Is ARHGAP22 p.Phe153Ser (c.458T>C) pathogenic?

ARHGAP22 p.Phe153Ser (c.458T>C) is classified Uncertain significance in ARHGAP22 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-09). AlphaMissense: likely pathogenic (0.9895); Very rare (popmax 8.48e-05%, nfe).

How common is ARHGAP22 p.Phe153Ser (c.458T>C) in the general population?

ARHGAP22 p.Phe153Ser (c.458T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ARHGAP22 p.Phe153Ser (c.458T>C)?

AlphaMissense predicts likely pathogenic (score 0.9895) — an in-silico prediction, not a clinical call.

ARHGAP22 p.Phe153Ser

c.458T>C · rs2539711044 · VCV3128626

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9895 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9895	likely pathogenic · top 3% in ARHGAP22
REVEL	0.742	pathogenic-leaning
SaProt	LLR -9.01	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 158 kb · p 0.069 · regional, not allelic
Overall
CADD	27.5	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 8.48e-05% European (non-Finnish) · 1/1,179,806 alleles

Overall 6.2e-05% 1/1,612,008 alleles · very rare exomes 1/1,459,698 · genomes 0/152,310 · joint denominator

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.Phe153Ser
Coding: c.458T>C
MANE Select: NM_021226
dbSNP: rs2539711044
Type: single nucleotide variant
Location: chr10:48459885 (GRCh38)
Gene constraint: LOEUF 1.141 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.00

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

Similar variants

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
ARHGAP22 p.Ala351Thr 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-phe153ser (accessed [today's date]).

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