Is ARHGAP9 p.Met331Val (c.991A>G) pathogenic?

ARHGAP9 p.Met331Val (c.991A>G) is classified Likely benign in ARHGAP9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-24). AlphaMissense: likely benign (0.0522); Ultra-rare (popmax 0.0165%, mid).

How common is ARHGAP9 p.Met331Val (c.991A>G) in the general population?

ARHGAP9 p.Met331Val (c.991A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ARHGAP9 p.Met331Val (c.991A>G)?

AlphaMissense predicts likely benign (score 0.0522) — an in-silico prediction, not a clinical call.

ARHGAP9 p.Met331Val

c.991A>G · VCV3781480

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0522 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0522	likely benign
REVEL	0.354	indeterminate
SaProt	LLR -5.45	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.43	GERP -2.4
Regional constraint	o/e 0.98	unconstrained · MANE · 6,886 bp · p 0.53 · regional, not allelic
Overall
CADD	12.83	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000205% 3/1,461,876 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
South Asian	0.0022%	45,539

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: ARHGAP9
Protein: p.Met331Val
Coding: c.991A>G
MANE Select: NM_032496
Type: single nucleotide variant
Location: chr12:57476624 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.99 · 3 PDB
Residue 331: the ph domain; a β-strand

Full ARHGAP9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MARS1 c.-18C>T Uncertain significance ★★ same type
MARS1 p.Glu27Lys Uncertain significance ★★ ⚠ same type
MARS1 p.Gly11Ser Uncertain significance ★★ ⚠ same type
MARS1 p.Gly24Ala Uncertain significance ★★ ⚠ same type
MARS1 p.Gly24Ser Uncertain significance ★★ ⚠ same type
MARS1 p.Thr32Ser Uncertain significance ★★ ⚠ same type
MARS1 p.Val5Met Uncertain significance ★★ ⚠ same type
ARHGAP9 p.Ala69= Benign ★★ same type

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/arhgap9-p-met331val (accessed [today's date]).

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