GRID2

Chr 4AR

glutamate ionotropic receptor delta type subunit 2

Also known as: GluD2, SCAR18

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.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismARLOEUF 0.171 OMIM phenotype
Clinical SummaryGRID2
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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint
0.17LOEUF
pLI 1.000
Z-score 6.29
OE 0.07 (0.040.17)
Highly constrained

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

Missense Constraint
0.71Z-score
OE missense 0.92 (0.850.98)
527 obs / 574.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.07 (0.040.17)
00.351.4
Missense OE0.92 (0.850.98)
00.61.4
Synonymous OE1.09
01.21.6
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
DN
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.PMID:32170608

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

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

GRID2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
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