GRIN2D

Summary

GRIN2D (glutamate ionotropic receptor NMDA type subunit 2D, HGNC:4588) is a protein-coding gene on chromosome 19q13.33, encoding Glutamate receptor ionotropic, NMDA 2D (O15399). Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+).

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).

Source: NCBI Gene 2906 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• Clinical variants (ClinVar): 1,408 total — 5 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 59
• Druggable target: yes — 29 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000836

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4588
Approved symbol	GRIN2D
Name	glutamate ionotropic receptor NMDA type subunit 2D
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Aliases	GluN2D, EB11, NR2D
Ensembl gene	ENSG00000105464
Ensembl biotype	protein_coding
OMIM	602717
Entrez	2906

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000263269, ENST00000911262

RefSeq mRNA: 1 — MANE Select: NM_000836 NM_000836

CCDS: CCDS12719

Canonical transcript exons

ENST00000263269 — 14 exons

Exon	Start	End
ENSE00000853310	48398367	48398857
ENSE00000853311	48404734	48405353
ENSE00000853312	48413991	48414105
ENSE00000853313	48414373	48414584
ENSE00000853314	48414864	48415032
ENSE00000853319	48442150	48442382
ENSE00000853320	48442600	48444931
ENSE00001058753	48394658	48394936
ENSE00001131289	48421785	48421945
ENSE00001131295	48419585	48419814
ENSE00001131302	48419234	48419359
ENSE00002440826	48441769	48441956
ENSE00002521672	48416002	48416155
ENSE00003911054	48393668	48393868

Expression profiles

Bgee: expression breadth ubiquitous, 144 present calls, max score 67.60.

FANTOM5 (CAGE): breadth broad, TPM avg 0.5645 / max 34.7282, expressed in 250 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176779	0.4599	222
176780	0.1046	54

Top tissues by expression

262 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cingulate cortex	UBERON:0003027	67.60	gold quality
anterior cingulate cortex	UBERON:0009835	67.37	gold quality
prefrontal cortex	UBERON:0000451	67.33	gold quality
ganglionic eminence	UBERON:0004023	67.18	gold quality
cortical plate	UBERON:0005343	67.10	gold quality
hypothalamus	UBERON:0001898	67.00	gold quality
ventricular zone	UBERON:0003053	66.94	gold quality
right frontal lobe	UBERON:0002810	65.92	gold quality
lateral nuclear group of thalamus	UBERON:0002736	65.59	silver quality
amygdala	UBERON:0001876	65.56	gold quality
neocortex	UBERON:0001950	64.76	gold quality
frontal cortex	UBERON:0001870	64.38	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	63.50	gold quality
cerebral cortex	UBERON:0000956	61.98	gold quality
Brodmann (1909) area 9	UBERON:0013540	61.83	gold quality
temporal lobe	UBERON:0001871	60.62	gold quality
telencephalon	UBERON:0001893	60.01	gold quality
embryo	UBERON:0000922	59.63	gold quality
right hemisphere of cerebellum	UBERON:0014890	59.60	gold quality
substantia nigra	UBERON:0002038	59.42	gold quality
vena cava	UBERON:0004087	59.12	gold quality
forebrain	UBERON:0001890	58.90	gold quality
placenta	UBERON:0001987	58.81	gold quality
brain	UBERON:0000955	58.51	gold quality
central nervous system	UBERON:0001017	58.36	gold quality
midbrain	UBERON:0001891	58.20	gold quality
cartilage tissue	UBERON:0002418	58.08	gold quality
cerebellar cortex	UBERON:0002129	57.64	gold quality
cerebellar hemisphere	UBERON:0002245	57.46	gold quality
cerebellum	UBERON:0002037	57.21	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.92

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, ESR2, TTBK1

miRNA regulators (miRDB)

48 targeting GRIN2D, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-6833-5P	99.50	68.93	1161
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-4695-5P	99.06	64.87	1151
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-622	98.99	66.48	1050
HSA-MIR-3196	98.96	63.91	326
HSA-MIR-7155-5P	98.65	66.14	1290
HSA-MIR-9500	98.62	66.54	1845

Literature-anchored findings (GeneRIF, showing 17)

• data show that the NMDAR2D was specifically expressed in cultivated keratinocytes (PMID:16328341)
• In microsatellite instable and microsatellite and chromosomally stable cancers, CIMP and BRAF/KRAS mutations are similarly distributed indicating common mechanisms of tumor initiation or progression in the molecular pathogenesis. (PMID:21915661)
• After 7 days of chronic alcohol exposure, there are significant increases in mRNA expression of GRIN2D in cultured neurons derived from alcoholic subjects, but not in cultures from nonalcoholics. (PMID:22486492)
• Absence of truncating mutation in GRIN1 and GRIN2D genes in patients with autism spectrum disorder and schizophrenia and controls. (PMID:22833210)
• High GRIN2D expression is associated with colorectal cancer. (PMID:26943033)
• GRIN2D Recurrent De Novo Dominant Mutation Causes a Severe Epileptic Encephalopathy Treatable with NMDA Receptor Channel Blockers (PMID:27616483)
• This study showed that the higher GluN2D mRNA level in healthy but not in depressed pregnant women as compared to non-pregnant individuals. (PMID:28284346)
• This study found that NMDAR activation, NR2D in particular, is involved in human fetal lung fibroblast proliferation and collagen production through a potential ERK1/2-mediated mechanism. (PMID:28987794)
• ultra-rare variants with loss of function (frameshift, nonsense or splice site) in NMDARs genes like GRIN2C and GRIN2D may contribute to possible risk of schizophrenia (PMID:29317596)
• we identified three patients with novel GRIN2D variants, providing the solid evidence that GRIN2D variants cause epileptic encephalopathy. (PMID:30280376)
• GluN2D-mediated excitatory drive onto medial prefrontal cortical PV+ fast-spiking inhibitory interneurons. (PMID:32497062)
• MicroRNA-129-1-3p Represses the Progression of Triple-Negative Breast Cancer by Targeting the GRIN2D Gene. (PMID:35295962)
• Structural insights into assembly and function of GluN1-2C, GluN1-2A-2C, and GluN1-2D NMDARs. (PMID:36309015)
• GRIN2D knockdown suppresses the progression of lung adenocarcinoma by regulating the E2F signalling pathway. (PMID:37084840)
• Potential Roles for the GluN2D NMDA Receptor Subunit in Schizophrenia. (PMID:37511595)
• Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning. (PMID:37794492)
• The promoting effects of Grin2d expression in tumorigenesis and the aggressiveness of esophageal cancer. (PMID:37982578)

