DLG3

Summary

DLG3 (discs large MAGUK scaffold protein 3, HGNC:2902) is a protein-coding gene on chromosome Xq13.1, encoding Disks large homolog 3 (Q92796). Required for learning most likely through its role in synaptic plasticity following NMDA receptor signaling.

This gene encodes a member of the membrane-associated guanylate kinase protein family. The encoded protein may play a role in clustering of NMDA receptors at excitatory synapses. It may also negatively regulate cell proliferation through interaction with the C-terminal region of the adenomatosis polyposis coli tumor suppressor protein. Mutations in this gene have been associated with X-linked cognitive disability. Alternatively spliced transcript variants have been described.

Source: NCBI Gene 1741 — RefSeq curated summary.

At a glance

• Gene–disease (curated): non-syndromic X-linked intellectual disability (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 384 total — 22 pathogenic, 18 likely-pathogenic
• Phenotypes (HPO): 16
• MANE Select transcript: NM_021120

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2902
Approved symbol	DLG3
Name	discs large MAGUK scaffold protein 3
Location	Xq13.1
Locus type	gene with protein product
Status	Approved
Aliases	NE-Dlg, SAP102, SAP-102, NEDLG, KIAA1232, MRX90, PPP1R82
Ensembl gene	ENSG00000082458
Ensembl biotype	protein_coding
OMIM	300189
Entrez	1741

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 5 protein_coding, 4 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000194900, ENST00000374355, ENST00000374360, ENST00000461646, ENST00000463252, ENST00000466140, ENST00000489733, ENST00000494493, ENST00000496931, ENST00000542398, ENST00000949779

RefSeq mRNA: 3 — MANE Select: NM_021120 NM_001166278, NM_020730, NM_021120

CCDS: CCDS14403, CCDS43967, CCDS55439

Canonical transcript exons

ENST00000374360 — 19 exons

Exon	Start	End
ENSE00000436378	70450169	70450305
ENSE00000672250	70450639	70450783
ENSE00001958108	70444835	70445558
ENSE00003469450	70492521	70492596
ENSE00003483338	70499877	70500049
ENSE00003511316	70498520	70498570
ENSE00003548284	70449359	70449483
ENSE00003562095	70451867	70452026
ENSE00003589163	70479150	70479264
ENSE00003615707	70499176	70499277
ENSE00003617252	70454214	70454316
ENSE00003626140	70492107	70492283
ENSE00003626326	70500898	70500989
ENSE00003643927	70448913	70448963
ENSE00003664498	70453637	70453793
ENSE00003686632	70500471	70500580
ENSE00003690291	70449690	70449859
ENSE00003692914	70495408	70495453
ENSE00003733449	70502163	70505490

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 95.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.2532 / max 253.7529, expressed in 1369 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196638	3.9657	834
196637	1.3603	687
196633	1.3343	849
196631	1.0505	139
196635	0.6116	245
196636	0.4417	256
196639	0.2234	101
196632	0.2036	77
196634	0.1127	32

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	95.45	gold quality
body of pancreas	UBERON:0001150	93.58	gold quality
buccal mucosa cell	CL:0002336	93.08	gold quality
ganglionic eminence	UBERON:0004023	92.70	gold quality
pancreas	UBERON:0001264	92.13	gold quality
rectum	UBERON:0001052	91.58	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.18	gold quality
islet of Langerhans	UBERON:0000006	90.92	gold quality
middle temporal gyrus	UBERON:0002771	90.87	gold quality
pancreatic ductal cell	CL:0002079	90.52	gold quality
mucosa of transverse colon	UBERON:0004991	90.39	gold quality
lower esophagus mucosa	UBERON:0035834	89.80	gold quality
prefrontal cortex	UBERON:0000451	89.76	gold quality
ventricular zone	UBERON:0003053	89.66	gold quality
minor salivary gland	UBERON:0001830	89.33	gold quality
esophagus mucosa	UBERON:0002469	89.30	gold quality
transverse colon	UBERON:0001157	88.82	gold quality
right uterine tube	UBERON:0001302	88.42	gold quality
gall bladder	UBERON:0002110	88.40	gold quality
saliva-secreting gland	UBERON:0001044	88.25	gold quality
right frontal lobe	UBERON:0002810	88.10	gold quality
Brodmann (1909) area 9	UBERON:0013540	88.01	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	87.89	gold quality
secondary oocyte	CL:0000655	87.84	gold quality
mouth mucosa	UBERON:0003729	87.77	gold quality
frontal cortex	UBERON:0001870	87.54	gold quality
neocortex	UBERON:0001950	87.40	gold quality
cerebellar cortex	UBERON:0002129	87.40	gold quality
cerebellar hemisphere	UBERON:0002245	87.40	gold quality
body of stomach	UBERON:0001161	87.34	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.71

