Is GABRA2 p.Asp381Glu (c.1143T>A) pathogenic?

GABRA2 p.Asp381Glu (c.1143T>A) is classified Uncertain significance in GABRA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-03). AlphaMissense: likely benign (0.185); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with GABRA2 p.Asp381Glu (c.1143T>A)?

GABRA2 p.Asp381Glu (c.1143T>A) is associated with Inborn genetic diseases (ClinVar).

How common is GABRA2 p.Asp381Glu (c.1143T>A) in the general population?

GABRA2 p.Asp381Glu (c.1143T>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about GABRA2 p.Asp381Glu (c.1143T>A)?

AlphaMissense predicts likely benign (score 0.185) — an in-silico prediction, not a clinical call.

GABRA2 p.Asp381Glu

c.1143T>A · rs2475199431 · VCV1995889

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.185 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.185	likely benign
REVEL	0.295	indeterminate
SaProt	LLR -5.86	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.077	GERP 1.8, phastCons 0.47
Regional constraint	o/e 0.80	unconstrained · MANE · 12 kb · p 0.023 · regional, not allelic
Overall
CADD	17.12	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.000339% European (non-Finnish) · 4/1,178,552 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,460,134 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GABRA2
Protein: p.Asp381Glu
Coding: c.1143T>A
MANE Select: NM_000807
dbSNP: rs2475199431
Type: single nucleotide variant
Location: chr4:46250521 (GRCh38)
Gene constraint: LOEUF 0.49 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 83.71 · 15 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GABRA2 p.Asp381Val Uncertain significance ★ ⚠ same residue
GABRA2 p.Pro280Leu Pathogenic/Likely pathogenic ★★ same condition
GABRA2 p.Asn9Ser Uncertain significance ★★ ⚠ same condition
GABRA2 p.Glu356Ala Uncertain significance ★★ ⚠ same condition
GABRA2 p.Lys133Arg Uncertain significance ★★ ⚠ same condition
GABRA2 p.Lys306Arg Uncertain significance ★★ ⚠ same condition
GABRA2 p.Thr392Ala Uncertain significance ★★ ⚠ same condition
GABRA2 p.Val26Ala 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/gabra2-p-asp381glu (accessed [today's date]).

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