Cross-species orthologs

36 orthologs

Organism	Symbol	Gene ID
danio_rerio	grin2db	ENSDARG00000070620
danio_rerio	grin2da	ENSDARG00000086207
mus_musculus	Grin2d	ENSMUSG00000002771
rattus_norvegicus	Grin2d	ENSRNOG00000021063
drosophila_melanogaster	GluRIIA	FBGN0004620
drosophila_melanogaster	GluRIIB	FBGN0020429
drosophila_melanogaster	clumsy	FBGN0026255
drosophila_melanogaster	GluRIID	FBGN0028422
drosophila_melanogaster	Ir7b	FBGN0029965
drosophila_melanogaster	Ir7c	FBGN0029966
drosophila_melanogaster	Ir7g	FBGN0029968
drosophila_melanogaster	Ir25a	FBGN0031634
drosophila_melanogaster	Ir60a	FBGN0034994
drosophila_melanogaster	Ir64a	FBGN0035604
drosophila_melanogaster	Ir68a	FBGN0036150
drosophila_melanogaster	Ir75a	FBGN0036757
drosophila_melanogaster	Ir75d	FBGN0036829
drosophila_melanogaster	Ir76b	FBGN0036937
drosophila_melanogaster	Ir84a	FBGN0037501
drosophila_melanogaster	Ir85a	FBGN0037630
drosophila_melanogaster	Ir92a	FBGN0038789
drosophila_melanogaster	Grik	FBGN0038840
drosophila_melanogaster	Ir41a	FBGN0040849
drosophila_melanogaster	GluRIIC	FBGN0046113
drosophila_melanogaster	GluRIIE	FBGN0051201
drosophila_melanogaster	Nmdar2	FBGN0053513
drosophila_melanogaster	Ir7e	FBGN0259189
drosophila_melanogaster	Ir94d	FBGN0259193
drosophila_melanogaster	Ir93a	FBGN0259215
drosophila_melanogaster	Ir40a	FBGN0259683
drosophila_melanogaster	Ir76a	FBGN0260874
drosophila_melanogaster	Ir75c	FBGN0261401
drosophila_melanogaster	Ir75b	FBGN0261402
caenorhabditis_elegans		WBGENE00001618
caenorhabditis_elegans		WBGENE00003775
caenorhabditis_elegans		WBGENE00012190

Paralogs (17): GRIK5 (ENSG00000105737), GRIN3B (ENSG00000116032), GRIA2 (ENSG00000120251), GRIA3 (ENSG00000125675), GRIK4 (ENSG00000149403), GRID2 (ENSG00000152208), GRIA4 (ENSG00000152578), GRIA1 (ENSG00000155511), GRIN2C (ENSG00000161509), GRIK3 (ENSG00000163873), GRIK2 (ENSG00000164418), GRIK1 (ENSG00000171189), GRIN1 (ENSG00000176884), GRID1 (ENSG00000182771), GRIN2A (ENSG00000183454), GRIN3A (ENSG00000198785), GRIN2B (ENSG00000273079)

Protein

Protein identifiers

Glutamate receptor ionotropic, NMDA 2D — O15399 (reviewed: O15399)

Alternative names: EB11, Glutamate [NMDA] receptor subunit epsilon-4, N-methyl D-aspartate receptor subtype 2D

All UniProt accessions (1): O15399

UniProt curated annotations — full annotation on UniProt →

Function. Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+). Participates in synaptic plasticity for learning and memory formation. Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit, plus membrane depolarization to eliminate channel inhibition by Mg(2+). NMDARs mediate simultaneously the potassium efflux and the influx of calcium and sodium. Each GluN2 subunit confers differential attributes to channel properties, including activation, deactivation and desensitization kinetics, pH sensitivity, Ca2(+) permeability, and binding to allosteric modulators.

Subunit / interactions. Heterotetramer. Forms heterotetrameric channels composed of two GluN1/zeta subunits (GRIN1), and two identical GluN2/epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) or GluN3 subunits (GRIN3A or GRIN3B) (in vitro). In vivo, the subunit composition may depend on the expression levels of the different subunits. Interacts with PDZ domains of PATJ and DLG4.

Subcellular location. Cell membrane. Postsynaptic cell membrane.

Disease relevance. Developmental and epileptic encephalopathy 46 (DEE46) [MIM:617162] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. A hydrophobic region that gives rise to the prediction of a transmembrane span does not cross the membrane, but is part of a discontinuously helical region that dips into the membrane and is probably part of the pore and of the selectivity filter.

Similarity. Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. NR2D/GRIN2D subfamily.

