Is ARHGAP4 p.Pro595Arg (c.1784C>G) pathogenic?

ARHGAP4 p.Pro595Arg (c.1784C>G) is classified Uncertain significance in ARHGAP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-03). AlphaMissense: likely benign (0.0883); Rare (popmax 0.122%, sas).

How common is ARHGAP4 p.Pro595Arg (c.1784C>G) in the general population?

ARHGAP4 p.Pro595Arg (c.1784C>G) is rare (popmax 0.122%, sas) (gnomAD).

What do computational predictors say about ARHGAP4 p.Pro595Arg (c.1784C>G)?

AlphaMissense predicts likely benign (score 0.0883) — an in-silico prediction, not a clinical call.

ARHGAP4 p.Pro595Arg

c.1784C>G · VCV3891288

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0883 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.122%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0883	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	LLR -6.34	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 1.8	GERP -3.1, phastCons 0.009
Regional constraint	o/e 1.15	unconstrained · MANE · 3,070 bp · p 0.006 · regional, not allelic
Overall
CADD	8.592	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.122% South Asian · 66/54,283 alleles

Filtering AF 0.098% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0894%

Overall 0.00864% 103/1,192,485 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.122%	822
African / African-American	0.0281%	3,563
Remaining individualsnot grpmax-eligible	0.00854%	11,713
East Asian	0.00304%	32,943
Admixed American	0.00227%	44,144
European (non-Finnish)	0.00169%	59,072

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.Pro595Arg
Coding: c.1784C>G
MANE Select: NM_001666
Type: single nucleotide variant
Location: chrX:153910732 (GRCh38)
Structure: AlphaFold pLDDT 76.48 · 1 PDB
Residue 595: the rho-gap 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-pro595arg (accessed [today's date]).

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