Is GNB2 p.Lys89Thr (c.266A>C) pathogenic?

GNB2 p.Lys89Thr (c.266A>C) is classified Pathogenic in GNB2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-04-25). AlphaMissense: likely pathogenic (0.9972); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with hypotonia and dysmorphic facies.

What condition is associated with GNB2 p.Lys89Thr (c.266A>C)?

GNB2 p.Lys89Thr (c.266A>C) is associated with neurodevelopmental disorder with hypotonia and dysmorphic facies (ClinVar).

How common is GNB2 p.Lys89Thr (c.266A>C) in the general population?

GNB2 p.Lys89Thr (c.266A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GNB2 p.Lys89Thr (c.266A>C)?

AlphaMissense predicts likely pathogenic (score 0.9972) — an in-silico prediction, not a clinical call.

GNB2 p.Lys89Thr

c.266A>C · rs2131350517 · VCV1217307

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9972 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

neurodevelopmental disorder with hypotonia and dysmorphic facies

Computational evidence

Protein change
AlphaMissense	0.9972	likely pathogenic ✓ concordant with ClinVar
REVEL	0.459	indeterminate
SaProt	LLR -16.75	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 4.9, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 2,532 bp · p 8.1e-18 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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: GNB2
Protein: p.Lys89Thr
Coding: c.266A>C
MANE Select: NM_005273
dbSNP: rs2131350517
Type: single nucleotide variant
Location: chr7:100677414 (GRCh38)
Gene constraint: LOEUF 0.372 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 96.89 · 1 PDB
Residue 89: a UniProt-annotated variant site (in nedhydf)

Full GNB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with hypotonia and dysmorphic facies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GNB2 p.Lys89Glu Pathogenic ★ same residue
GNB2 p.Ala73Thr Pathogenic/Likely pathogenic ★★ same condition
GNB2 p.Asn268Ile Likely pathogenic ★ ⚠ same condition
GNB2 p.Asp76Gly Pathogenic ★ same condition
GNB2 p.Gly77Trp Likely pathogenic ★ same condition
GNB2 p.Arg280Ser Uncertain significance ★ ⚠ same condition
GNB2 p.Ile80Asn Uncertain significance ★ ⚠ same condition
GNB2 p.Leu262Phe 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/gnb2-p-lys89thr (accessed [today's date]).

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