Is GNB3 p.Arg251His (c.752G>A) pathogenic?

GNB3 p.Arg251His (c.752G>A) is classified Uncertain significance in GNB3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-03). AlphaMissense: likely pathogenic (0.6873); Ultra-rare (popmax 0.0233%, amr).

How common is GNB3 p.Arg251His (c.752G>A) in the general population?

GNB3 p.Arg251His (c.752G>A) is ultra-rare (popmax 0.0233%, amr) (gnomAD).

What do computational predictors say about GNB3 p.Arg251His (c.752G>A)?

AlphaMissense predicts likely pathogenic (score 0.6873) — an in-silico prediction, not a clinical call.

GNB3 p.Arg251His

c.752G>A · rs782467023 · VCV840114

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6873 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0233%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6873	likely pathogenic
REVEL	0.486	indeterminate
SaProt	LLR -10.83	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 10	GERP 2.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 5,607 bp · p 0.03 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0233% Admixed American · 14/60,032 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.00248% 40/1,613,660 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0233%	4,288
Middle Eastern	0.0165%	6,062
Finnishnot grpmax-eligible	0.0126%	7,956
East Asian	0.0111%	8,974
Remaining individualsnot grpmax-eligible	0.008%	12,502
European (non-Finnish)	0.000593%	168,562

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: GNB3
Protein: p.Arg251His
Coding: c.752G>A
MANE Select: NM_031299 · reported on NM_002075
dbSNP: rs782467023
Type: single nucleotide variant
Location: chr12:6845638 (GRCh38)

Full GNB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/gnb3-p-arg251his (accessed [today's date]).

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