Is ARHGAP12 p.Arg74Cys (c.220C>T) pathogenic?

ARHGAP12 p.Arg74Cys (c.220C>T) is classified Uncertain significance in ARHGAP12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: ambiguous (0.378); Ultra-rare (popmax 0.0131%, nfe).

How common is ARHGAP12 p.Arg74Cys (c.220C>T) in the general population?

ARHGAP12 p.Arg74Cys (c.220C>T) is ultra-rare (popmax 0.0131%, nfe) (gnomAD).

What do computational predictors say about ARHGAP12 p.Arg74Cys (c.220C>T)?

AlphaMissense predicts ambiguous (score 0.378) — an in-silico prediction, not a clinical call.

ARHGAP12 p.Arg74Cys

c.220C>T · VCV4828103

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.378 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0131%, nfe)

Computational evidence

Protein change
AlphaMissense	0.378	ambiguous
REVEL	0.344	indeterminate
SaProt	LLR -10.45	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 101 kb · p 0.038 · regional, not allelic
Overall
CADD	28.0	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 0.0131% European (non-Finnish) · 154/1,180,030 alleles

Filtering AF 0.0113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0107%

Overall 0.0103% 166/1,614,002 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0131%	7,663
African / African-American	0.00935%	10,697
Remaining individualsnot grpmax-eligible	0.0032%	31,242
South Asian	0.0022%	45,546
Finnishnot grpmax-eligible	0.00156%	64,016

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.Arg74Cys
Coding: c.220C>T
MANE Select: NM_018287
Type: single nucleotide variant
Location: chr10:31908636 (GRCh38)
Gene constraint: LOEUF 0.681 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.68
Residue 74: the sh3 domain

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

Similar variants

ARHGAP12 p.Arg74His Uncertain significance ★ ⚠ same residue
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

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-arg74cys (accessed [today's date]).

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