RefSeq proteins (1): NP_000827* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001320	Iontro_rcpt_C	Domain
IPR001508	Iono_Glu_rcpt_met	Family
IPR001828	ANF_lig-bd_rcpt	Domain
IPR015683	Ionotropic_Glu_rcpt	Family
IPR019594	Glu/Gly-bd	Domain
IPR028082	Peripla_BP_I	Homologous_superfamily

Pfam: PF00060, PF01094, PF10613

Catalyzed reactions (Rhea), 3 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)
• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)
• Na(+)(in) = Na(+)(out) (RHEA:34963)

UniProt features (139 total): strand 42, helix 32, sequence variant 13, compositionally biased region 7, binding site 6, glycosylation site 6, topological domain 5, turn 4, region of interest 4, disulfide bond 4, sequence conflict 4, transmembrane region 3, modified residue 2, mutagenesis site 2, signal peptide 1, chain 1, short sequence motif 1, site 1, intramembrane region 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
9D37	ELECTRON MICROSCOPY	3.34
8E96	ELECTRON MICROSCOPY	3.38
7YFF	ELECTRON MICROSCOPY	3.6
9D39	ELECTRON MICROSCOPY	3.65
9D3B	ELECTRON MICROSCOPY	3.71
9D3A	ELECTRON MICROSCOPY	3.78
7YFL	ELECTRON MICROSCOPY	3.9
9D38	ELECTRON MICROSCOPY	3.95
9D3C	ELECTRON MICROSCOPY	3.96
8Y1V	ELECTRON MICROSCOPY	4.2
7YFM	ELECTRON MICROSCOPY	5.1
7YFR	ELECTRON MICROSCOPY	5.1
7YFO	ELECTRON MICROSCOPY	6.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15399-F1	64.00	0.15

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 642 (functional determinant of nmda receptors)

Ligand- & substrate-binding residues (6): 539; 541; 546; 717; 718; 759

Post-translational modifications (2): 1316, 1326

Disulfide bonds (4): 104–348, 455–483, 462–484, 773–828

Glycosylation sites (6): 92, 352, 366, 384, 467, 569

Mutagenesis-validated functional residues (2):

Position	Phenotype
580	changed glutamate-gated calcium ion channel activity characterized by increased glutamate and glycine potency.
845	increased glutamate and glycine agonist potency.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-438066	Unblocking of NMDA receptors, glutamate binding and activation
R-HSA-442982	Ras activation upon Ca2+ influx through NMDA receptor
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6794361	Neurexins and neuroligins
R-HSA-8849932	Synaptic adhesion-like molecules
R-HSA-9609736	Assembly and cell surface presentation of NMDA receptors
R-HSA-9617324	Negative regulation of NMDA receptor-mediated neuronal transmission
R-HSA-9620244	Long-term potentiation

MSigDB gene sets: 325 (showing top): GOBP_POSITIVE_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BENPORATH_ES_WITH_H3K27ME3, GOBP_BEHAVIOR, GOMF_GLUTAMATE_GATED_RECEPTOR_ACTIVITY, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_REGULATION_OF_NEURONAL_SYNAPTIC_PLASTICITY, GOBP_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GCANCTGNY_MYOD_Q6, GOBP_ADULT_BEHAVIOR, GOBP_CELLULAR_RESPONSE_TO_ACID_CHEMICAL, GOBP_ADULT_LOCOMOTORY_BEHAVIOR, GGGTGGRR_PAX4_03, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, BIOCARTA_NOS1_PATHWAY

GO Biological Process (21): startle response (GO:0001964), brain development (GO:0007420), adult locomotory behavior (GO:0008344), ionotropic glutamate receptor signaling pathway (GO:0035235), synaptic transmission, glutamatergic (GO:0035249), regulation of synaptic plasticity (GO:0048167), regulation of neuronal synaptic plasticity (GO:0048168), regulation of sensory perception of pain (GO:0051930), positive regulation of synaptic transmission, glutamatergic (GO:0051968), excitatory postsynaptic potential (GO:0060079), long-term synaptic potentiation (GO:0060291), calcium ion transmembrane import into cytosol (GO:0097553), monoatomic cation transmembrane transport (GO:0098655), excitatory chemical synaptic transmission (GO:0098976), regulation of monoatomic cation transmembrane transport (GO:1904062), cellular response to L-glutamate (GO:1905232), positive regulation of excitatory postsynaptic potential (GO:2000463), monoatomic ion transport (GO:0006811), calcium-mediated signaling (GO:0019722), monoatomic ion transmembrane transport (GO:0034220), regulation of presynaptic membrane potential (GO:0099505)

GO Molecular Function (12): glutamate-gated receptor activity (GO:0004970), NMDA glutamate receptor activity (GO:0004972), glutamate binding (GO:0016595), voltage-gated monoatomic cation channel activity (GO:0022843), glutamate-gated calcium ion channel activity (GO:0022849), ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential (GO:0099507), transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential (GO:1904315), monoatomic ion channel activity (GO:0005216), monoatomic cation channel activity (GO:0005261), protein binding (GO:0005515), ligand-gated monoatomic ion channel activity (GO:0015276), signaling receptor activity (GO:0038023)

GO Cellular Component (11): endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), NMDA selective glutamate receptor complex (GO:0017146), postsynaptic membrane (GO:0045211), presynaptic active zone membrane (GO:0048787), hippocampal mossy fiber to CA3 synapse (GO:0098686), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), membrane (GO:0016020), presynaptic membrane (GO:0042734), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Activation of NMDA receptors and postsynaptic events	3
Protein-protein interactions at synapses	2
CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling	1
MAPK1/MAPK3 signaling	1
Post NMDA receptor activation events	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
glutamate-gated receptor activity	3
synaptic membrane	3
chemical synaptic transmission	2
regulation of synaptic plasticity	2
positive regulation of synaptic transmission	2
regulation of postsynaptic membrane potential	2
excitatory postsynaptic potential	2
transmitter-gated monoatomic ion channel activity	2
voltage-gated monoatomic ion channel activity	2
presynaptic membrane	2
monoatomic ion channel activity	2
response to external stimulus	1
neuromuscular process	1
central nervous system development	1
animal organ development	1
head development	1
locomotory behavior	1
adult behavior	1
glutamate receptor signaling pathway	1
ligand-gated ion channel signaling pathway	1
modulation of chemical synaptic transmission	1
regulation of biological quality	1
sensory perception of pain	1
regulation of sensory perception	1
synaptic transmission, glutamatergic	1
regulation of synaptic transmission, glutamatergic	1
chemical synaptic transmission, postsynaptic	1
calcium ion transmembrane transport	1
monoatomic cation transport	1
monoatomic ion transmembrane transport	1
regulation of monoatomic ion transmembrane transport	1
monoatomic cation transmembrane transport	1
cellular response to amino acid stimulus	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
response to L-glutamate	1
positive regulation of signal transduction	1
modulation of excitatory postsynaptic potential	1
transport	1
intracellular signaling cassette	1

