Is ARHGAP26 p.Val756Met (c.2266G>A) pathogenic?

ARHGAP26 p.Val756Met (c.2266G>A) is classified Uncertain significance in ARHGAP26 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-06). AlphaMissense: likely pathogenic (0.9682); Very rare (popmax 0.00448%, eas).

How common is ARHGAP26 p.Val756Met (c.2266G>A) in the general population?

ARHGAP26 p.Val756Met (c.2266G>A) is very rare (popmax 0.00448%, eas) (gnomAD).

What do computational predictors say about ARHGAP26 p.Val756Met (c.2266G>A)?

AlphaMissense predicts likely pathogenic (score 0.9682) — an in-silico prediction, not a clinical call.

ARHGAP26 p.Val756Met

c.2266G>A · rs989365937 · VCV2520485

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9682 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00448%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9682	likely pathogenic
REVEL	0.513	indeterminate
SaProt	LLR -10.41	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 88 kb · p 0.1 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V811M vs ClinVar V756M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00448% East Asian · 2/44,692 alleles

Filtering AF 0.000742% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000369%

Overall 0.000876% 14/1,597,694 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00448%	22,346
African / African-American	0.00134%	74,750
European (non-Finnish)	0.000941%	106,245

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: ARHGAP26
Protein: p.Val756Met
Coding: c.2266G>A
MANE Select: NM_001135608
dbSNP: rs989365937
Type: single nucleotide variant
Location: chr5:143222432 (GRCh38)
Gene constraint: LOEUF 0.493 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 78.09 · 1 PDB
Residue 756: the sh3 domain

Full ARHGAP26 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP26 c.2099+147C>T Uncertain significance ★ ⚠ same type
ARHGAP26 c.2099+149G>A Uncertain significance ★ ⚠ same type
ARHGAP26 c.2099+38G>C Uncertain significance ★ ⚠ same type
ARHGAP26 c.2099+93A>G Uncertain significance ★ ⚠ same type
ARHGAP26 p.Ala126Thr Uncertain significance ★ ⚠ same type
ARHGAP26 p.Ala163Ser Uncertain significance ★ ⚠ same type
ARHGAP26 p.Ala477Thr Uncertain significance ★ ⚠ same type
ARHGAP26 p.Ala56Val Uncertain significance ★ ⚠ 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/arhgap26-p-val756met (accessed [today's date]).

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