Is ARHGAP40 p.Ala508Ser (c.1522G>T) pathogenic?

ARHGAP40 p.Ala508Ser (c.1522G>T) is classified Uncertain significance in ARHGAP40 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: likely benign (0.1362); Very rare (popmax 0.00172%, nfe).

How common is ARHGAP40 p.Ala508Ser (c.1522G>T) in the general population?

ARHGAP40 p.Ala508Ser (c.1522G>T) is very rare (popmax 0.00172%, nfe) (gnomAD).

What do computational predictors say about ARHGAP40 p.Ala508Ser (c.1522G>T)?

AlphaMissense predicts likely benign (score 0.1362) — an in-silico prediction, not a clinical call.

ARHGAP40 p.Ala508Ser

c.1522G>T · VCV4137599

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1362 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00172%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1362	likely benign
REVEL	0.18	moderately benign-leaning
SaProt	LLR -8.15	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 1.9, phastCons 0.51
Regional constraint	o/e 0.85	unconstrained · MANE · 48 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	21.4	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 A455S vs ClinVar A508S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00172% European (non-Finnish) · 17/988,920 alleles

Filtering AF 0.00105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000856%

Overall 0.0013% 17/1,305,200 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: ARHGAP40
Protein: p.Ala508Ser
Coding: c.1522G>T
MANE Select: NM_001164431
Type: single nucleotide variant
Location: chr20:38643863 (GRCh38)
Gene constraint: LOEUF 0.718 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.96
Residue 508: 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-ala508ser (accessed [today's date]).

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