Is GABRD p.Ser299Phe (c.896C>T) pathogenic?

GABRD p.Ser299Phe (c.896C>T) is classified Uncertain significance in GABRD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-04). AlphaMissense: ambiguous (0.5239); Very rare (popmax 0.0011%, sas); Associated with idiopathic generalized epilepsy.

What condition is associated with GABRD p.Ser299Phe (c.896C>T)?

GABRD p.Ser299Phe (c.896C>T) is associated with idiopathic generalized epilepsy (ClinVar).

How common is GABRD p.Ser299Phe (c.896C>T) in the general population?

GABRD p.Ser299Phe (c.896C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about GABRD p.Ser299Phe (c.896C>T)?

AlphaMissense predicts ambiguous (score 0.5239) — an in-silico prediction, not a clinical call.

GABRD p.Ser299Phe

c.896C>T · rs1302098541 · VCV2133931

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5239 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

idiopathic generalized epilepsy

Computational evidence

Protein change
AlphaMissense	0.5239	ambiguous
REVEL	0.509	indeterminate
SaProt	LLR -9.81	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 4,715 bp · p 4e-13 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,084 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,156 alleles · very rare exomes 3/1,460,808 · genomes 0/152,348 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,084
European (non-Finnish)	0.000169%	589,998

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.Ser299Phe
Coding: c.896C>T
MANE Select: NM_000815
dbSNP: rs1302098541
Type: single nucleotide variant
Location: chr1:2029599 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.82 · 10 PDB
Residue 299: an α-helix

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.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
GABRD p.Arg378His Uncertain significance ★★ ⚠ same condition
GABRD p.Arg379Pro 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-ser299phe (accessed [today's date]).

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