Is ARHGAP12 p.Ala458Val (c.1373C>T) pathogenic?

ARHGAP12 p.Ala458Val (c.1373C>T) is classified Uncertain significance in ARHGAP12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: likely benign (0.0751); Very rare (popmax 0.00518%, nfe).

How common is ARHGAP12 p.Ala458Val (c.1373C>T) in the general population?

ARHGAP12 p.Ala458Val (c.1373C>T) is very rare (popmax 0.00518%, nfe) (gnomAD).

What do computational predictors say about ARHGAP12 p.Ala458Val (c.1373C>T)?

AlphaMissense predicts likely benign (score 0.0751) — an in-silico prediction, not a clinical call.

ARHGAP12 p.Ala458Val

c.1373C>T · rs142038327 · VCV2564434

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0751 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00518%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0751	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -6.34	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1	GERP -0.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 101 kb · p 0.038 · regional, not allelic
Overall
CADD	16.03	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 0.00518% European (non-Finnish) · 61/1,177,354 alleles

Filtering AF 0.00411% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.00379% 61/1,609,272 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: ARHGAP12
Protein: p.Ala458Val
Coding: c.1373C>T
MANE Select: NM_018287
dbSNP: rs142038327
Type: single nucleotide variant
Location: chr10:31839318 (GRCh38)
Gene constraint: LOEUF 0.681 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.68
Residue 458: the 'disordered' region

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

Similar variants

ARHGAP12 p.Ala458Ser Uncertain significance ★ ⚠ same residue
ARHGAP12 p.Arg6= Benign ★★ same type
ARHGAP12 p.Ala393Val 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.Ala753Ser 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-ala458val (accessed [today's date]).

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