Is ARHGAP23 p.Arg609Cys (c.1825C>T) pathogenic?

ARHGAP23 p.Arg609Cys (c.1825C>T) is classified Uncertain significance in ARHGAP23 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-12). AlphaMissense: likely pathogenic (0.7428); Ultra-rare (popmax 0.0343%, afr).

How common is ARHGAP23 p.Arg609Cys (c.1825C>T) in the general population?

ARHGAP23 p.Arg609Cys (c.1825C>T) is ultra-rare (popmax 0.0343%, afr) (gnomAD).

What do computational predictors say about ARHGAP23 p.Arg609Cys (c.1825C>T)?

AlphaMissense predicts likely pathogenic (score 0.7428) — an in-silico prediction, not a clinical call.

ARHGAP23 p.Arg609Cys

c.1825C>T · rs764868130 · VCV2349249

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7428 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0343%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7428	likely pathogenic
REVEL	0.166	moderately benign-leaning
SaProt	LLR -8.88	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Overall
CADD	28.1	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 0.0343% African / African-American · 25/72,970 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0203%

Overall 0.00265% 41/1,548,334 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0343%	2,919
Finnishnot grpmax-eligible	0.00169%	59,082
Remaining individualsnot grpmax-eligible	0.00167%	59,876
European (non-Finnish)	0.00122%	81,904

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.Arg609Cys
Coding: c.1825C>T
MANE Select: NM_001199417
dbSNP: rs764868130
Type: single nucleotide variant
Location: chr17:38469544 (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.Arg609His Uncertain significance ★ ⚠ same residue
ARHGAP23 p.Arg609Pro 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-arg609cys (accessed [today's date]).

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