Is ARHGAP23 p.Ala754Val (c.2261C>T) pathogenic?

ARHGAP23 p.Ala754Val (c.2261C>T) is classified Uncertain significance in ARHGAP23 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: likely benign (0.0994); Ultra-rare (popmax 0.0393%, eas).

How common is ARHGAP23 p.Ala754Val (c.2261C>T) in the general population?

ARHGAP23 p.Ala754Val (c.2261C>T) is ultra-rare (popmax 0.0393%, eas) (gnomAD).

What do computational predictors say about ARHGAP23 p.Ala754Val (c.2261C>T)?

AlphaMissense predicts likely benign (score 0.0994) — an in-silico prediction, not a clinical call.

ARHGAP23 p.Ala754Val

c.2261C>T · rs1405163893 · VCV2468577

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0994 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0393%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0994	likely benign
REVEL	0.273	benign-leaning
SaProt	LLR -7.21	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 5.8	GERP -1, phastCons 1
Overall
CADD	25.0	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 0.0393% East Asian · 16/40,700 alleles

Filtering AF 0.0246% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.02%

Overall 0.00414% 64/1,544,196 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0393%	2,544
Middle Eastern	0.0192%	5,196
African / African-American	0.0151%	6,619
Remaining individualsnot grpmax-eligible	0.0117%	8,530
South Asian	0.00238%	41,982
European (non-Finnish)	0.00236%	42,368

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.Ala754Val
Coding: c.2261C>T
MANE Select: NM_001199417
dbSNP: rs1405163893
Type: single nucleotide variant
Location: chr17:38477721 (GRCh38)
Gene constraint: LOEUF 0.414 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.82
Residue 754: the ph domain

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

Similar variants

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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
ARHGAP23 p.Ala1363Val Uncertain significance ★ ⚠ same type
ARHGAP23 p.Ala1457Val 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-ala754val (accessed [today's date]).

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