Protein interactions and networks

STRING

1206 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GRIN2D	GRIN1	P35437	990
GRIN2D	GRIN3B	O60391	988
GRIN2D	GRIN3A	Q8TCU5	988
GRIN2D	GRIN2A	Q12879	984
GRIN2D	GRIN2B	Q13224	984
GRIN2D	GRIN2C	Q14957	983
GRIN2D	EBAG9	O00559	856
GRIN2D	COX7A2L	O14548	839
GRIN2D	PRNP	P04156	775
GRIN2D	DLG4	P78352	670
GRIN2D	GRM7	Q14831	666
GRIN2D	GRM3	Q14832	664
GRIN2D	GRM1	Q13255	656
GRIN2D	GRINA	Q7Z429	629
GRIN2D	BDNF	P23560	628

IntAct

10 interactions, top by confidence:

A	B	Type	Score
DLG1	GRIN2D	psi-mi:“MI:0407”(direct interaction)	0.440
Dlg3	GRIN2D	psi-mi:“MI:0407”(direct interaction)	0.440
DLG4	GRIN2D	psi-mi:“MI:0407”(direct interaction)	0.440
GRIN2D	Dlg4	psi-mi:“MI:0407”(direct interaction)	0.440
CRK	GRIN2D	psi-mi:“MI:0915”(physical association)	0.400
M		psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
NME3	VWA8	psi-mi:“MI:0914”(association)	0.350

BioGRID (14): GRIN2D (Affinity Capture-RNA), GRIN2D (Affinity Capture-Western), Dlgap2 (Two-hybrid), GRIN2D (Affinity Capture-RNA), GRIN2D (Affinity Capture-Western), GRIN2D (Affinity Capture-Western), GRIN2D (Affinity Capture-MS), GRIN2D (Co-fractionation), GRIN2D (Co-fractionation), GRIN2D (Co-fractionation), GRIN2D (Cross-Linking-MS (XL-MS)), GRIN2D (Affinity Capture-Western), NEDD4 (Affinity Capture-Western), GRIN2D (Affinity Capture-MS)

ESM2 similar proteins: A2A259, A2AIR5, H2Q5A1, O00222, O15399, O60242, O75077, O75882, O97741, P15209, P24786, P31423, P35400, P37088, P47743, P55270, P70579, Q00961, Q01098, Q03351, Q03391, Q13507, Q14833, Q14957, Q16288, Q1ZZH0, Q4R766, Q5IS37, Q5RDQ8, Q62645, Q63604, Q68ED2, Q68EF4, Q6AYT7, Q80ZF8, Q8CIW5, Q8TCU5, Q8VHN2, Q91044, Q91YD4

Diamond homologs: A0A1L8F5J9, A2AIR5, O15399, O60391, Q8TCU5, Q8VHN2, Q91ZU9, Q9R1M7, A0A2R8QF68, A7XY94, B1AS29, B7ZSK1, O43424, P0AEQ3, P0AEQ4, P0AEQ5, P22756, P35436, P39086, P42264, Q00959, Q00960, Q00961, Q01097, Q01098, Q01812, Q03391, Q10914, Q12879, Q13003, Q13224, Q14957, Q38PU2, Q38PU4, Q5IS45, Q5R1P3, Q60934, Q61625, Q62645, Q63226

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
GRIN2D	“form complex”	“NMDA receptor_2D”	binding
NEDD4	“down-regulates activity”	GRIN2D	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

1408 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	8
Uncertain significance	790
Likely benign	517
Benign	29

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
1325736	NM_000836.4(GRIN2D):c.1718C>T (p.Ser573Phe)	Pathogenic
1499341	NM_000836.4(GRIN2D):c.2024C>A (p.Ala675Asp)	Pathogenic
1685871	NM_000836.4(GRIN2D):c.1997C>T (p.Ala666Val)	Pathogenic
599388	NM_000836.4(GRIN2D):c.2043G>C (p.Met681Ile)	Pathogenic
599389	NM_000836.4(GRIN2D):c.2080A>C (p.Ser694Arg)	Pathogenic
1013175	NM_000836.4(GRIN2D):c.2511C>A (p.Ser837Arg)	Likely pathogenic
1325737	NM_000836.4(GRIN2D):c.2033C>A (p.Ala678Asp)	Likely pathogenic
1333739	NM_000836.4(GRIN2D):c.2029C>G (p.Leu677Val)	Likely pathogenic
1803034	NM_000836.4(GRIN2D):c.2330C>T (p.Thr777Ile)	Likely pathogenic
3652336	NM_000836.4(GRIN2D):c.2082T>A (p.Ser694Arg)	Likely pathogenic
3725727	NM_000836.4(GRIN2D):c.1762ATG[1] (p.Met589del)	Likely pathogenic
3901882	NM_000836.4(GRIN2D):c.2530A>C (p.Asn844His)	Likely pathogenic
599390	NM_000836.4(GRIN2D):c.1345G>A (p.Asp449Asn)	Likely pathogenic

SpliceAI

2150 predictions. Top by Δscore:

