Is ARHGAP8 p.Phe255Val (c.763T>G) pathogenic?

ARHGAP8 p.Phe255Val (c.763T>G) is classified Uncertain significance in ARHGAP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-05). AlphaMissense: ambiguous (0.5465); Rare (popmax 0.102%, amr).

How common is ARHGAP8 p.Phe255Val (c.763T>G) in the general population?

ARHGAP8 p.Phe255Val (c.763T>G) is rare (popmax 0.102%, amr) (gnomAD).

What do computational predictors say about ARHGAP8 p.Phe255Val (c.763T>G)?

AlphaMissense predicts ambiguous (score 0.5465) — an in-silico prediction, not a clinical call.

ARHGAP8 p.Phe255Val

c.763T>G · rs763538272 · VCV3128979

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5465 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.102%, amr)

Computational evidence

Protein change
AlphaMissense	0.5465	ambiguous
REVEL	0.412	indeterminate
SaProt	LLR -10.31	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.4, phastCons 1
Regional constraint	o/e 1.62	unconstrained · MANE · 76 kb · p 4.7e-50 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F286V vs ClinVar F255V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.102% Admixed American · 61/60,006 alleles

Filtering AF 0.0811% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0738%

Overall 0.00384% 62/1,613,978 alleles · rare exomes 56/1,461,826 · genomes 6/152,152 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.102%	984
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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: ARHGAP8
Protein: p.Phe255Val
Coding: c.763T>G
MANE Select: NM_181335
dbSNP: rs763538272
Type: single nucleotide variant
Location: chr22:44848946 (GRCh38)
Gene constraint: LOEUF 1.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.51
Residue 286 UniProt numbering: the rho-gap domain

Full ARHGAP8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP8 p.Ile374= Benign ★★ same type
ARHGAP8 p.Pro176Leu Benign ★★ same type
ARHGAP8 p.Ala235Thr Uncertain significance ★ ⚠ same type
ARHGAP8 p.Ala362Thr Uncertain significance ★ ⚠ same type
ARHGAP8 p.Ala386Val Uncertain significance ★ ⚠ same type
ARHGAP8 p.Ala413Val Uncertain significance ★ ⚠ same type
ARHGAP8 p.Arg162Gly Uncertain significance ★ ⚠ same type
ARHGAP8 p.Arg185Gln 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/arhgap8-p-phe255val (accessed [today's date]).

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