Is ARHGAP42 p.Ser816Pro (c.2446T>C) pathogenic?

ARHGAP42 p.Ser816Pro (c.2446T>C) is classified Uncertain significance in ARHGAP42 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-09). AlphaMissense: likely benign (0.054); Very rare (popmax 0.00981%, amr).

How common is ARHGAP42 p.Ser816Pro (c.2446T>C) in the general population?

ARHGAP42 p.Ser816Pro (c.2446T>C) is very rare (popmax 0.00981%, amr) (gnomAD).

What do computational predictors say about ARHGAP42 p.Ser816Pro (c.2446T>C)?

AlphaMissense predicts likely benign (score 0.054) — an in-silico prediction, not a clinical call.

ARHGAP42 p.Ser816Pro

c.2446T>C · rs538314873 · VCV3128867

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.054 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00981%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.054	likely benign
REVEL	0.159	moderately benign-leaning
SaProt	LLR -6.70	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 2.6	GERP 0.48, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 15 kb · p 0.0013 · regional, not allelic
Overall
CADD	16.92	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00981% Admixed American · 5/50,992 alleles

Filtering AF 0.00382% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00248%

Overall 0.000838% 13/1,551,552 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00981%	10,198
European (non-Finnish)	0.000698%	143,351

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: ARHGAP42
Protein: p.Ser816Pro
Coding: c.2446T>C
MANE Select: NM_152432
dbSNP: rs538314873
Type: single nucleotide variant
Location: chr11:100979039 (GRCh38)
Gene constraint: LOEUF 0.666 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.04
Residue 816: the sh3 domain

Full ARHGAP42 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP42 c.*3518A>G Uncertain significance ★ same type
ARHGAP42 c.*3523T>C Uncertain significance ★ same type
ARHGAP42 c.*3551G>T Uncertain significance ★ same type
ARHGAP42 c.*3554C>T Uncertain significance ★ same type
ARHGAP42 c.*3572A>C Uncertain significance ★ same type
ARHGAP42 c.*3622C>T Uncertain significance ★ same type
ARHGAP42 c.*3632A>T Uncertain significance ★ same type
ARHGAP42 c.*3634A>C 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/arhgap42-p-ser816pro (accessed [today's date]).

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