Variant	Effect	Δscore
19:48394934:AAGG:A	donor_loss	1.0000
19:48394936:GGT:G	donor_loss	1.0000
19:48394937:G:GA	donor_loss	1.0000
19:48405352:AGGTG:A	donor_loss	1.0000
19:48405353:GGT:G	donor_loss	1.0000
19:48405354:G:A	donor_loss	1.0000
19:48405354:G:GG	donor_gain	1.0000
19:48405355:T:G	donor_loss	1.0000
19:48413984:T:A	acceptor_gain	1.0000
19:48413985:G:A	acceptor_gain	1.0000
19:48413987:GCA:G	acceptor_loss	1.0000
19:48413988:CAG:C	acceptor_loss	1.0000
19:48413989:AGGTA:A	acceptor_loss	1.0000
19:48413990:G:GA	acceptor_loss	1.0000
19:48414093:G:GT	donor_gain	1.0000
19:48414103:GTG:G	donor_gain	1.0000
19:48414365:T:A	acceptor_gain	1.0000
19:48414370:A:AG	acceptor_gain	1.0000
19:48414370:AAG:A	acceptor_gain	1.0000
19:48414370:AAGGT:A	acceptor_gain	1.0000
19:48414371:A:T	acceptor_loss	1.0000
19:48414372:G:GC	acceptor_loss	1.0000
19:48419358:GC:G	donor_gain	1.0000
19:48419360:G:GG	donor_gain	1.0000
19:48419773:G:GT	donor_gain	1.0000
19:48419773:GAGGA:G	donor_gain	1.0000
19:48419775:GGA:G	donor_gain	1.0000
19:48419776:GAG:G	donor_gain	1.0000
19:48419778:G:GG	donor_gain	1.0000
19:48419812:AAG:A	donor_loss	1.0000

AlphaMissense

8554 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:48398703:G:A	C104Y	1.000
19:48398733:G:A	G114D	1.000
19:48398814:T:A	I141N	1.000
19:48404750:T:G	F161C	1.000
19:48404753:T:C	L162P	1.000
19:48404783:T:C	L172P	1.000
19:48404804:T:C	L179P	1.000
19:48404911:T:A	W215R	1.000
19:48404911:T:C	W215R	1.000
19:48404913:G:C	W215C	1.000
19:48404913:G:T	W215C	1.000
19:48405082:T:A	W272R	1.000
19:48405082:T:C	W272R	1.000
19:48405256:G:C	G330R	1.000
19:48405257:G:A	G330D	1.000
19:48414031:T:C	F376L	1.000
19:48414032:T:C	F376S	1.000
19:48414032:T:G	F376C	1.000
19:48414033:C:A	F376L	1.000
19:48414033:C:G	F376L	1.000
19:48414044:G:T	G380V	1.000
19:48414071:T:A	V389D	1.000
19:48414467:T:C	L432P	1.000
19:48414479:C:A	T436K	1.000
19:48414482:T:C	L437P	1.000
19:48414487:G:A	E439K	1.000
19:48414488:A:T	E439V	1.000
19:48414493:C:A	P441T	1.000
19:48414493:C:T	P441S	1.000
19:48414494:C:A	P441Q	1.000

dbSNP variants (sampled 300 via entrez): RS1000020080 (19:48415806 T>C), RS1000031629 (19:48415169 G>A,C), RS1000047358 (19:48440445 T>TAGCC), RS1000125913 (19:48392020 G>A), RS1000140066 (19:48402574 G>A,C), RS1000162027 (19:48441013 G>C), RS1000278688 (19:48440741 C>T), RS1000319960 (19:48397051 C>T), RS1000335782 (19:48422130 A>C,G), RS1000335815 (19:48428008 T>C), RS1000396161 (19:48415190 G>A), RS1000409250 (19:48392748 C>A,G,T), RS1000487816 (19:48402409 C>T), RS1000496847 (19:48413678 A>AT), RS1000536151 (19:48422395 A>C)

Disease associations

OMIM: gene MIM:602717 | disease phenotypes: MIM:617162

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 46	Strong	Autosomal dominant
undetermined early-onset epileptic encephalopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (3): developmental and epileptic encephalopathy, 46 (MONDO:0014947), intellectual disability (MONDO:0001071), undetermined early-onset epileptic encephalopathy (MONDO:0018614)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

59 total (30 of 59 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000252	Microcephaly
HP:0000348	High forehead
HP:0000494	Downslanted palpebral fissures
HP:0000504	Abnormality of vision
HP:0000508	Ptosis
HP:0000546	Retinal degeneration
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000668	Hypodontia
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001273	Abnormal corpus callosum morphology
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001315	Reduced tendon reflexes
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001344	Absent speech
HP:0001508	Failure to thrive
HP:0001558	Decreased fetal movement

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2094124 (PROTEIN COMPLEX GROUP), CHEMBL2591 (SINGLE PROTEIN), CHEMBL3038505 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

29 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,394,487 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL52440	DEXTROMETHORPHAN	4	33,223
CHEMBL592	LEVORPHANOL	4	75,131
CHEMBL660	AMANTADINE	4	69,750
CHEMBL71	CHLORPROMAZINE	4	45,827
CHEMBL742	KETAMINE	4	101,983
CHEMBL807	MEMANTINE	4	34,597
CHEMBL86715	PROCYCLIDINE	4	5,456
CHEMBL900	ORPHENADRINE	4	8,087
CHEMBL771	CYCLOSERINE	4	23,487
CHEMBL575060	GLUTAMIC ACID	3	929,756
CHEMBL5095095	DALZANEMDOR	3	20
CHEMBL350719	ESMETHADONE	3	26,004
CHEMBL1254766	DEXTRORPHAN	2	6,521
CHEMBL14935	TEZAMPANEL ANHYDROUS	2	106
CHEMBL17350	TRAXOPRODIL	2	2,547
CHEMBL182066	RADIPRODIL	2	126
CHEMBL22207	RACEMETHORPHAN	2	748
CHEMBL275528	PHENCYCLIDINE	2	25,537
CHEMBL284237	DIZOCILPINE	2	5,015
CHEMBL289832	LICOSTINEL	2	566
CHEMBL334491	BUDIPINE	2
CHEMBL39664	SELFOTEL	2
CHEMBL452461	PERZINFOTEL	2
CHEMBL467084	LANICEMINE	2
CHEMBL305187	IFENPRODIL	2
CHEMBL159659	LEVOMETHADONE	2
CHEMBL159660	ALPHAMETHADOL	2
CHEMBL162243	BETAMETHADOL	2
CHEMBL299155	TRANSTORINE	1

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: lgic — Ionotropic glutamate receptors

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
DQP-1105	Negative	5.57	pIC50
QNZ 46	Negative	5.49	pIC50

