Is GABRB2 p.Leu309Pro (c.926T>C) pathogenic?

GABRB2 p.Leu309Pro (c.926T>C) is classified Uncertain significance in GABRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-01). AlphaMissense: likely pathogenic (1); Absent from gnomAD v4.1.

How common is GABRB2 p.Leu309Pro (c.926T>C) in the general population?

GABRB2 p.Leu309Pro (c.926T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GABRB2 p.Leu309Pro (c.926T>C)?

AlphaMissense predicts likely pathogenic (score 1) — an in-silico prediction, not a clinical call.

GABRB2 p.Leu309Pro

c.926T>C · rs2546555594 · VCV2656019

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

1 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	1	likely pathogenic · top 7% in GABRB2
REVEL	0.935	strongly pathogenic-leaning
SaProt	LLR -15.00	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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	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: GABRB2
Protein: p.Leu309Pro
Coding: c.926T>C
MANE Select: NM_001371727
dbSNP: rs2546555594
Type: single nucleotide variant
Location: chr5:161331034 (GRCh38)
Gene constraint: LOEUF 0.426 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.65 · 31 PDB
Residue 309: 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-leu309pro (accessed [today's date]).

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