Is ARHGAP11A p.Pro423Ser (c.1267C>T) pathogenic?

ARHGAP11A p.Pro423Ser (c.1267C>T) is classified Uncertain significance in ARHGAP11A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-02). AlphaMissense: likely pathogenic (0.6502); Very rare (popmax 0.00452%, sas).

How common is ARHGAP11A p.Pro423Ser (c.1267C>T) in the general population?

ARHGAP11A p.Pro423Ser (c.1267C>T) is very rare (popmax 0.00452%, sas) (gnomAD).

What do computational predictors say about ARHGAP11A p.Pro423Ser (c.1267C>T)?

AlphaMissense predicts likely pathogenic (score 0.6502) — an in-silico prediction, not a clinical call.

ARHGAP11A p.Pro423Ser

c.1267C>T · rs1347626253 · VCV3128480

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6502 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00452%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6502	likely pathogenic · top 10% in ARHGAP11A
REVEL	0.76	pathogenic-leaning
SaProt	LLR -6.06	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 8,081 bp · p 0.57 · regional, not allelic
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 0.00452% South Asian · 4/88,514 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000911%

Overall 0.000561% 9/1,604,434 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00452%	22,128
European (non-Finnish)	0.000425%	235,466

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: ARHGAP11A
Protein: p.Pro423Ser
Coding: c.1267C>T
MANE Select: NM_014783
dbSNP: rs1347626253
Type: single nucleotide variant
Location: chr15:32633964 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 51.52 · 1 PDB

Full ARHGAP11A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP11A c.1235+5T>G Benign ★★ same type
ARHGAP11A p.Arg400= Benign ★★ same type
ARHGAP11A p.Asn978= Benign ★★ same type
ARHGAP11A p.Gln903= Benign ★★ same type
ARHGAP11A p.Pro366= Benign ★★ same type
ARHGAP11A p.Ala112Ser Uncertain significance ★ ⚠ same type
ARHGAP11A p.Ala112Val Uncertain significance ★ ⚠ same type
ARHGAP11A p.Ala235Thr 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/arhgap11a-p-pro423ser (accessed [today's date]).

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