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

149 targeting DLG3, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-12121	99.99	66.64	255
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-369-3P	99.85	70.52	2264

Literature-anchored findings (GeneRIF, showing 21)

• Loss may lead to altered synaptic plasticity and may explain the intellectual impairment observed in individuals with DLG3 mutations (PMID:15185169)
• The results of this study suggested a putative role for DLG3/SAP102 in cortical hyperexcitability and epileptogenicity of malformations of cortical development. (PMID:19167192)
• Results identified a novel splice site mutation in the disc-large homolog 3 (DLG3) gene, encoding the synapse-associated protein 102 (SAP102) in one out of 300 families with moderate to severe non-syndromic mental retardation. (PMID:19795139)
• DLG3 was identified by genome-wide gene expression analyses as correlated with cellular sensitivity to cisplatin and carboplatin. DLG3 was also found to correlate with cellular sensitivity to platinating agents in NCI-60 cancer cell lines. (PMID:21252287)
• DLG3 did not associate with non-syndromic mental retardation in Chinese Han population; however, further studies are needed. (PMID:21369957)
• A total of six novel and 11 known single nucleotide polymorphisms were identified. Further studies are warranted to analyze the candidate genes at Xq11.1-q21.33. (PMID:21384559)
• Synapse associated protein 102 (SAP102) binds the C-terminal part of the scaffolding protein neurobeachin. (PMID:22745750)
• The PDZ-independent interaction between SAP102 and GluN2B mediates the synaptic clearance of GluN2B-containing NMDARs.(SAP102 protein) (PMID:23103165)
• The data of this study suggested that DLG3 is down-regulated in this cancer type. (PMID:24381070)
• This study identified DLG3 significantly associated loci with a biologically plausible role in schizophrenia. (PMID:24507884)
• miR-1246 might play a role in neurological pathogenesis of human enterovirus 71 by regulating DLG3 gene in infected cells. (PMID:24739954)
• Trans-homophilic interaction of CADM1 activates PI3K by forming a complex with MAGuK-family proteins MPP3 and Dlg. (PMID:25268382)
• These data shed new light on the role of SAP102 in the regulation of NMDAR trafficking. (PMID:25555912)
• Insertion of a guanine into the DLG3 5’ UTR, 7 bp upstream of the start codon, down regulated DLG3 protein levels. This non-coding variant segregates with X-linked intellectual disability in a large family. (PMID:27222290)
• The dupG DLG3 variant segregated with non-syndromic X-linked intellectual disability in a large family and was predicted to disrupt folding of the mRNA. (PMID:27222290)
• Following the critical period NMDA receptor function was unaffected by loss of SAP102 but there was a reduction in the divergence of TC connectivity. These data suggest that changes in synaptic function early in development caused by mutations in SAP102 result in changes in network connectivity later in life. (PMID:27466188)
• This family broadens the mutational and phenotypical spectrum of DLG3-associated non-syndromic X-linked intellectual disability and demonstrates that heterozygous female mutation carriers can be as severely affected as males. (PMID:28777483)
• These data provide evidence for a novel mechanism in regulating SAP102 function and glutamate receptor trafficking. (PMID:29282697)
• High expression of DLG3 is associated with decreased survival from breast cancer. (PMID:31271664)
• Silence of lncRNA MIAT-mediated inhibition of DLG3 promoter methylation suppresses breast cancer progression via the Hippo signaling pathway. (PMID:32593652)
• Identification of a DLG3 stop mutation in the MRX20 family. (PMID:38273165)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dlg3	ENSDARG00000076796
mus_musculus	Dlg3	ENSMUSG00000000881
rattus_norvegicus	Dlg3	ENSRNOG00000002767

Paralogs (3): DLG1 (ENSG00000075711), DLG4 (ENSG00000132535), DLG2 (ENSG00000150672)

Protein

Protein identifiers

Disks large homolog 3 — Q92796 (reviewed: Q92796)

Alternative names: Neuroendocrine-DLG, Synapse-associated protein 102, XLMR

All UniProt accessions (2): Q92796, Q5JUW8

UniProt curated annotations — full annotation on UniProt →

Function. Required for learning most likely through its role in synaptic plasticity following NMDA receptor signaling.

