Is GNB3 p.Pro194Ala (c.580C>G) pathogenic?

GNB3 p.Pro194Ala (c.580C>G) is classified Uncertain significance in GNB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely benign (0.2188); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with GNB3 p.Pro194Ala (c.580C>G)?

GNB3 p.Pro194Ala (c.580C>G) is associated with Inborn genetic diseases (ClinVar).

How common is GNB3 p.Pro194Ala (c.580C>G) in the general population?

GNB3 p.Pro194Ala (c.580C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GNB3 p.Pro194Ala (c.580C>G)?

AlphaMissense predicts likely benign (score 0.2188) — an in-silico prediction, not a clinical call.

GNB3 p.Pro194Ala

c.580C>G · VCV4620956

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2188 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2188	likely benign
REVEL	0.519	indeterminate
SaProt	LLR -9.09	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.20 · evaluated, not missing
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	25.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GNB3
Protein: p.Pro194Ala
Coding: c.580C>G
MANE Select: NM_002075
Type: single nucleotide variant
Location: chr12:6843859 (GRCh38)
Gene constraint: LOEUF 1.072 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.19 · 2 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GNB3 p.Pro194Ser Uncertain significance ★★ ⚠ same residue
GNB3 p.Ala106Ser Uncertain significance ★★ ⚠ same condition
GNB3 p.Ala231Thr Uncertain significance ★★ ⚠ same condition
GNB3 p.Ala64Thr Uncertain significance ★★ ⚠ same condition
GNB3 p.Arg129His Uncertain significance ★★ ⚠ same condition
GNB3 p.Arg150Cys Uncertain significance ★★ ⚠ same condition
GNB3 p.Arg8His Uncertain significance ★★ ⚠ same condition
GNB3 p.Arg96His Uncertain significance ★★ ⚠ same condition

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-pro194ala (accessed [today's date]).

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