Is GABRA2 p.Ile255Phe (c.763A>T) pathogenic?

GABRA2 p.Ile255Phe (c.763A>T) is classified Uncertain significance in GABRA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-29). AlphaMissense: likely pathogenic (0.9656); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy, 78.

What condition is associated with GABRA2 p.Ile255Phe (c.763A>T)?

GABRA2 p.Ile255Phe (c.763A>T) is associated with developmental and epileptic encephalopathy, 78 (ClinVar).

How common is GABRA2 p.Ile255Phe (c.763A>T) in the general population?

GABRA2 p.Ile255Phe (c.763A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GABRA2 p.Ile255Phe (c.763A>T)?

AlphaMissense predicts likely pathogenic (score 0.9656) — an in-silico prediction, not a clinical call.

GABRA2 p.Ile255Phe

c.763A>T · VCV3376148

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9656 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 78

Computational evidence

Protein change
AlphaMissense	0.9656	likely pathogenic
REVEL	0.794	moderately pathogenic-leaning
SaProt	LLR -11.74	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 6.2	GERP 1.5, phastCons 1
Regional constraint	o/e 0.21	constrained · MANE · 42 kb · p 3.9e-17 · regional, not allelic
Overall
CADD	32.0	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.Ile255Phe
Coding: c.763A>T
MANE Select: NM_000807
Type: single nucleotide variant
Location: chr4:46303553 (GRCh38)
Gene constraint: LOEUF 0.49 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 83.71 · 15 PDB
Residue 255: an α-helix

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

Disease context

developmental and epileptic encephalopathy, 78 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GABRA2 p.Ile255Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
GABRA2 p.Ala332Val Pathogenic/Likely pathogenic ★★ same condition
GABRA2 p.Thr294Ile Pathogenic/Likely pathogenic ★★ same condition
GABRA2 p.Arg56Trp Uncertain significance ★★ ⚠ same condition
GABRA2 p.Met10Thr Uncertain significance ★★ ⚠ same condition
GABRA2 p.Thr392Ala Uncertain significance ★★ ⚠ same condition
GABRA2 p.Leu154Val Likely pathogenic ★ ⚠ same condition
GABRA2 p.Leu215Ser Likely pathogenic ★ 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/gabra2-p-ile255phe (accessed [today's date]).

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