Is ARHGAP40 p.Arg319His (c.956G>A) pathogenic?

ARHGAP40 p.Arg319His (c.956G>A) is classified Uncertain significance in ARHGAP40 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely benign (0.0795); Ultra-rare (popmax 0.0212%, mid).

How common is ARHGAP40 p.Arg319His (c.956G>A) in the general population?

ARHGAP40 p.Arg319His (c.956G>A) is ultra-rare (popmax 0.0212%, mid) (gnomAD).

What do computational predictors say about ARHGAP40 p.Arg319His (c.956G>A)?

AlphaMissense predicts likely benign (score 0.0795) — an in-silico prediction, not a clinical call.

ARHGAP40 p.Arg319His

c.956G>A · rs933363348 · VCV2369521

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0795 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0212%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.0795	likely benign
REVEL	0.019	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 1.4	GERP -0.94, phastCons 0.004
Regional constraint	o/e 0.85	unconstrained · MANE · 48 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	20.7	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 R266H vs ClinVar R319H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0212% Middle Eastern · 1/4,720 alleles

Filtering AF 0.00165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00129%

Overall 0.00253% 33/1,305,058 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0212%	4,720
East Asian	0.00555%	18,020
South Asian	0.00494%	20,253
Remaining individualsnot grpmax-eligible	0.00457%	21,861
European (non-Finnish)	0.00233%	42,996
Admixed American	0.0023%	43,514
African / African-American	0.00152%	65,794

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.Arg319His
Coding: c.956G>A
MANE Select: NM_001164431
dbSNP: rs933363348
Type: single nucleotide variant
Location: chr20:38637714 (GRCh38)
Gene constraint: LOEUF 0.718 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.96

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-arg319his (accessed [today's date]).

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