GRIN2D

Chr 19AD

glutamate ionotropic receptor NMDA type subunit 2D

Also known as: DEE46, EB11, EIEE46, GluN2D, NMDAR2D, NR2D

NCBI Gene: 2906 ENSG00000105464 UniProt: O15399 OMIM: 602717

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

N-methyl-D-aspartate (NMDA) receptors are a class of ionotropic glutamate receptors. NMDA channel has been shown to be involved in long-term potentiation, an activity-dependent increase in the efficiency of synaptic transmission thought to underlie certain kinds of memory and learning. NMDA receptor channels are heteromers composed of the key receptor subunit NMDAR1 (GRIN1) and 1 or more of the 4 NMDAR2 subunits: NMDAR2A (GRIN2A), NMDAR2B (GRIN2B), NMDAR2C (GRIN2C), and NMDAR2D (GRIN2D). [provided by RefSeq, Mar 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.171 OMIM phenotype

VCEP Guidelines: GRIN DisordersPilot

ClinGen Panel

Clinical Summary— GRIN2D

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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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ClinVar Variants

14 unique Pathogenic / Likely Pathogenic· 795 VUS of 1416 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GRIN2D

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?

0.17LOEUF

pLI 1.000

Z-score 5.39

OE 0.05 (0.02–0.17)

Highly constrained

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

Missense Constraint?

4.85Z-score

OE missense 0.44 (0.40–0.49)

266 obs / 600.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.17)

0≤0.351.4

Missense OE?0.44 (0.40–0.49)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 2 / 37.8Missense obs/exp: 266 / 600.2Syn Z: 2.11

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongGRIN2D-related severe epileptic encephalopathy treatable with NMDA receptor channel blockersGOFAD

This gene — mechanism propensity

0.4983th %ile

GOF

0.6735th %ile

LOF

0.66top 25%

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.

LOFprediction above median · LOEUF 0.17

GOFprediction above median · 1 literature citation · 93% of P/LP are missense

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

GOFOverall, these results suggest that NMDAR antagonists can be useful as adjuvant epilepsy therapy in individuals with GRIN2D gain-of-function mutations.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

1.PMID 27616483 ↗

ClinVar Variant Classifications

1416 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic10

VUS795

Likely Benign524

Benign29

Conflicting43

Pathogenic

Likely Pathogenic

795

VUS

524

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	4	0	0	4
Likely Pathogenic	0	9	1	0	10
VUS	34	730	22	9	795
Likely Benign	0	21	101	402	524
Benign	0	1	7	21	29
Conflicting	—				43
Total	34	765	131	432	1,405

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

10 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap GRIN2D — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →