GRID2

Chr 4AR

glutamate ionotropic receptor delta type subunit 2

ENSG00000152208 UniProt: O43424 OMIM: 602368

This protein is an ionotropic glutamate receptor family member expressed selectively in cerebellar Purkinje cells that mediates synaptic organization and long-term depression at parallel fiber-Purkinje cell synapses. Mutations cause spinocerebellar ataxia, autosomal recessive 18 through loss of cerebellar Purkinje cells via cell-autonomous apoptosis. The inheritance pattern is autosomal recessive.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Member of the ionotropic glutamate receptor family, which plays a crucial role in synaptic organization and signal transduction in the central nervous system (PubMed:34936451, PubMed:27418511, PubMed:40957579). Although it shares structural features with ionotropic glutamate receptors, does not bind glutamate as a primary ligand (PubMed:34936451). Promotes synaptogenesis and mediates the D-serine-dependent long term depression signals and AMPA receptor endocytosis of cerebellar parallel fiber-Purkinje cell (PF-PC) synapses through the NRX1B-CBLN1-GRID2 triad complex (PubMed:27418511). In the presence of neurexins and cerebellins, forms cation-selective channels that are proposed to be gated by glycine and D-serine (PubMed:34936451). Cation-selective ion channel activity can be triggered by GRM1 in Purkinje cells (PubMed:24357660, PubMed:27276689)

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.171 OMIM phenotype

Clinical Summary— GRID2

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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.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.17LOEUF

pLI 1.000

Z-score 6.29

OE 0.07 (0.04–0.17)

Highly constrained

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

Missense Constraint?

0.71Z-score

OE missense 0.92 (0.85–0.98)

527 obs / 574.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.07 (0.04–0.17)

0≤0.351.4

Missense OE?0.92 (0.85–0.98)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 4 / 53.8Missense obs/exp: 527 / 574.8Syn Z: -1.07

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongGRID2-related cerebellar ataxia (monoallelic)OTHERAD

strongGRID2-related cerebellar ataxia (biallelic)LOFAR

This gene — mechanism propensity

0.4785th %ile

GOF

0.6737th %ile

LOF

0.57top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

LOFLOEUF 0.17

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

GOFMissense mutations in the GRID2 cause ataxia with the gain-of-function mechanism.1

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

References