Is GABRD p.Arg418Pro (c.1253G>C) pathogenic?

GABRD p.Arg418Pro (c.1253G>C) is classified Uncertain significance in GABRD (ClinVar, Single submitter, 1 submitter; last evaluated 2019-01-01). AlphaMissense: likely benign (0.108); Absent from gnomAD v4.1; Associated with epilepsy, idiopathic generalized, susceptibility to, 10.

What condition is associated with GABRD p.Arg418Pro (c.1253G>C)?

GABRD p.Arg418Pro (c.1253G>C) is associated with epilepsy, idiopathic generalized, susceptibility to, 10 (ClinVar).

How common is GABRD p.Arg418Pro (c.1253G>C) in the general population?

GABRD p.Arg418Pro (c.1253G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GABRD p.Arg418Pro (c.1253G>C)?

AlphaMissense predicts likely benign (score 0.108) — an in-silico prediction, not a clinical call.

GABRD p.Arg418Pro

c.1253G>C · rs145055222 · VCV982605

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.108 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epilepsy, idiopathic generalized, susceptibility to, 10

Computational evidence

Protein change
AlphaMissense	0.108	likely benign
REVEL	0.254	benign-leaning
SaProt	LLR -9.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 5.3	phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 223 bp · p 0.98 · regional, not allelic
Overall
CADD	21.3	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

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: GABRD
Protein: p.Arg418Pro
Coding: c.1253G>C
MANE Select: NM_000815
dbSNP: rs145055222
Type: single nucleotide variant
Location: chr1:2030176 (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

epilepsy, idiopathic generalized, susceptibility to, 10 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GABRD p.Arg418Gln Uncertain significance ★ ⚠ same residue
GABRD p.Arg418Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
GABRD p.Ala212Val Pathogenic/Likely pathogenic ★★ same condition
GABRD p.Ala331Gly Uncertain significance ★★ ⚠ same condition
GABRD p.Arg379Trp Uncertain significance ★★ ⚠ same condition
GABRD p.Arg416His Uncertain significance ★★ ⚠ same condition
GABRD p.Arg96Trp Uncertain significance ★★ ⚠ same condition
GABRD p.Asn35Ser 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-arg418pro (accessed [today's date]).

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