Is ARHGAP4 p.Arg334Cys (c.1000C>T) pathogenic?

ARHGAP4 p.Arg334Cys (c.1000C>T) is classified Uncertain significance in ARHGAP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-15). AlphaMissense: likely benign (0.0943); Ultra-rare (popmax 0.0218%, amr).

How common is ARHGAP4 p.Arg334Cys (c.1000C>T) in the general population?

ARHGAP4 p.Arg334Cys (c.1000C>T) is ultra-rare (popmax 0.0218%, amr) (gnomAD).

What do computational predictors say about ARHGAP4 p.Arg334Cys (c.1000C>T)?

AlphaMissense predicts likely benign (score 0.0943) — an in-silico prediction, not a clinical call.

ARHGAP4 p.Arg334Cys

c.1000C>T · rs201244043 · VCV2458378

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0943 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0218%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0943	likely benign
REVEL	0.123	moderately benign-leaning
SaProt	LLR -10.25	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	Δ0.25	donor gain · deltas
Constraint at this position
Conservation	phyloP 7.4	GERP -0.64, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 15 kb · p 5.9e-06 · 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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0218% Admixed American · 10/45,942 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00851% 103/1,211,019 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0218%	4,594
European (non-Finnish)	0.0101%	9,948
Remaining individualsnot grpmax-eligible	0.0042%	23,812
African / African-American	0.00174%	57,498

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.Arg334Cys
Coding: c.1000C>T
MANE Select: NM_001666
dbSNP: rs201244043
Type: single nucleotide variant
Location: chrX:153918864 (GRCh38)
Structure: AlphaFold pLDDT 76.48 · 1 PDB

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-arg334cys (accessed [today's date]).

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