Is ARHGAP1 p.Pro398Ser (c.1192C>T) pathogenic?

ARHGAP1 p.Pro398Ser (c.1192C>T) is classified Uncertain significance in ARHGAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-31). AlphaMissense: likely pathogenic (0.9937); Very rare (popmax 6.84e-05%).

How common is ARHGAP1 p.Pro398Ser (c.1192C>T) in the general population?

ARHGAP1 p.Pro398Ser (c.1192C>T) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about ARHGAP1 p.Pro398Ser (c.1192C>T)?

AlphaMissense predicts likely pathogenic (score 0.9937) — an in-silico prediction, not a clinical call.

ARHGAP1 p.Pro398Ser

c.1192C>T · rs2064503899 · VCV3128455

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9937 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9937	likely pathogenic · top 7% in ARHGAP1
REVEL	0.431	indeterminate
SaProt	LLR -14.27	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 17 kb · p 0.00064 · regional, not allelic
Overall
CADD	28.5	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 6.84e-05%

Overall 6.84e-05% 1/1,461,244 alleles · very rare

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.Pro398Ser
Coding: c.1192C>T
MANE Select: NM_004308
dbSNP: rs2064503899
Type: single nucleotide variant
Location: chr11:46679165 (GRCh38)
Gene constraint: LOEUF 0.601 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 82.64 · 11 PDB
Residue 398: the rho-gap domain; an α-helix

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-pro398ser (accessed [today's date]).

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