Is ARHGAP4 p.Gln489Arg (c.1466A>G) pathogenic?

ARHGAP4 p.Gln489Arg (c.1466A>G) is classified Uncertain significance in ARHGAP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-26). AlphaMissense: likely benign (0.0783); Very rare (popmax 0.00348%, afr).

How common is ARHGAP4 p.Gln489Arg (c.1466A>G) in the general population?

ARHGAP4 p.Gln489Arg (c.1466A>G) is very rare (popmax 0.00348%, afr) (gnomAD).

What do computational predictors say about ARHGAP4 p.Gln489Arg (c.1466A>G)?

AlphaMissense predicts likely benign (score 0.0783) — an in-silico prediction, not a clinical call.

ARHGAP4 p.Gln489Arg

c.1466A>G · VCV3424162

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0783 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00348%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0783	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -3.67	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 1.4	GERP -0.41, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 15 kb · p 5.9e-06 · regional, not allelic
Overall
CADD	16.52	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 0.00348% African / African-American · 2/57,400 alleles

Filtering AF 0.000578% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000216%

Overall 0.000661% 8/1,209,683 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00348%	28,700
South Asian	0.00176%	56,797
European (non-Finnish)	0.000559%	178,910

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.Gln489Arg
Coding: c.1466A>G
MANE Select: NM_001666
Type: single nucleotide variant
Location: chrX:153912776 (GRCh38)
Structure: AlphaFold pLDDT 76.48 · 1 PDB

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

Similar variants

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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
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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-gln489arg (accessed [today's date]).

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