Is ARHGAP23 p.Arg644Cys (c.1930C>T) pathogenic?

ARHGAP23 p.Arg644Cys (c.1930C>T) is classified Uncertain significance in ARHGAP23 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: ambiguous (0.4598); Ultra-rare (popmax 0.0167%, mid).

How common is ARHGAP23 p.Arg644Cys (c.1930C>T) in the general population?

ARHGAP23 p.Arg644Cys (c.1930C>T) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about ARHGAP23 p.Arg644Cys (c.1930C>T)?

AlphaMissense predicts ambiguous (score 0.4598) — an in-silico prediction, not a clinical call.

ARHGAP23 p.Arg644Cys

c.1930C>T · rs751152407 · VCV2554704

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4598 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4598	ambiguous
REVEL	0.164	moderately benign-leaning
SaProt	LLR -9.91	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 4.9	GERP 2.1, phastCons 1
Overall
CADD	26.5	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 0.0167% Middle Eastern · 1/5,990 alleles

Filtering AF 0.0108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.00973% 151/1,551,682 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,990
European (non-Finnish)	0.0125%	8,021
Admixed American	0.00588%	17,005
Remaining individualsnot grpmax-eligible	0.00499%	20,037
South Asian	0.00119%	84,062

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.Arg644Cys
Coding: c.1930C>T
MANE Select: NM_001199417
dbSNP: rs751152407
Type: single nucleotide variant
Location: chr17:38469860 (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.Arg644His 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
ARHGAP23 p.Ala1363Val 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-arg644cys (accessed [today's date]).

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