Is GNB3 p.Ala19Val (c.56C>T) pathogenic?

GNB3 p.Ala19Val (c.56C>T) is classified Uncertain significance in GNB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-15). AlphaMissense: likely benign (0.1156); Very rare (popmax 0.00246%, nfe).

How common is GNB3 p.Ala19Val (c.56C>T) in the general population?

GNB3 p.Ala19Val (c.56C>T) is very rare (popmax 0.00246%, nfe) (gnomAD).

What do computational predictors say about GNB3 p.Ala19Val (c.56C>T)?

AlphaMissense predicts likely benign (score 0.1156) — an in-silico prediction, not a clinical call.

GNB3 p.Ala19Val

c.56C>T · rs201491226 · VCV1007682

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1156 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1156	likely benign
REVEL	0.162	moderately benign-leaning
SaProt	LLR -7.01	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.66	donor gain · deltas
Pangolin	Δ0.23	gain · loss 0.16 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 5,607 bp · p 0.03 · regional, not allelic
Overall
CADD	34.0	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 0.00246% European (non-Finnish) · 29/1,179,228 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00229% 37/1,612,702 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00781%	12,797
Remaining individualsnot grpmax-eligible	0.0032%	31,231
European (non-Finnish)grpmax	0.00246%	40,663
African / African-American	0.00133%	75,018

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala19Val
Coding: c.56C>T
MANE Select: NM_002075
dbSNP: rs201491226
Type: single nucleotide variant
Location: chr12:6841343 (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

Similar variants

GNB3 c.203+6G>A Uncertain significance ★★ same type
GNB3 p.Ala106Ser Uncertain significance ★★ ⚠ same type
GNB3 p.Ala231Thr Uncertain significance ★★ ⚠ same type
GNB3 p.Ala64Thr Uncertain significance ★★ ⚠ same type
GNB3 p.Arg129His Uncertain significance ★★ ⚠ same type
GNB3 p.Arg137Gln Uncertain significance ★★ ⚠ same type
GNB3 p.Arg150Cys Uncertain significance ★★ ⚠ same type
GNB3 p.Arg42Gln 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/gnb3-p-ala19val (accessed [today's date]).

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