Is ARHGAP40 p.Leu445Phe (c.1333C>T) pathogenic?

ARHGAP40 p.Leu445Phe (c.1333C>T) is classified Uncertain significance in ARHGAP40 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-15). AlphaMissense: likely pathogenic (0.6022); Absent from gnomAD v4.1.

How common is ARHGAP40 p.Leu445Phe (c.1333C>T) in the general population?

ARHGAP40 p.Leu445Phe (c.1333C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ARHGAP40 p.Leu445Phe (c.1333C>T)?

AlphaMissense predicts likely pathogenic (score 0.6022) — an in-silico prediction, not a clinical call.

ARHGAP40 p.Leu445Phe

c.1333C>T · rs2516765327 · VCV2261374

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6022 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.6022	likely pathogenic
REVEL	0.798	moderately pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP 1.9, phastCons 0.77
Regional constraint	o/e 0.85	unconstrained · MANE · 48 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	24.1	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L392F vs ClinVar L445F) — 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.Leu445Phe
Coding: c.1333C>T
MANE Select: NM_001164431
dbSNP: rs2516765327
Type: single nucleotide variant
Location: chr20:38641779 (GRCh38)
Gene constraint: LOEUF 0.718 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.96
Residue 445: 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-leu445phe (accessed [today's date]).

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