Subunit / interactions. Interacts through its PDZ domains with NETO1, GRIN2B and SYNGAP1. Interacts through its guanylate kinase-like domain with DLGAP1, DLGAP2, DLGAP3 and DLGAP4. Interacts with FLTP/C1orf192. Interacts through its PDZ domains with APC. Interacts through its first two PDZ domains with ERBB4. Interacts through its third PDZ domain with NLGN1, and probably with NLGN2 and NLGN3. Interacts with FRMPD4 (via C-terminus). Interacts with LRFN1, LRFN2 and LRFN4. Interacts with DGKI (via PDZ-binding motif).

Disease relevance. Intellectual developmental disorder, X-linked 90 (XLID90) [MIM:300850] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked intellectual disability, while syndromic forms presents with associated physical, neurological and/or psychiatric manifestations. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the MAGUK family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q92796-1	1	yes
Q92796-2	2
Q92796-3	3

RefSeq proteins (3): NP_001159750, NP_065781, NP_066943* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR001478	PDZ	Domain
IPR008144	Guanylate_kin-like_dom	Domain
IPR008145	GK/Ca_channel_bsu	Domain
IPR016313	DLG1-like	Family
IPR019583	DLG1-4_PDZ_assoc	Domain
IPR019590	DLG1_PEST_dom	Domain
IPR020590	Guanylate_kinase_CS	Conserved_site
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR035763	DLG3_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR050614	Synaptic_Scaffolding_LAP-MAGUK	Family

Pfam: PF00018, PF00595, PF00625, PF10600

UniProt features (43 total): strand 15, helix 7, domain 5, modified residue 4, splice variant 4, sequence conflict 2, compositionally biased region 2, chain 1, sequence variant 1, initiator methionine 1, region of interest 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2FE5	X-RAY DIFFRACTION	1.1
2I1N	X-RAY DIFFRACTION	1.85
1UM7	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92796-F1	74.35	0.49

Functional residue map

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

Post-translational modifications (4): 673, 1, 2, 139

Function

Pathways and Gene Ontology

Reactome pathways

10 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-447038	NrCAM interactions
R-HSA-451308	Activation of Ca-permeable Kainate 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: 347 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, RNGTGGGC_UNKNOWN, RRAGTTGT_UNKNOWN, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_IONOTROPIC_ACTIVITY_OF_KAINATE_RECEPTORS, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, PAX4_01, NKX25_02, BROWNE_HCMV_INFECTION_16HR_UP, GGGTGGRR_PAX4_03, GOBP_CELL_CELL_SIGNALING, GOBP_CELL_CELL_ADHESION, E2F1DP1_01, E2F1DP2_01, MILI_PSEUDOPODIA_HAPTOTAXIS_UP

GO Biological Process (10): establishment of planar polarity (GO:0001736), chemical synaptic transmission (GO:0007268), nervous system development (GO:0007399), negative regulation of cell population proliferation (GO:0008285), protein localization to synapse (GO:0035418), receptor clustering (GO:0043113), establishment or maintenance of epithelial cell apical/basal polarity (GO:0045197), receptor localization to synapse (GO:0097120), cell-cell adhesion (GO:0098609), regulation of postsynaptic membrane neurotransmitter receptor levels (GO:0099072)

GO Molecular Function (6): kinase binding (GO:0019900), protein kinase binding (GO:0019901), phosphatase binding (GO:0019902), ubiquitin protein ligase binding (GO:0031625), ionotropic glutamate receptor binding (GO:0035255), protein binding (GO:0005515)

GO Cellular Component (13): obsolete extracellular space (GO:0005615), cytosol (GO:0005829), plasma membrane (GO:0005886), adherens junction (GO:0005912), bicellular tight junction (GO:0005923), basolateral plasma membrane (GO:0016323), neuromuscular junction (GO:0031594), AMPA glutamate receptor complex (GO:0032281), neuron projection (GO:0043005), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), cell-cell junction (GO:0005911)

Reactome top-level categories

Rollup of top-7 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
L1CAM interactions	1
Ionotropic activity of kainate receptors	1
MAPK1/MAPK3 signaling	1
Post NMDA receptor activation events	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
enzyme binding	2
cellular anatomical structure	2
synapse	2
morphogenesis of a polarized epithelium	1
establishment of tissue polarity	1
anterograde trans-synaptic signaling	1
system development	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
protein localization to cell junction	1
plasma membrane	1
protein localization to membrane	1
establishment or maintenance of apical/basal cell polarity	1
localization	1
cell adhesion	1
regulation of biological quality	1
kinase binding	1
ubiquitin-like protein ligase binding	1
glutamate receptor binding	1
binding	1
cytoplasm	1
membrane	1
cell periphery	1
cell-cell junction	1
apical junction complex	1
tight junction	1
basal plasma membrane	1
plasma membrane region	1
ionotropic glutamate receptor complex	1
plasma membrane bounded cell projection	1
postsynaptic density	1
postsynaptic membrane	1
postsynaptic specialization membrane	1
intracellular anatomical structure	1
anchoring junction	1

