Is ARHGAP8 p.Gln277Pro (c.830A>C) pathogenic?

ARHGAP8 p.Gln277Pro (c.830A>C) is classified Uncertain significance in ARHGAP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-19). AlphaMissense: ambiguous (0.4809); Very rare (popmax 0.000763%, nfe).

How common is ARHGAP8 p.Gln277Pro (c.830A>C) in the general population?

ARHGAP8 p.Gln277Pro (c.830A>C) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about ARHGAP8 p.Gln277Pro (c.830A>C)?

AlphaMissense predicts ambiguous (score 0.4809) — an in-silico prediction, not a clinical call.

ARHGAP8 p.Gln277Pro

c.830A>C · rs1264328406 · VCV3128983

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4809 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4809	ambiguous
REVEL	0.267	benign-leaning
SaProt	LLR -13.34	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.39, phastCons 1
Regional constraint	o/e 1.62	unconstrained · MANE · 76 kb · p 4.7e-50 · regional, not allelic
Overall
CADD	24.7	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 Q308P vs ClinVar Q277P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000763% European (non-Finnish) · 9/1,179,938 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,613,902 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: ARHGAP8
Protein: p.Gln277Pro
Coding: c.830A>C
MANE Select: NM_181335
dbSNP: rs1264328406
Type: single nucleotide variant
Location: chr22:44849013 (GRCh38)
Gene constraint: LOEUF 1.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.51
Residue 277: 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-gln277pro (accessed [today's date]).

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