Is GABRB2 p.Pro252Ser (c.754C>T) pathogenic?

GABRB2 p.Pro252Ser (c.754C>T) is classified Likely pathogenic in GABRB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-09-23). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy 92.

What condition is associated with GABRB2 p.Pro252Ser (c.754C>T)?

GABRB2 p.Pro252Ser (c.754C>T) is associated with developmental and epileptic encephalopathy 92 (ClinVar).

How common is GABRB2 p.Pro252Ser (c.754C>T) in the general population?

GABRB2 p.Pro252Ser (c.754C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GABRB2 p.Pro252Ser (c.754C>T)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

GABRB2 p.Pro252Ser

c.754C>T · rs869312861 · VCV1338859

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy 92

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic ✓ concordant with ClinVar · top 7% in GABRB2
REVEL	0.968	strongly pathogenic-leaning
SaProt	LLR -14.89	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 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.18	constrained · MANE · 5,691 bp · p 8.7e-22 · regional, not allelic
Overall
CADD	32.0	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

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: GABRB2
Protein: p.Pro252Ser
Coding: c.754C>T
MANE Select: NM_001371727
dbSNP: rs869312861
Type: single nucleotide variant
Location: chr5:161334830 (GRCh38)
Gene constraint: LOEUF 0.426 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.65 · 31 PDB
Residue 252: an α-helix

Full GABRB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy 92 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GABRB2 p.Pro252Ala Likely pathogenic ★ same residue
GABRB2 p.Pro252Thr Likely pathogenic ★ same residue
GABRB2 p.Pro252Leu Pathogenic ★ same residue
GABRB2 p.Arg293Trp Pathogenic/Likely pathogenic ★★ same condition
GABRB2 p.Lys303Asn Pathogenic/Likely pathogenic ★★ same condition
GABRB2 p.Tyr301Cys Pathogenic/Likely pathogenic ★★ same condition
GABRB2 p.Tyr301Phe Pathogenic/Likely pathogenic ★★ same condition
GABRB2 p.Val302Met Pathogenic/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/gabrb2-p-pro252ser (accessed [today's date]).

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