Is GABRB2 p.Ile66Val (c.196A>G) pathogenic?

GABRB2 p.Ile66Val (c.196A>G) is classified Uncertain significance in GABRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-30). AlphaMissense: likely benign (0.2143); Very rare (popmax 0.00134%, afr); Associated with intellectual disability.

What condition is associated with GABRB2 p.Ile66Val (c.196A>G)?

GABRB2 p.Ile66Val (c.196A>G) is associated with intellectual disability (ClinVar).

How common is GABRB2 p.Ile66Val (c.196A>G) in the general population?

GABRB2 p.Ile66Val (c.196A>G) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about GABRB2 p.Ile66Val (c.196A>G)?

AlphaMissense predicts likely benign (score 0.2143) — an in-silico prediction, not a clinical call.

GABRB2 p.Ile66Val

c.196A>G · rs2113486744 · VCV1413518

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2143 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intellectual disability

Computational evidence

Protein change
AlphaMissense	0.2143	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -6.80	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.42	unconstrained · MANE · 87 kb · p 7.5e-09 · regional, not allelic
Overall
CADD	23.5	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 0.00134% African / African-American · 1/74,580 alleles

Overall 6.87e-05% 1/1,456,470 alleles · very rare

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.Ile66Val
Coding: c.196A>G
MANE Select: NM_001371727
dbSNP: rs2113486744
Type: single nucleotide variant
Location: chr5:161545268 (GRCh38)
Gene constraint: LOEUF 0.426 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.65 · 31 PDB
Residue 66: a β-strand

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.Ile66Thr Uncertain significance ★ ⚠ same residue
GABRB2 p.Ile66= Likely benign ★ 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

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-ile66val (accessed [today's date]).

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