Is ARHGAP23 p.Arg528His (c.1583G>A) pathogenic?

ARHGAP23 p.Arg528His (c.1583G>A) is classified Likely benign in ARHGAP23 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-01). AlphaMissense: likely benign (0.0645); Low-frequency (popmax 1.16%, nfe).

How common is ARHGAP23 p.Arg528His (c.1583G>A) in the general population?

ARHGAP23 p.Arg528His (c.1583G>A) is low-frequency (popmax 1.16%, nfe) (gnomAD).

What do computational predictors say about ARHGAP23 p.Arg528His (c.1583G>A)?

AlphaMissense predicts likely benign (score 0.0645) — an in-silico prediction, not a clinical call.

ARHGAP23 p.Arg528His

c.1583G>A · rs138289112 · VCV2647699

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0645 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.16%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0645	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -8.20	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 4	GERP -0.29, phastCons 1
Overall
CADD	21.6	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 1.16% European (non-Finnish) · 13,239/1,144,438 alleles

Filtering AF 1.14% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.13%

Overall 0.925% 14,309/1,546,288 alleles · low-frequency

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.16%	86
Remaining individualsnot grpmax-eligible	0.915%	109
Amishnot grpmax-eligible	0.768%	130
Admixed American	0.456%	219
African / African-American	0.199%	503
Ashkenazi Jewishnot grpmax-eligible	0.176%	568
Finnishnot grpmax-eligible	0.131%	765
Middle Eastern	0.0839%	1,192
South Asian	0.012%	8,342

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.Arg528His
Coding: c.1583G>A
MANE Select: NM_001199417
dbSNP: rs138289112
Type: single nucleotide variant
Location: chr17:38467266 (GRCh38)
Gene constraint: LOEUF 0.414 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.82
Residue 528: the 'disordered' region

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

Similar variants

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
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-arg528his (accessed [today's date]).

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