Is ARHGAP12 p.Pro295Arg (c.884C>G) pathogenic?

ARHGAP12 p.Pro295Arg (c.884C>G) is classified Uncertain significance in ARHGAP12 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-19). AlphaMissense: likely pathogenic (0.9536); Very rare (popmax 0.00449%, nfe).

How common is ARHGAP12 p.Pro295Arg (c.884C>G) in the general population?

ARHGAP12 p.Pro295Arg (c.884C>G) is very rare (popmax 0.00449%, nfe) (gnomAD).

What do computational predictors say about ARHGAP12 p.Pro295Arg (c.884C>G)?

AlphaMissense predicts likely pathogenic (score 0.9536) — an in-silico prediction, not a clinical call.

ARHGAP12 p.Pro295Arg

c.884C>G · VCV3310819

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9536 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00449%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9536	likely pathogenic
REVEL	0.695	pathogenic-leaning
SaProt	LLR -11.73	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 101 kb · p 0.038 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00449% European (non-Finnish) · 53/1,180,034 alleles

Filtering AF 0.0035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00318%

Overall 0.00341% 55/1,614,046 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00449%	22,265
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00133%	74,922

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.Pro295Arg
Coding: c.884C>G
MANE Select: NM_018287
Type: single nucleotide variant
Location: chr10:31861459 (GRCh38)
Gene constraint: LOEUF 0.681 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.68
Residue 295: the ww 1 domain; the 'disordered' region

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.Ala753Ser 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-pro295arg (accessed [today's date]).

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