Is ARHGAP12 p.Ala753Ser (c.2257G>T) pathogenic?

ARHGAP12 p.Ala753Ser (c.2257G>T) is classified Uncertain significance in ARHGAP12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: likely benign (0.2221); Absent from gnomAD v4.1.

How common is ARHGAP12 p.Ala753Ser (c.2257G>T) in the general population?

ARHGAP12 p.Ala753Ser (c.2257G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ARHGAP12 p.Ala753Ser (c.2257G>T)?

AlphaMissense predicts likely benign (score 0.2221) — an in-silico prediction, not a clinical call.

ARHGAP12 p.Ala753Ser

c.2257G>T · VCV4133155

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2221 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2221	likely benign
REVEL	0.311	indeterminate
SaProt	LLR -9.71	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 101 kb · p 0.038 · regional, not allelic
Overall
CADD	27.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ARHGAP12
Protein: p.Ala753Ser
Coding: c.2257G>T
MANE Select: NM_018287
Type: single nucleotide variant
Location: chr10:31809000 (GRCh38)
Gene constraint: LOEUF 0.681 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.68
Residue 753: the rho-gap domain

Full ARHGAP12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP12 p.Arg6= Benign ★★ same type
ARHGAP12 p.Ala393Val Uncertain significance ★ ⚠ same type
ARHGAP12 p.Ala458Ser Uncertain significance ★ ⚠ same type
ARHGAP12 p.Ala458Val Uncertain significance ★ ⚠ same type
ARHGAP12 p.Ala491Ser Uncertain significance ★ ⚠ same type
ARHGAP12 p.Ala491Val Uncertain significance ★ ⚠ same type
ARHGAP12 p.Ala698Thr Uncertain significance ★ ⚠ same type
ARHGAP12 p.Arg175His 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/arhgap12-p-ala753ser (accessed [today's date]).

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