GRIN2D
Chr 19ADglutamate ionotropic receptor NMDA type subunit 2D
Also known as: DEE46, EB11, EIEE46, GluN2D, NMDAR2D, NR2D
The protein forms part of NMDA receptor channels that are ionotropic glutamate receptors involved in synaptic transmission, learning, and memory. Loss-of-function mutations cause developmental and epileptic encephalopathy 46, inherited in an autosomal dominant pattern. The gene is highly intolerant to loss-of-function variants, indicating that haploinsufficiency disrupts normal NMDA receptor function critical for neuronal development and excitability.
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Highly missense-constrained (top ~0.1%)
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). 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.
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
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
500 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 0 | 0 | 0 |
Likely Pathogenic | 0 | 2 | 1 | 0 | 3 |
VUS | 14 | 266 | 12 | 4 | 296 |
Likely Benign | 0 | 4 | 31 | 150 | 185 |
Benign | 0 | 0 | 1 | 0 | 1 |
Conflicting | — | 4 | |||
| Total | 14 | 272 | 45 | 154 | 489 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
GRIN2D · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
External Resources
Links to major genomics databases and tools