Is GABRD p.Pro63Ala (c.187C>G) pathogenic?

GABRD p.Pro63Ala (c.187C>G) is classified Uncertain significance in GABRD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-30). AlphaMissense: likely benign (0.1162); Ultra-rare (popmax 0.0164%, mid); Associated with idiopathic generalized epilepsy.

What condition is associated with GABRD p.Pro63Ala (c.187C>G)?

GABRD p.Pro63Ala (c.187C>G) is associated with idiopathic generalized epilepsy (ClinVar).

How common is GABRD p.Pro63Ala (c.187C>G) in the general population?

GABRD p.Pro63Ala (c.187C>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about GABRD p.Pro63Ala (c.187C>G)?

AlphaMissense predicts likely benign (score 0.1162) — an in-silico prediction, not a clinical call.

GABRD p.Pro63Ala

c.187C>G · rs911958534 · VCV2160901

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1162 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

idiopathic generalized epilepsy

Computational evidence

Protein change
AlphaMissense	0.1162	likely benign
REVEL	0.287	benign-leaning
SaProt	LLR -7.40	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 5,915 bp · p 0.55 · regional, not allelic
Overall
CADD	19.15	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00462%

Overall 0.00477% 77/1,613,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.00619%	16,164
Remaining individualsnot grpmax-eligible	0.0032%	31,236
South Asian	0.0011%	91,090

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: GABRD
Protein: p.Pro63Ala
Coding: c.187C>G
MANE Select: NM_000815
dbSNP: rs911958534
Type: single nucleotide variant
Location: chr1:2025339 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.82 · 10 PDB

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

Disease context

idiopathic generalized epilepsy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GABRD p.Pro63= Likely benign ★ same residue
GABRD p.Pro63His Uncertain significance ★ ⚠ same residue
GABRD p.Pro257Leu Likely pathogenic ★★ same condition
GABRD p.Ala24Val Uncertain significance ★★ ⚠ same condition
GABRD p.Ala331Gly Uncertain significance ★★ ⚠ same condition
GABRD p.Ala437Val Uncertain significance ★★ ⚠ same condition
GABRD p.Arg23Gly Uncertain significance ★★ ⚠ same condition
GABRD p.Arg244Trp 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/gabrd-p-pro63ala (accessed [today's date]).

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