Is ARHGAP8 p.Pro384Ala (c.1150C>G) pathogenic?

ARHGAP8 p.Pro384Ala (c.1150C>G) is classified Uncertain significance in ARHGAP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-31). AlphaMissense: likely benign (0.0595); Ultra-rare (popmax 0.0349%, nfe).

How common is ARHGAP8 p.Pro384Ala (c.1150C>G) in the general population?

ARHGAP8 p.Pro384Ala (c.1150C>G) is ultra-rare (popmax 0.0349%, nfe) (gnomAD).

What do computational predictors say about ARHGAP8 p.Pro384Ala (c.1150C>G)?

AlphaMissense predicts likely benign (score 0.0595) — an in-silico prediction, not a clinical call.

ARHGAP8 p.Pro384Ala

c.1150C>G · rs566631776 · VCV3128939

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0595 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0349%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0595	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -8.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.74	GERP 1.2, phastCons 0.003
Regional constraint	o/e 1.62	unconstrained · MANE · 76 kb · p 4.7e-50 · regional, not allelic
Overall
CADD	2.831	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 P415A vs ClinVar P384A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0349% European (non-Finnish) · 412/1,179,996 alleles

Filtering AF 0.0321% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.031%

Overall 0.0299% 483/1,614,082 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.115%	871
European (non-Finnish)grpmax	0.0349%	2,864
Remaining individualsnot grpmax-eligible	0.0272%	3,677
Admixed American	0.025%	4,002
African / African-American	0.004%	25,009
East Asian	0.00223%	44,860
Finnishnot grpmax-eligible	0.00156%	64,008

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro384Ala
Coding: c.1150C>G
MANE Select: NM_181335
dbSNP: rs566631776
Type: single nucleotide variant
Location: chr22:44862443 (GRCh38)
Gene constraint: LOEUF 1.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.51
Residue 384: 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-pro384ala (accessed [today's date]).

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