Is ARHGAP1 p.Pro42Arg (c.125C>G) pathogenic?

ARHGAP1 p.Pro42Arg (c.125C>G) is classified Uncertain significance in ARHGAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: likely benign (0.1125); Ultra-rare (popmax 0.0867%, sas).

How common is ARHGAP1 p.Pro42Arg (c.125C>G) in the general population?

ARHGAP1 p.Pro42Arg (c.125C>G) is ultra-rare (popmax 0.0867%, sas) (gnomAD).

What do computational predictors say about ARHGAP1 p.Pro42Arg (c.125C>G)?

AlphaMissense predicts likely benign (score 0.1125) — an in-silico prediction, not a clinical call.

ARHGAP1 p.Pro42Arg

c.125C>G · VCV4642080

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1125 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0867%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1125	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -8.08	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 17 kb · p 0.00064 · regional, not allelic
Overall
CADD	24.3	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 0.0867% South Asian · 79/91,086 alleles

Filtering AF 0.0713% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0656%

Overall 0.007% 113/1,614,186 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0867%	1,153
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0064%	15,628
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
European (non-Finnish)	0.00229%	43,705

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: ARHGAP1
Protein: p.Pro42Arg
Coding: c.125C>G
MANE Select: NM_004308
Type: single nucleotide variant
Location: chr11:46695983 (GRCh38)
Gene constraint: LOEUF 0.601 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 82.64 · 11 PDB
Residue 42: the 'disordered' region

Full ARHGAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP1 p.Leu263Phe Benign ★★ same type
ARHGAP1 p.Pro52= Benign ★★ same type
ARHGAP1 p.Ala225Ser Uncertain significance ★ ⚠ same type
ARHGAP1 p.Ala26Val Uncertain significance ★ ⚠ same type
ARHGAP1 p.Ala373Thr Uncertain significance ★ ⚠ same type
ARHGAP1 p.Ala68Pro Uncertain significance ★ ⚠ same type
ARHGAP1 p.Arg234Gln Uncertain significance ★ ⚠ same type
ARHGAP1 p.Arg234Trp 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/arhgap1-p-pro42arg (accessed [today's date]).

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