ChEMBL bioactivities

451 potent at pChembl≥5 of 598 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.30	IC50	0.5	nM	CHEMBL276708
9.10	IC50	0.8	nM	CHEMBL12513
9.02	Ki	0.96	nM	CHEMBL39881
9.00	IC50	1	nM	CHEMBL12804
8.92	IC50	1.2	nM	CHEMBL12242
8.92	Ki	1.2	nM	DIZOCILPINE
8.85	Ki	1.4	nM	CHEMBL5185347
8.82	IC50	1.5	nM	CHEMBL537478
8.82	IC50	1.5	nM	CHEMBL274422
8.82	IC50	1.5	nM	CHEMBL273662
8.77	IC50	1.7	nM	CHEMBL269683
8.71	Ki	1.94	nM	CNS-5161
8.70	IC50	2	nM	CHEMBL536107
8.70	Ki	2	nM	CHEMBL299294
8.64	Ki	2.3	nM	CHEMBL39773
8.59	Ki	2.6	nM	CHEMBL290738
8.59	IC50	2.6	nM	CHEMBL450325
8.52	Ki	3	nM	CHEMBL5208012
8.52	IC50	3	nM	CHEMBL552664
8.52	Ki	3	nM	CHEMBL166935
8.52	Ki	3	nM	CHEMBL166991
8.51	Ki	3.1	nM	CHEMBL290649
8.48	Ki	3.3	nM	CHEMBL5208606
8.47	Ki	3.4	nM	CHEMBL66626
8.46	Ki	3.5	nM	CHEMBL50872
8.42	Ki	3.8	nM	CHEMBL68831
8.42	Ki	3.8	nM	CHEMBL306899
8.40	IC50	4	nM	CHEMBL363010
8.40	IC50	4	nM	BESONPRODIL
8.40	IC50	4	nM	CHEMBL317229
8.40	Ki	4	nM	CHEMBL354482
8.40	Ki	4	nM	CHEMBL170552
8.40	Ki	4	nM	CHEMBL169695
8.39	IC50	4.1	nM	CHEMBL557993
8.36	Ki	4.4	nM	CHEMBL40730
8.36	IC50	4.4	nM	CHEMBL61720
8.35	Ki	4.5	nM	CHEMBL100656
8.33	IC50	4.7	nM	CHEMBL297881
8.31	Ki	4.9	nM	CHEMBL70918
8.30	IC50	5	nM	CHEMBL363722
8.30	Ki	5	nM	CHEMBL166697
8.29	Ki	5.1	nM	CHEMBL38994
8.25	Ki	5.6	nM	CHEMBL305195
8.23	IC50	5.9	nM	LICOSTINEL
8.22	IC50	6	nM	RADIPRODIL
8.22	IC50	6	nM	CHEMBL305195
8.22	Ki	6	nM	CHEMBL305195
8.22	IC50	6	nM	CHEMBL126929
8.18	Ki	6.6	nM	CHEMBL289607
8.17	Ki	6.8	nM	DIZOCILPINE

