Is ARHGAP40 p.His558Pro (c.1673A>C) pathogenic?

ARHGAP40 p.His558Pro (c.1673A>C) is classified Uncertain significance in ARHGAP40 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-08). AlphaMissense: likely benign (0.1171); Ultra-rare (popmax 0.0106%, afr).

How common is ARHGAP40 p.His558Pro (c.1673A>C) in the general population?

ARHGAP40 p.His558Pro (c.1673A>C) is ultra-rare (popmax 0.0106%, afr) (gnomAD).

What do computational predictors say about ARHGAP40 p.His558Pro (c.1673A>C)?

AlphaMissense predicts likely benign (score 0.1171) — an in-silico prediction, not a clinical call.

ARHGAP40 p.His558Pro

c.1673A>C · rs1012854055 · VCV2519882

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1171 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0106%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.1171	likely benign
REVEL	0.166	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 4.2	GERP 1.3, phastCons 0.88
Regional constraint	o/e 0.85	unconstrained · MANE · 48 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	23.3	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 H505P vs ClinVar H558P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0106% African / African-American · 7/65,892 alleles

Filtering AF 0.0049% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00353%

Overall 0.000614% 8/1,303,882 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0106%	9,413
European (non-Finnish)	0.000101%	988,728

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.His558Pro
Coding: c.1673A>C
MANE Select: NM_001164431
dbSNP: rs1012854055
Type: single nucleotide variant
Location: chr20:38646150 (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-his558pro (accessed [today's date]).

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