GRIA2

Chr 4AD

glutamate ionotropic receptor AMPA type subunit 2

Also known as: GLUR2, GLURB, GluA2, GluR-K2, HBGR2, NEDLIB, gluR-2, gluR-B

NCBI Gene: 2891 ENSG00000120251 UniProt: P42262 OMIM: 138247

The protein functions as the GRIA2 subunit of AMPA glutamate receptors, which are ligand-activated cation channels that mediate excitatory neurotransmission in the brain and undergo RNA editing to become impermeable to calcium. Mutations cause autosomal dominant neurodevelopmental disorder with language impairment and behavioral abnormalities. The pathogenic mechanism likely involves disrupted excitatory neurotransmission due to altered AMPA receptor function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismADLOEUF 0.251 OMIM phenotype

Clinical Summary— GRIA2

🧬

Gene-Disease Validity (ClinGen)

neurodevelopmental disorder with language impairment and behavioral abnormalities · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

74 unique Pathogenic / Likely Pathogenic· 153 VUS of 273 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — GRIA2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.25LOEUF

pLI 0.999

Z-score 5.33

OE 0.12 (0.06–0.25)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

4.56Z-score

OE missense 0.41 (0.37–0.47)

197 obs / 477.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.12 (0.06–0.25)

0≤0.351.4

Missense OE0.41 (0.37–0.47)

0≤0.61.4

Synonymous OE0.95

0≤1.21.6

LoF obs/exp: 5 / 42.5Missense obs/exp: 197 / 477.1Syn Z: 0.57

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongGRIA2-related developmental disorderLOFAD

0.5378th %ile

GOF

0.6735th %ile

LOF

0.59top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 18% of P/LP variants are LoF · LOEUF 0.25

GOFprediction above median

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNWe assume that either haploinsufficiency of GRIA2 or a GLRB/GRIA2 fusion gene leading to a protein with dominant-negative properties is causing the phenotype of the patient.PMID:22669415

LOFWe assume that either haploinsufficiency of GRIA2 or a GLRB/GRIA2 fusion gene leading to a protein with dominant-negative properties is causing the phenotype of the patient.PMID:22669415

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.