PubChem BioAssay actives

390 with measured affinity, of 927 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylphosphonic acid	144039: Compound was tested in vitro for its inhibitory activity at 1 uM concentration against N-methyl-D-aspartate glutamate receptor by using [3H]CGP-39653 binding assay	ic50	0.0005	uM
[7-(4-chlorophenyl)-2,3-dioxo-1,4-dihydroquinoxalin-5-yl]methylphosphonic acid	144043: In vitro inhibitory activity at 1 uM concentration against N-methyl-D-aspartate glutamate receptor, using [3H]CGP-39653 binding assay	ic50	0.0008	uM
(7-fluoro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylphosphonic acid	144043: In vitro inhibitory activity at 1 uM concentration against N-methyl-D-aspartate glutamate receptor, using [3H]CGP-39653 binding assay	ic50	0.0010	uM
2-[(12S)-7-bromo-2,3-dioxo-1,4-diazatricyclo[7.3.1.05,13]trideca-5,7,9(13)-trien-12-yl]-N-phenylacetamide	1859114: Displacement of [3H]DCKA from NMDA receptor (unknown origin)	ki	0.0010	uM
(1S,9R)-1-methyl-16-azatetracyclo[7.6.1.02,7.010,15]hexadeca-2,4,6,10,12,14-hexaene	156805: The compound was tested for its ability to block PCP N-methyl-D-aspartate glutamate receptor at the PCP (phencyclidine) binding site in postmortem human frontal cortex.	ki	0.0012	uM
[hydroxy-(7-nitro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methyl]phosphonic acid	144043: In vitro inhibitory activity at 1 uM concentration against N-methyl-D-aspartate glutamate receptor, using [3H]CGP-39653 binding assay	ic50	0.0012	uM
2-[(11S)-7-bromo-11-ethyl-2,3-dioxo-1,4-diazatricyclo[7.3.1.05,13]trideca-5,7,9(13)-trien-12-yl]acetic acid	1859114: Displacement of [3H]DCKA from NMDA receptor (unknown origin)	ki	0.0014	uM
(7-bromo-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylphosphonic acid	144043: In vitro inhibitory activity at 1 uM concentration against N-methyl-D-aspartate glutamate receptor, using [3H]CGP-39653 binding assay	ic50	0.0015	uM
[(2,3-dioxo-1,4-dihydroquinoxalin-5-yl)-hydroxymethyl]phosphonic acid	144043: In vitro inhibitory activity at 1 uM concentration against N-methyl-D-aspartate glutamate receptor, using [3H]CGP-39653 binding assay	ic50	0.0015	uM
[(benzylamino)-(7-nitro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methyl]phosphonic acid;hydrobromide	144043: In vitro inhibitory activity at 1 uM concentration against N-methyl-D-aspartate glutamate receptor, using [3H]CGP-39653 binding assay	ic50	0.0015	uM
(7-chloro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylphosphonic acid	144043: In vitro inhibitory activity at 1 uM concentration against N-methyl-D-aspartate glutamate receptor, using [3H]CGP-39653 binding assay	ic50	0.0017	uM
2-(2-chloro-5-methylsulfanylphenyl)-1-methyl-1-(3-methylsulfanylphenyl)guanidine	143453: In vitro displacement of [3H]MK-801 from N-methyl-D-aspartate glutamate receptor	ki	0.0019	uM
[(benzylamino)-(2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methyl]phosphonic acid;hydrobromide	144043: In vitro inhibitory activity at 1 uM concentration against N-methyl-D-aspartate glutamate receptor, using [3H]CGP-39653 binding assay	ic50	0.0020	uM
2-[[2-(3,4-dihydro-1H-isoquinolin-2-yl)-4-pyridinyl]amino]ethanol	143451: Binding affinity against NMDA receptor by displacement of [3H]Ro-256981	ki	0.0020	uM
2-[(12S)-7-bromo-2,3-dioxo-1,4-diazatricyclo[7.3.1.05,13]trideca-5,7,9(13)-trien-12-yl]acetic acid	1859114: Displacement of [3H]DCKA from NMDA receptor (unknown origin)	ki	0.0023	uM
2-(7-bromo-2,3-dioxo-1,4-diazatricyclo[7.3.1.05,13]trideca-5,7,9(13)-trien-12-yl)-N-phenylacetamide	1859114: Displacement of [3H]DCKA from NMDA receptor (unknown origin)	ki	0.0026	uM
6,7-dichloro-5-[1-(1,2,4-triazol-4-yl)propyl]-1,4-dihydroquinoxaline-2,3-dione	1859120: Displacement of [3H]L-689560 from NMDA receptor (unknown origin)	ic50	0.0026	uM
2-[(11S)-7-bromo-11-methyl-2,3-dioxo-1,4-diazatricyclo[7.3.1.05,13]trideca-5,7,9(13)-trien-12-yl]-N-phenylacetamide	1859114: Displacement of [3H]DCKA from NMDA receptor (unknown origin)	ki	0.0030	uM
[(cyclohexylmethylamino)-(7-nitro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methyl]phosphonic acid;hydrochloride	144043: In vitro inhibitory activity at 1 uM concentration against N-methyl-D-aspartate glutamate receptor, using [3H]CGP-39653 binding assay	ic50	0.0030	uM
2-(3,4-dihydro-1H-isoquinolin-2-yl)pyridin-4-amine	143451: Binding affinity against NMDA receptor by displacement of [3H]Ro-256981	ki	0.0030	uM
2-(3,4-dihydro-1H-isoquinolin-2-yl)-6-ethylpyridin-4-amine	143451: Binding affinity against NMDA receptor by displacement of [3H]Ro-256981	ki	0.0030	uM
2-[(11S)-7-chloro-11-methyl-2,3-dioxo-1,4-diazatricyclo[7.3.1.05,13]trideca-5,7,9(13)-trien-12-yl]-N-phenylacetamide	1859114: Displacement of [3H]DCKA from NMDA receptor (unknown origin)	ki	0.0031	uM
2-[(11S)-7-bromo-11-methyl-2,3-dioxo-1,4-diazatricyclo[7.3.1.05,13]trideca-5,7,9(13)-trien-12-yl]acetic acid	1859114: Displacement of [3H]DCKA from NMDA receptor (unknown origin)	ki	0.0033	uM
4-[3-(4-benzylpiperidin-1-yl)-2-methylpropyl]phenol	143454: Displacement of [3H]25-6981 from N-methyl-D-aspartate glutamate receptor	ki	0.0034	uM
2-[[2-(3,4-dihydro-1H-isoquinolin-2-yl)quinolin-4-yl]amino]ethanol	143451: Binding affinity against NMDA receptor by displacement of [3H]Ro-256981	ki	0.0035	uM
4-[3-(4-benzylpiperidin-1-yl)-1-hydroxypropyl]phenol	143454: Displacement of [3H]25-6981 from N-methyl-D-aspartate glutamate receptor	ki	0.0038	uM
4-[3-(4-benzylpiperidin-1-yl)-2-hydroxypropyl]phenol	143454: Displacement of [3H]25-6981 from N-methyl-D-aspartate glutamate receptor	ki	0.0038	uM
2-(4-benzylpiperidin-1-yl)-2-oxo-N-(2-oxo-1,3-dihydrobenzimidazol-5-yl)acetamide	241037: Inhibition of [3H]-Ro-25-6981 binding to NMDA receptor	ic50	0.0040	uM
6-[2-[4-[(4-fluorophenyl)methyl]piperidin-1-yl]ethylsulfinyl]-3H-1,3-benzoxazol-2-one	143455: Inhibition of [3H]Ro-256981 binding to N-methyl-D-aspartate glutamate receptor	ic50	0.0040	uM
1-[2-(4-hydroxyphenoxy)ethyl]-4-[(4-methylphenyl)methyl]piperidin-4-ol	241037: Inhibition of [3H]-Ro-25-6981 binding to NMDA receptor	ic50	0.0040	uM
[4-amino-6-(3,4-dihydro-1H-isoquinolin-2-yl)-2-pyridinyl]methanol	143451: Binding affinity against NMDA receptor by displacement of [3H]Ro-256981	ki	0.0040	uM
2-[[2-(3,4-dihydro-1H-isoquinolin-2-yl)-6-methyl-4-pyridinyl]amino]ethanol	143451: Binding affinity against NMDA receptor by displacement of [3H]Ro-256981	ki	0.0040	uM
2-(3,4-dihydro-1H-isoquinolin-2-yl)-5-methylpyridin-4-amine	143451: Binding affinity against NMDA receptor by displacement of [3H]Ro-256981	ki	0.0040	uM
[(furan-2-ylmethylamino)-(7-nitro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methyl]phosphonic acid;hydrobromide	144043: In vitro inhibitory activity at 1 uM concentration against N-methyl-D-aspartate glutamate receptor, using [3H]CGP-39653 binding assay	ic50	0.0041	uM
6,7-dichloro-5-[(1-propylimidazol-4-yl)methyl]-1,4-dihydroquinoxaline-2,3-dione	1859120: Displacement of [3H]L-689560 from NMDA receptor (unknown origin)	ic50	0.0044	uM
2-[(11S)-7-chloro-11-methyl-2,3-dioxo-1,4-diazatricyclo[7.3.1.05,13]trideca-5,7,9(13)-trien-12-yl]acetic acid	1859114: Displacement of [3H]DCKA from NMDA receptor (unknown origin)	ki	0.0044	uM
(1S,9R)-10-[(2R)-2-methoxypropyl]-1,13,13-trimethyl-10-azatricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-5-ol	1960006: Antagonist activity at NMDA receptor (unknown origin) assessed as inhibition constant	ki	0.0045	uM
7-chloro-6-methyl-5-nitro-1,4-dihydroquinoxaline-2,3-dione	143443: Inhibition of [3H]DCKA binding to N-methyl-D-aspartate glutamate receptor	ic50	0.0047	uM
1-[(2R)-2-hydroxy-3-(4-hydroxyphenyl)propyl]-4-[(4-methylphenyl)methyl]piperidin-4-ol	143454: Displacement of [3H]25-6981 from N-methyl-D-aspartate glutamate receptor	ki	0.0049	uM
2-[4-[(4-fluorophenyl)methyl]piperidin-1-yl]-2-oxo-N-(2-oxo-1,3-dihydrobenzimidazol-5-yl)acetamide	241037: Inhibition of [3H]-Ro-25-6981 binding to NMDA receptor	ic50	0.0050	uM
2-(3,4-dihydro-1H-isoquinolin-2-yl)-6-methylpyridin-4-amine	143451: Binding affinity against NMDA receptor by displacement of [3H]Ro-256981	ki	0.0050	uM
2-(7-chloro-2,3-dioxo-1,4-diazatricyclo[7.3.1.05,13]trideca-5,7,9(13)-trien-12-yl)acetic acid	1859114: Displacement of [3H]DCKA from NMDA receptor (unknown origin)	ki	0.0051	uM
4-[(1R,2S)-3-(4-benzylpiperidin-1-yl)-1-hydroxy-2-methylpropyl]phenol	143454: Displacement of [3H]25-6981 from N-methyl-D-aspartate glutamate receptor	ki	0.0056	uM
6,7-dichloro-5-nitro-1,4-dihydroquinoxaline-2,3-dione	143443: Inhibition of [3H]DCKA binding to N-methyl-D-aspartate glutamate receptor	ic50	0.0059	uM
2-[4-[(4-fluorophenyl)methyl]piperidin-1-yl]-2-oxo-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide	241037: Inhibition of [3H]-Ro-25-6981 binding to NMDA receptor	ic50	0.0060	uM
(4-benzylpiperidin-1-yl)-(4,6-dihydroxy-1H-indol-2-yl)methanone	143455: Inhibition of [3H]Ro-256981 binding to N-methyl-D-aspartate glutamate receptor	ic50	0.0060	uM
2-(7-chloro-2,3-dioxo-1,4-diazatricyclo[7.3.1.05,13]trideca-5,7,9(13)-trien-12-yl)-N-phenylacetamide	1859114: Displacement of [3H]DCKA from NMDA receptor (unknown origin)	ki	0.0066	uM
5,6,7-trichloro-4-hydroxy-3-nitroso-1H-quinolin-2-one	143443: Inhibition of [3H]DCKA binding to N-methyl-D-aspartate glutamate receptor	ic50	0.0070	uM
1-[(1S,2S)-1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl]-4-phenylpiperidin-4-ol	241037: Inhibition of [3H]-Ro-25-6981 binding to NMDA receptor	ic50	0.0070	uM
(1R)-1-(4-chlorophenyl)-2-[(1R)-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-1-yl]ethanol	238983: Mean inhibitory constant against porcine N-methyl-D-aspartate (NMDA) glutamate receptor; n=3	ki	0.0070	uM

