Is GNB4 p.Lys89Thr (c.266A>C) pathogenic?

GNB4 p.Lys89Thr (c.266A>C) is classified Uncertain significance in GNB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-01). AlphaMissense: likely pathogenic (0.9973); Absent from gnomAD v4.1.

How common is GNB4 p.Lys89Thr (c.266A>C) in the general population?

GNB4 p.Lys89Thr (c.266A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GNB4 p.Lys89Thr (c.266A>C)?

AlphaMissense predicts likely pathogenic (score 0.9973) — an in-silico prediction, not a clinical call.

GNB4 p.Lys89Thr

c.266A>C · rs2473908246 · VCV2654289

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9973 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9973	likely pathogenic
REVEL	0.508	indeterminate
SaProt	LLR -16.55	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Pangolin	Δ0.38	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 25 kb · p 4.2e-07 · 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

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: GNB4
Protein: p.Lys89Thr
Coding: c.266A>C
MANE Select: NM_021629
dbSNP: rs2473908246
Type: single nucleotide variant
Location: chr3:179416494 (GRCh38)
Gene constraint: LOEUF 0.863 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 97.14
Residue 89: a UniProt-annotated variant site (in cmtdif; the mutant protein has impaired bradykinin-induced g protein-coupled receptor intracellular signaling compared to the wild-type protein)

Full GNB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GNB4 p.Lys89Glu Pathogenic ★ same residue
GNB4 p.Lys89Gln Uncertain significance ★ ⚠ same residue
GNB4 p.Gly77Arg Pathogenic ★★ same type
GNB4 p.Lys57Glu Pathogenic/Likely pathogenic ★★ same type
GNB4 c.497+1G>C Uncertain significance ★★ same type
GNB4 p.Arg137Ter Uncertain significance ★★ same type
GNB4 p.Arg15Trp Uncertain significance ★★ ⚠ same type
GNB4 p.Arg214Ter 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/gnb4-p-lys89thr (accessed [today's date]).

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