Protein interactions and networks

STRING

2598 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DLG3	GRIN2A	Q12879	995
DLG3	GRIN2B	Q13224	994
DLG3	DLG4	P78352	955
DLG3	SYNGAP1	Q96PV0	917
DLG3	LRFN2	Q9ULH4	876
DLG3	GDA	Q9Y2T3	854
DLG3	CACNG2	Q9Y698	850
DLG3	DLG2	Q15700	815
DLG3	CADM3	Q8N126	802
DLG3	CADM1	Q9BY67	774
DLG3	NLGN1	Q8N2Q7	720
DLG3	FBXO45	P0C2W1	716
DLG3	GRIN1	P35437	715
DLG3	LLGL1	Q15334	706
DLG3	NLGN4X	Q8N0W4	705

IntAct

1204 interactions, top by confidence:

A	B	Type	Score
DLG3	PLEKHA2	psi-mi:“MI:0915”(physical association)	0.680
KCNJ2	KCNJ18	psi-mi:“MI:2364”(proximity)	0.660
ptchd1	Dlg4	psi-mi:“MI:0914”(association)	0.650
DLG3	GRIN2C	psi-mi:“MI:0407”(direct interaction)	0.620
DLG3	NET1	psi-mi:“MI:0407”(direct interaction)	0.620
DLG3	CYSLTR2	psi-mi:“MI:0407”(direct interaction)	0.620
DLG3	FRMPD4	psi-mi:“MI:0407”(direct interaction)	0.620
DLG3	GRIN2B	psi-mi:“MI:0407”(direct interaction)	0.620
FRMPD4	DLG3	psi-mi:“MI:0407”(direct interaction)	0.620
NET1	DLG3	psi-mi:“MI:0407”(direct interaction)	0.620
CYSLTR2	DLG3	psi-mi:“MI:0407”(direct interaction)	0.620
GRIN2C	DLG3	psi-mi:“MI:0407”(direct interaction)	0.620
GRIN2B	DLG3	psi-mi:“MI:0407”(direct interaction)	0.620
ABCA1	DLG3	psi-mi:“MI:0407”(direct interaction)	0.610
DLGAP4	LIN7A	psi-mi:“MI:0914”(association)	0.590
DLG3	EVI5	psi-mi:“MI:0407”(direct interaction)	0.590
DLG3	KCNA4	psi-mi:“MI:0407”(direct interaction)	0.590
EVI5	DLG3	psi-mi:“MI:0407”(direct interaction)	0.590
ARHGEF26	DLG3	psi-mi:“MI:0407”(direct interaction)	0.590
ERBB4	DLG3	psi-mi:“MI:0407”(direct interaction)	0.590
DLG3	OSBP2	psi-mi:“MI:0915”(physical association)	0.560
DHRS11	DLG3	psi-mi:“MI:0915”(physical association)	0.560
RPS8	DLG3	psi-mi:“MI:0915”(physical association)	0.560
DLGAP1	DLG3	psi-mi:“MI:0915”(physical association)	0.560
EIF4H	DLG3	psi-mi:“MI:0915”(physical association)	0.560
DLG3	DLGAP2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (165): DLG3 (Affinity Capture-MS), DLG3 (Affinity Capture-MS), ARFGAP1 (Co-fractionation), RPS6KA4 (Co-fractionation), DLG1 (Affinity Capture-MS), DLG3 (Affinity Capture-MS), AP3B1 (Affinity Capture-MS), RB1CC1 (Affinity Capture-MS), COBLL1 (Affinity Capture-MS), KCTD2 (Affinity Capture-MS), ACAD8 (Affinity Capture-MS), WDR91 (Affinity Capture-MS), MRPL18 (Affinity Capture-MS), MRPL22 (Affinity Capture-MS), SS18L2 (Affinity Capture-MS)

ESM2 similar proteins: A4II46, A6QQZ7, A7MBL8, A8KBF6, B4F7E7, D3ZAA9, E2QY99, O00560, O88910, O88954, P15498, P27870, P29074, P31016, P54100, P70175, P78352, Q08DN7, Q12959, Q13368, Q14168, Q15700, Q16513, Q28C55, Q5PYH6, Q5PYH7, Q5RDQ2, Q5T2T1, Q5U2Y3, Q62108, Q62696, Q62936, Q63622, Q6P0D7, Q6R005, Q8AVG0, Q8BPM2, Q8BVD5, Q8BWW9, Q8N3R9