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Aflatoxin B1	decreases methylation	2
sotorasib	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
deguelin	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
thifluzamide	decreases expression	1
pyrachlostrobin	decreases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Leflunomide	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases methylation, affects methylation	1
Estradiol	affects cotreatment, increases expression	1
Niclosamide	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tretinoin	increases expression	1
Valproic Acid	increases methylation	1
1-Methyl-4-phenylpyridinium	increases expression	1
Asbestos, Serpentine	decreases methylation	1
Excitatory Amino Acid Agonists	increases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	increases abundance, increases expression	1

ChEMBL screening assays

227 unique, capped per target: 214 binding, 8 functional, 4 admet, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1247908	Binding	Binding affinity to human recombinant NMDA receptor	Spiroindolones, a potent compound class for the treatment of malaria. — Science
CHEMBL2208698	Functional	Antagonist activity at NMDA receptor (unknwon origin)	Synopsis of some recent tactical application of bioisosteres in drug design. — J Med Chem
CHEMBL4680007	ADMET	Inhibition of NMDA receptor (unknown origin)	Fragment-Based Discovery of Novel Allosteric MEK1 Binders. — ACS Med Chem Lett

Cellosaurus cell lines

6 cell lines: 3 cancer cell line, 1 induced pluripotent stem cell, 1 spontaneously immortalized cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A4YK	BGUi011-A	Induced pluripotent stem cell	Male
CVCL_B3U1	CHO-hGluN1-hGluN2D	Spontaneously immortalized cell line	Female
CVCL_C9D4	B’SYS HEK 293 NMDA NR1/NR2D	Transformed cell line	Female
CVCL_D7QZ	Ubigene A-549 GRIN2D KO	Cancer cell line	Male
CVCL_D8M4	Ubigene HCT 116 GRIN2D KO	Cancer cell line	Male
CVCL_E2UZ	Ubigene AGS GRIN2D KO	Cancer cell line	Female

Clinical trials (associated diseases)

197 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders