Is ARHGAP4 p.Ser76Ile (c.227G>T) pathogenic?

ARHGAP4 p.Ser76Ile (c.227G>T) is classified Uncertain significance in ARHGAP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-20). AlphaMissense: likely benign (0.1595); Ultra-rare (popmax 0.0385%, eas).

How common is ARHGAP4 p.Ser76Ile (c.227G>T) in the general population?

ARHGAP4 p.Ser76Ile (c.227G>T) is ultra-rare (popmax 0.0385%, eas) (gnomAD).

What do computational predictors say about ARHGAP4 p.Ser76Ile (c.227G>T)?

AlphaMissense predicts likely benign (score 0.1595) — an in-silico prediction, not a clinical call.

ARHGAP4 p.Ser76Ile

c.227G>T · rs782801752 · VCV3128839

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1595 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0385%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1595	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -10.01	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -0.89, phastCons 0.99
Regional constraint	o/e 0.80	unconstrained · MANE · 15 kb · p 5.9e-06 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0385% East Asian · 13/33,743 alleles

Filtering AF 0.0228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.018%

Overall 0.00405% 49/1,208,827 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0385%	2,596
South Asian	0.0265%	3,777
Middle Eastern	0.023%	4,350
Remaining individualsnot grpmax-eligible	0.00843%	11,866
European (non-Finnish)	0.00179%	55,917

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: ARHGAP4
Protein: p.Ser76Ile
Coding: c.227G>T
MANE Select: NM_001666
dbSNP: rs782801752
Type: single nucleotide variant
Location: chrX:153921650 (GRCh38)
Structure: AlphaFold pLDDT 76.48 · 1 PDB
Residue 76: the f-bar domain

Full ARHGAP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP4 p.Val705Ile Uncertain significance ★★ ⚠ same type
ARHGAP4 c.2415-4G>A Benign ★★ same type
ARHGAP4 c.2608-6C>T Benign ★★ same type
ARHGAP4 p.Asp420= Benign ★★ same type
ARHGAP4 p.His572= Benign ★★ same type
ARHGAP4 p.Pro627= Benign ★★ same type
ARHGAP4 c.682-292A>C Uncertain significance ★ same type
ARHGAP4 c.682-302C>G 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/arhgap4-p-ser76ile (accessed [today's date]).

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