Is ARHGAP39 p.Trp475Arg (c.1423T>C) pathogenic?

ARHGAP39 p.Trp475Arg (c.1423T>C) is classified Uncertain significance in ARHGAP39 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely pathogenic (0.9027); Very rare (popmax 0.00135%, afr).

How common is ARHGAP39 p.Trp475Arg (c.1423T>C) in the general population?

ARHGAP39 p.Trp475Arg (c.1423T>C) is very rare (popmax 0.00135%, afr) (gnomAD).

What do computational predictors say about ARHGAP39 p.Trp475Arg (c.1423T>C)?

AlphaMissense predicts likely pathogenic (score 0.9027) — an in-silico prediction, not a clinical call.

ARHGAP39 p.Trp475Arg

c.1423T>C · VCV4831742

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9027 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9027	likely pathogenic
REVEL	0.297	indeterminate
SaProt	LLR -5.83	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 35 kb · p 0.0019 · regional, not allelic
Overall
CADD	23.8	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 0.00135% African / African-American · 1/74,166 alleles

Overall 7.11e-05% 1/1,406,152 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: ARHGAP39
Protein: p.Trp475Arg
Coding: c.1423T>C
MANE Select: NM_025251
Type: single nucleotide variant
Location: chr8:144547663 (GRCh38)
Gene constraint: LOEUF 0.658 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.42
Residue 475: the 'disordered' region

Full ARHGAP39 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP39 p.Arg933Cys Uncertain significance ★★ ⚠ same type
ARHGAP39 p.Ala227= Benign ★★ same type
ARHGAP39 p.Thr818= Benign ★★ same type
ARHGAP39 p.Ala1033Val Uncertain significance ★ ⚠ same type
ARHGAP39 p.Ala1056Val Uncertain significance ★ ⚠ same type
ARHGAP39 p.Ala120Val Uncertain significance ★ ⚠ same type
ARHGAP39 p.Ala322Asp Uncertain significance ★ ⚠ same type
ARHGAP39 p.Ala322Thr 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/arhgap39-p-trp475arg (accessed [today's date]).

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