Is ARHGAP23 p.Arg476Trp (c.1426C>T) pathogenic?

ARHGAP23 p.Arg476Trp (c.1426C>T) is classified Uncertain significance in ARHGAP23 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-13). AlphaMissense: likely benign (0.1007); Ultra-rare (popmax 0.0216%, amr).

How common is ARHGAP23 p.Arg476Trp (c.1426C>T) in the general population?

ARHGAP23 p.Arg476Trp (c.1426C>T) is ultra-rare (popmax 0.0216%, amr) (gnomAD).

What do computational predictors say about ARHGAP23 p.Arg476Trp (c.1426C>T)?

AlphaMissense predicts likely benign (score 0.1007) — an in-silico prediction, not a clinical call.

ARHGAP23 p.Arg476Trp

c.1426C>T · rs752560672 · VCV2351775

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1007 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0216%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1007	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -8.22	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 1.5	GERP -0.61, phastCons 0.9
Overall
CADD	22.0	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 0.0216% Admixed American · 11/50,976 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00932%

Overall 0.00826% 128/1,550,292 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0216%	4,634
Remaining individualsnot grpmax-eligible	0.0117%	8,580
European (non-Finnish)	0.00907%	11,026
South Asian	0.00357%	28,012
East Asian	0.00244%	40,906
Finnishnot grpmax-eligible	0.0017%	58,960
African / African-American	0.00137%	73,062

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: ARHGAP23
Protein: p.Arg476Trp
Coding: c.1426C>T
MANE Select: NM_001199417
dbSNP: rs752560672
Type: single nucleotide variant
Location: chr17:38467109 (GRCh38)
Gene constraint: LOEUF 0.414 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.82
Residue 476: the 'disordered' region

Full ARHGAP23 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP23 p.Arg476Gln Uncertain significance ★ ⚠ same residue
ARHGAP23 p.Arg476Gly Uncertain significance ★ ⚠ same residue
ARHGAP23 p.Ala1010Thr Uncertain significance ★ ⚠ same type
ARHGAP23 p.Ala1010Val Uncertain significance ★ ⚠ same type
ARHGAP23 p.Ala1153Val Uncertain significance ★ ⚠ same type
ARHGAP23 p.Ala1222Val Uncertain significance ★ ⚠ same type
ARHGAP23 p.Ala1324Val Uncertain significance ★ ⚠ same type
ARHGAP23 p.Ala1340Thr 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/arhgap23-p-arg476trp (accessed [today's date]).

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