Is ARHGAP8 p.Ser296Arg (c.886A>C) pathogenic?

ARHGAP8 p.Ser296Arg (c.886A>C) is classified Likely benign in ARHGAP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-04-10). AlphaMissense: likely pathogenic (0.9328); Rare (popmax 0.421%, afr).

How common is ARHGAP8 p.Ser296Arg (c.886A>C) in the general population?

ARHGAP8 p.Ser296Arg (c.886A>C) is rare (popmax 0.421%, afr) (gnomAD).

What do computational predictors say about ARHGAP8 p.Ser296Arg (c.886A>C)?

AlphaMissense predicts likely pathogenic (score 0.9328) — an in-silico prediction, not a clinical call.

ARHGAP8 p.Ser296Arg

c.886A>C · rs140395831 · VCV742556

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9328 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.421%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9328	likely pathogenic · top 3% in ARHGAP8
REVEL	0.279	benign-leaning
SaProt	LLR -6.92	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 8.3	GERP 0.4, phastCons 1
Regional constraint	o/e 1.62	unconstrained · MANE · 76 kb · p 4.7e-50 · regional, not allelic
Overall
CADD	24.2	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 S327R vs ClinVar S296R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.421% African / African-American · 316/75,010 alleles

Filtering AF 0.383% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.368%

Overall 0.0217% 350/1,613,622 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.421%	237
Remaining individualsnot grpmax-eligible	0.04%	2,500
Admixed American	0.0117%	8,574
European (non-Finnish)	0.000169%	589,998

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.Ser296Arg
Coding: c.886A>C
MANE Select: NM_181335
dbSNP: rs140395831
Type: single nucleotide variant
Location: chr22:44859739 (GRCh38)
Gene constraint: LOEUF 1.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.51
Residue 296: 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-ser296arg (accessed [today's date]).

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