val (c.3596C>T)?

AlphaMissense predicts likely pathogenic (score 0.6647) — an in-silico prediction, not a clinical call.

ARHGAP31 p.Ala1199Val

c.3596C>T · rs534166705 · VCV1408682

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6647 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0233%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Adams-Oliver syndrome 1

Computational evidence

Protein change
AlphaMissense	0.6647	likely pathogenic
REVEL	0.328	indeterminate
SaProt	LLR -7.26	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 121 kb · p 1.9e-07 · regional, not allelic
Overall
CADD	28.0	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 0.0233% Admixed American · 14/60,026 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.00366% 59/1,614,124 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0233%	4,288
Remaining individualsnot grpmax-eligible	0.008%	12,501
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
South Asian	0.00329%	30,357
European (non-Finnish)	0.00288%	34,707
African / African-American	0.00267%	37,522

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.Ala1199Val
Coding: c.3596C>T
MANE Select: NM_020754
dbSNP: rs534166705
Type: single nucleotide variant
Location: chr3:119415525 (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-ala1199val (accessed [today's date]).

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