Is ARHGAP23 p.Ser1265Arg (c.3795C>G) pathogenic?

ARHGAP23 p.Ser1265Arg (c.3795C>G) is classified Uncertain significance in ARHGAP23 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-17). AlphaMissense: likely benign (0.218); Very rare (popmax 0.000393%, nfe).

How common is ARHGAP23 p.Ser1265Arg (c.3795C>G) in the general population?

ARHGAP23 p.Ser1265Arg (c.3795C>G) is very rare (popmax 0.000393%, nfe) (gnomAD).

What do computational predictors say about ARHGAP23 p.Ser1265Arg (c.3795C>G)?

AlphaMissense predicts likely benign (score 0.218) — an in-silico prediction, not a clinical call.

ARHGAP23 p.Ser1265Arg

c.3795C>G · VCV3890157

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.218 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000393%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.218	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -7.67	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 -2.1	GERP -1.4
Overall
CADD	2.322	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 0.000393% European (non-Finnish) · 4/1,017,550 alleles

Filtering AF 9.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.2e-05%

Overall 0.000311% 4/1,287,080 alleles · very rare

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.Ser1265Arg
Coding: c.3795C>G
MANE Select: NM_001199417
Type: single nucleotide variant
Location: chr17:38510291 (GRCh38)
Gene constraint: LOEUF 0.414 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.82
Residue 1265: 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-ser1265arg (accessed [today's date]).

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