Is GNB3 p.Arg283Cys (c.847C>T) pathogenic?

GNB3 p.Arg283Cys (c.847C>T) is classified Uncertain significance in GNB3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-13). AlphaMissense: likely pathogenic (0.8997); Ultra-rare (popmax 0.0217%, amr).

How common is GNB3 p.Arg283Cys (c.847C>T) in the general population?

GNB3 p.Arg283Cys (c.847C>T) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about GNB3 p.Arg283Cys (c.847C>T)?

AlphaMissense predicts likely pathogenic (score 0.8997) — an in-silico prediction, not a clinical call.

GNB3 p.Arg283Cys

c.847C>T · rs202103093 · VCV939284

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8997 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8997	likely pathogenic
REVEL	0.583	indeterminate
SaProt	LLR -15.61	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 6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 5,607 bp · p 0.03 · regional, not allelic
Overall
CADD	33.0	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 0.0217% Admixed American · 13/60,018 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.00291% 47/1,614,074 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,617
Middle Eastern	0.0165%	6,060
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,868
South Asian	0.00549%	18,215
Remaining individualsnot grpmax-eligible	0.0048%	20,835
African / African-American	0.004%	25,005
European (non-Finnish)	0.00161%	62,104

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.Arg283Cys
Coding: c.847C>T
MANE Select: NM_031299 · reported on NM_002075
dbSNP: rs202103093
Type: single nucleotide variant
Location: chr12:6845733 (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-arg283cys (accessed [today's date]).

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