Is ARHGAP4 p.Phe593Leu (c.1779C>A) pathogenic?

ARHGAP4 p.Phe593Leu (c.1779C>A) is classified Uncertain significance in ARHGAP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-25). AlphaMissense: likely pathogenic (0.8369); Ultra-rare (popmax 0.082%, eas).

How common is ARHGAP4 p.Phe593Leu (c.1779C>A) in the general population?

ARHGAP4 p.Phe593Leu (c.1779C>A) is ultra-rare (popmax 0.082%, eas) (gnomAD).

What do computational predictors say about ARHGAP4 p.Phe593Leu (c.1779C>A)?

AlphaMissense predicts likely pathogenic (score 0.8369) — an in-silico prediction, not a clinical call.

ARHGAP4 p.Phe593Leu

c.1779C>A · rs782693083 · VCV2599762

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8369 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.082%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8369	likely pathogenic
REVEL	0.218	benign-leaning
SaProt	LLR -7.28	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 1.1	GERP -2, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 3,070 bp · p 0.006 · regional, not allelic
Overall
CADD	21.2	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 0.082% East Asian · 27/32,931 alleles

Filtering AF 0.0579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0497%

Overall 0.00252% 30/1,192,588 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.082%	1,220
African / African-American	0.00351%	28,516
Admixed American	0.00226%	44,220

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.Phe593Leu
Coding: c.1779C>A
MANE Select: NM_001666
dbSNP: rs782693083
Type: single nucleotide variant
Location: chrX:153910737 (GRCh38)
Structure: AlphaFold pLDDT 76.48 · 1 PDB
Residue 593: 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-phe593leu (accessed [today's date]).

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