Is GABRB2 p.Glu419= (c.1257G>A) pathogenic?

GABRB2 p.Glu419= (c.1257G>A) is classified Likely benign in GABRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-28). Very rare (popmax 0.00446%, eas); Associated with intellectual disability.

What condition is associated with GABRB2 p.Glu419= (c.1257G>A)?

GABRB2 p.Glu419= (c.1257G>A) is associated with intellectual disability (ClinVar).

How common is GABRB2 p.Glu419= (c.1257G>A) in the general population?

GABRB2 p.Glu419= (c.1257G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

GABRB2 p.Glu419=

c.1257G>A · rs752546514 · VCV2175003

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

intellectual disability

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.45	GERP -3.2, phastCons 1
Overall
CADD	5.89	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,886 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000434% 7/1,614,006 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00625%	16,009
East Asiangrpmax	0.00446%	22,443
European (non-Finnish)	8.47e-05%	1,179,999

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: GABRB2
Protein: p.Glu419=
Coding: c.1257G>A
MANE Select: NM_001371727
dbSNP: rs752546514
Type: single nucleotide variant
Location: chr5:161294363 (GRCh38)
Gene constraint: LOEUF 0.426 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.65 · 31 PDB

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

Disease context

intellectual disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GABRB2 p.Glu419Val Uncertain significance ★ ⚠ same residue
GABRB2 p.Ala304Val Pathogenic/Likely pathogenic ★★ same condition
GABRB2 p.Arg293Trp Pathogenic/Likely pathogenic ★★ same condition
GABRB2 p.Asp125Asn Pathogenic ★★ same condition
GABRB2 p.Ile288Thr Likely pathogenic ★★ same condition
GABRB2 p.Phe245Leu Pathogenic/Likely pathogenic ★★ same condition
GABRB2 p.Thr284Ile Pathogenic/Likely pathogenic ★★ same condition
GABRB2 p.Tyr301Cys 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-glu419 (accessed [today's date]).

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