Is ARHGAP22 p.Pro30Arg (c.89C>G) pathogenic?

ARHGAP22 p.Pro30Arg (c.89C>G) is classified Uncertain significance in ARHGAP22 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely benign (0.1028); Very rare (popmax 0.00167%, amr).

How common is ARHGAP22 p.Pro30Arg (c.89C>G) in the general population?

ARHGAP22 p.Pro30Arg (c.89C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ARHGAP22 p.Pro30Arg (c.89C>G)?

AlphaMissense predicts likely benign (score 0.1028) — an in-silico prediction, not a clinical call.

ARHGAP22 p.Pro30Arg

c.89C>G · VCV3939041

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1028 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1028	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -7.61	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 1.2	GERP -3.3, phastCons 0.22
Regional constraint	o/e 1.06	unconstrained · MANE · 158 kb · p 0.069 · regional, not allelic
Overall
CADD	6.922	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 0.00167% Admixed American · 1/60,028 alleles

Overall 0.000186% 3/1,614,254 alleles · very rare exomes 3/1,461,864 · genomes 0/152,390 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,028
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	8.47e-05%	1,180,052

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: ARHGAP22
Protein: p.Pro30Arg
Coding: c.89C>G
MANE Select: NM_021226
Type: single nucleotide variant
Location: chr10:48583098 (GRCh38)
Gene constraint: LOEUF 1.141 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.00
Residue 30: the 'disordered' region

Full ARHGAP22 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP22 p.Pro30Leu Uncertain significance ★ ⚠ same residue
ARHGAP22 p.Ala662= Benign ★★ same type
MAPK8 c.*154A>G Benign ★★ same type
MAPK8 p.Ser393= Benign ★★ same type
ARHGAP22 c.660-2A>G Uncertain significance ★ same type
ARHGAP22 p.Ala172Val Uncertain significance ★ ⚠ same type
ARHGAP22 p.Ala200Ser Uncertain significance ★ ⚠ same type
ARHGAP22 p.Ala246Ser 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/arhgap22-p-pro30arg (accessed [today's date]).

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