Is ARHGAP23 p.Arg428His (c.1283G>A) pathogenic?

ARHGAP23 p.Arg428His (c.1283G>A) is classified Uncertain significance in ARHGAP23 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: ambiguous (0.4906); Very rare (popmax 0.00489%, eas).

How common is ARHGAP23 p.Arg428His (c.1283G>A) in the general population?

ARHGAP23 p.Arg428His (c.1283G>A) is very rare (popmax 0.00489%, eas) (gnomAD).

What do computational predictors say about ARHGAP23 p.Arg428His (c.1283G>A)?

AlphaMissense predicts ambiguous (score 0.4906) — an in-silico prediction, not a clinical call.

ARHGAP23 p.Arg428His

c.1283G>A · VCV3939215

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4906 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00489%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4906	ambiguous
REVEL	0.13	moderately benign-leaning
SaProt	LLR -8.70	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.6, phastCons 1
Overall
CADD	26.1	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 0.00489% East Asian · 2/40,910 alleles

Filtering AF 0.00142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00119%

Overall 0.00186% 26/1,398,138 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00489%	20,455
European (non-Finnish)	0.00209%	47,789

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.Arg428His
Coding: c.1283G>A
MANE Select: NM_001199417
Type: single nucleotide variant
Location: chr17:38466966 (GRCh38)
Gene constraint: LOEUF 0.414 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.82

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-arg428his (accessed [today's date]).

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