Is GABRB2 p.Ile246Thr (c.737T>C) pathogenic?

GABRB2 p.Ile246Thr (c.737T>C) is classified Pathogenic in GABRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-02-24). AlphaMissense: likely pathogenic (0.967); Absent from gnomAD v4.1.

How common is GABRB2 p.Ile246Thr (c.737T>C) in the general population?

GABRB2 p.Ile246Thr (c.737T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GABRB2 p.Ile246Thr (c.737T>C)?

AlphaMissense predicts likely pathogenic (score 0.967) — an in-silico prediction, not a clinical call.

GABRB2 p.Ile246Thr

c.737T>C · rs1064793551 · VCV418957

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.967 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.967	likely pathogenic ✓ concordant with ClinVar
REVEL	0.861	moderately pathogenic-leaning
SaProt	LLR -9.19	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.18	constrained · MANE · 5,691 bp · p 8.7e-22 · regional, not allelic
Overall
CADD	28.6	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: GABRB2
Protein: p.Ile246Thr
Coding: c.737T>C
MANE Select: NM_001371727
dbSNP: rs1064793551
Type: single nucleotide variant
Location: chr5:161334847 (GRCh38)
Gene constraint: LOEUF 0.426 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.65 · 31 PDB
Residue 246: an α-helix

Full GABRB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GABRB2 p.Ala304Val Pathogenic/Likely pathogenic ★★ same type
GABRB2 p.Arg293Trp Pathogenic/Likely pathogenic ★★ same type
GABRB2 p.Asp125Asn Pathogenic ★★ same type
GABRB2 p.Ile288Thr Likely pathogenic ★★ same type
GABRB2 p.Lys303Asn Pathogenic/Likely pathogenic ★★ same type
GABRB2 p.Phe245Leu Pathogenic/Likely pathogenic ★★ same type
GABRB2 p.Pro252Ser Likely pathogenic ★★ same type
GABRB2 p.Thr284Ile Pathogenic/Likely pathogenic ★★ 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/gabrb2-p-ile246thr (accessed [today's date]).

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