Is ARHGAP40 p.Pro324Ser (c.970C>T) pathogenic?

ARHGAP40 p.Pro324Ser (c.970C>T) is classified Uncertain significance in ARHGAP40 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-01). AlphaMissense: likely benign (0.0998); Absent from gnomAD v4.1.

How common is ARHGAP40 p.Pro324Ser (c.970C>T) in the general population?

ARHGAP40 p.Pro324Ser (c.970C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ARHGAP40 p.Pro324Ser (c.970C>T)?

AlphaMissense predicts likely benign (score 0.0998) — an in-silico prediction, not a clinical call.

ARHGAP40 p.Pro324Ser

c.970C>T · VCV3941218

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.0998	likely benign
REVEL	0.145	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.19	GERP -1.7
Regional constraint	o/e 0.85	unconstrained · MANE · 48 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	3.162	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P271S vs ClinVar P324S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ARHGAP40
Protein: p.Pro324Ser
Coding: c.970C>T
MANE Select: NM_001164431
Type: single nucleotide variant
Location: chr20:38637728 (GRCh38)
Gene constraint: LOEUF 0.718 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.96
Residue 324: the rho-gap domain

Full ARHGAP40 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP40 p.Ala153Val Uncertain significance ★ ⚠ same type
ARHGAP40 p.Ala200Asp Uncertain significance ★ ⚠ same type
ARHGAP40 p.Ala227Asp Uncertain significance ★ ⚠ same type
ARHGAP40 p.Ala233Val Uncertain significance ★ ⚠ same type
ARHGAP40 p.Ala296Val Uncertain significance ★ ⚠ same type
ARHGAP40 p.Ala385Gly Uncertain significance ★ ⚠ same type
ARHGAP40 p.Ala398Thr Uncertain significance ★ ⚠ same type
ARHGAP40 p.Ala423Thr 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/arhgap40-p-pro324ser (accessed [today's date]).

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