Is GABRA2 p.Pro167Ser (c.499C>T) pathogenic?

GABRA2 p.Pro167Ser (c.499C>T) is classified Uncertain significance in GABRA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-23). AlphaMissense: likely pathogenic (0.6633); Absent from gnomAD v4.1.

How common is GABRA2 p.Pro167Ser (c.499C>T) in the general population?

GABRA2 p.Pro167Ser (c.499C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GABRA2 p.Pro167Ser (c.499C>T)?

AlphaMissense predicts likely pathogenic (score 0.6633) — an in-silico prediction, not a clinical call.

GABRA2 p.Pro167Ser

c.499C>T · VCV3372472

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6633 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6633	likely pathogenic
REVEL	0.679	pathogenic-leaning
SaProt	LLR -12.60	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 83 kb · p 2.6e-19 · regional, not allelic
Overall
CADD	31.0	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: GABRA2
Protein: p.Pro167Ser
Coding: c.499C>T
MANE Select: NM_000807
Type: single nucleotide variant
Location: chr4:46310233 (GRCh38)
Gene constraint: LOEUF 0.49 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 83.71 · 15 PDB
Residue 167: a disulfide bond

Full GABRA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GABRA2 p.Ala332Val Pathogenic/Likely pathogenic ★★ same type
GABRA2 p.Pro280Leu Pathogenic/Likely pathogenic ★★ same type
GABRA2 p.Thr294Ile Pathogenic/Likely pathogenic ★★ same type
GABRA2 c.1059+1G>A Uncertain significance ★★ same type
GABRA2 c.1060-5643C>T Uncertain significance ★★ same type
GABRA2 c.1060-5644A>G Uncertain significance ★★ same type
GABRA2 p.Arg301Trp Uncertain significance ★★ ⚠ same type
GABRA2 p.Arg56Trp 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/gabra2-p-pro167ser (accessed [today's date]).

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