Is ARHGAP6 p.Val974Phe (c.2920G>T) pathogenic?

ARHGAP6 p.Val974Phe (c.2920G>T) is classified Uncertain significance in ARHGAP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). AlphaMissense: likely pathogenic (0.813); Very rare (popmax 0.00229%, amr).

How common is ARHGAP6 p.Val974Phe (c.2920G>T) in the general population?

ARHGAP6 p.Val974Phe (c.2920G>T) is very rare (popmax 0.00229%, amr) (gnomAD).

What do computational predictors say about ARHGAP6 p.Val974Phe (c.2920G>T)?

AlphaMissense predicts likely pathogenic (score 0.813) — an in-silico prediction, not a clinical call.

ARHGAP6 p.Val974Phe

c.2920G>T · VCV3424729

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.813 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.813	likely pathogenic
REVEL	0.264	benign-leaning
SaProt	LLR -9.92	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 7.5	GERP 2.5, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 647 bp · p 0.82 · regional, not allelic
Overall
CADD	24.1	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 0.00229% Admixed American · 1/43,629 alleles

Overall 9.37e-05% 1/1,066,726 alleles · very rare

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: ARHGAP6
Protein: p.Val974Phe
Coding: c.2920G>T
MANE Select: NM_013427
Type: single nucleotide variant
Location: chrX:11138868 (GRCh38)
Structure: AlphaFold pLDDT 56.60

Full ARHGAP6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP6 c.589-9G>T Likely benign ★★ same type
ARHGAP6 p.Ala533= Benign ★★ same type
ARHGAP6 p.Leu413= Benign ★★ same type
ARHGAP6 p.Leu526= Benign ★★ same type
ARHGAP6 p.Leu841= Benign ★★ same type
ARHGAP6 p.Tyr190= Benign ★★ same type
HCCS c.521+7A>G Benign/Likely benign ★★ same type
AMELX p.Ala16Asp Likely pathogenic ★ 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/arhgap6-p-val974phe (accessed [today's date]).

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