Diamond homologs: A0A8C0TYJ0, A0A8P0N4K0, B4F7E7, D3ZAA9, E2QY99, E2QYC9, E7FDW2, F1MAD2, G5ECY0, O14910, O15018, O55164, O75970, O84033, O88382, O88951, O88952, P15454, P31006, P31007, P31016, P46195, P57105, P68907, P70175, P78352, P93757, Q0P5F3, Q0SS73, Q0TPK6, Q12959, Q13425, Q13884, Q14160, Q15700, Q16774, Q24210, Q255A8, Q28C55, Q2KIB6

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
DLG3	“form complex”	Scribble_complex_DLG3-LLGL2_variant	binding
DLG3	“form complex”	Scribble_complex_DLG3-LLGL1_variant	binding
NBEA	“up-regulates activity”	DLG3	binding
DLG3	“up-regulates activity”	NMDA	relocalization
DLG3	“up-regulates activity”	“NMDA receptor_2A”	relocalization
DLG3	“up-regulates activity”	“NMDA receptor_2B”	relocalization
DLG3	“up-regulates activity”	“NMDA receptor_2C”	relocalization
DLG3	“up-regulates activity”	“NMDA receptor_2D”	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 142 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Unblocking of NMDA receptors, glutamate binding and activation	8	45.8×	6e-10
Negative regulation of NMDA receptor-mediated neuronal transmission	8	45.8×	6e-10
Long-term potentiation	9	45.1×	9e-11
Ras activation upon Ca2+ influx through NMDA receptor	6	36.1×	9e-07
Trafficking of AMPA receptors	6	34.4×	1e-06
Synaptic adhesion-like molecules	6	34.4×	1e-06
Assembly and cell surface presentation of NMDA receptors	9	24.0×	1e-08
Phase 0 - rapid depolarisation	6	21.9×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of synaptic transmission, glutamatergic	8	38.7×	2e-08
regulation of neuronal synaptic plasticity	5	26.1×	2e-04
positive regulation of excitatory postsynaptic potential	6	24.5×	5e-05
long-term synaptic potentiation	5	10.9×	5e-03
learning or memory	5	9.3×	8e-03
intermediate filament organization	5	9.3×	8e-03
modulation of chemical synaptic transmission	6	8.5×	5e-03
chemical synaptic transmission	10	6.0×	8e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	18
Uncertain significance	168
Likely benign	43
Benign	24

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
11519	NM_021120.4(DLG3):c.1302+1G>A	Pathogenic
127193	NM_021120.4(DLG3):c.357+1G>C	Pathogenic
127194	NM_021120.4(DLG3):c.985+1G>C	Pathogenic
1319664	NM_021120.4(DLG3):c.2266C>T (p.Arg756Ter)	Pathogenic
166996	NM_021120.4(DLG3):c.2280T>G (p.Tyr760Ter)	Pathogenic
1747664	NM_021120.4(DLG3):c.546_549del (p.Val183fs)	Pathogenic
2576624	NM_021120.4(DLG3):c.-8dup	Pathogenic
2577711	NM_021120.4(DLG3):c.100C>T (p.Gln34Ter)	Pathogenic
29942	NM_021120.4(DLG3):c.1092dup (p.Thr365fs)	Pathogenic
29943	NM_021120.4(DLG3):c.1373C>G (p.Ser458Ter)	Pathogenic
3272237	NM_021120.4(DLG3):c.158del (p.Gly53fs)	Pathogenic
3393533	NM_021120.4(DLG3):c.649C>T (p.Arg217Ter)	Pathogenic
3598422	NM_021120.4(DLG3):c.1669C>T (p.Gln557Ter)	Pathogenic
3770157	NM_021120.4(DLG3):c.1349_1350del (p.Ala450fs)	Pathogenic
3899003	NM_021120.4(DLG3):c.791del (p.Gly264fs)	Pathogenic
4734248	NM_021120.4(DLG3):c.1513_1519del (p.Tyr505fs)	Pathogenic
521239	NM_021120.4(DLG3):c.351T>A (p.Tyr117Ter)	Pathogenic
521892	NM_021120.4(DLG3):c.631C>T (p.Arg211Ter)	Pathogenic
58553	GRCh38/hg38 Xp22.33-q28(chrX:26101-155999293)x3	Pathogenic
625217	NM_021120.4(DLG3):c.1375_1378del (p.Val459fs)	Pathogenic
981256	NM_021120.4(DLG3):c.1761dup (p.Glu588Ter)	Pathogenic
987145	NM_021120.4(DLG3):c.1369del (p.Gln457fs)	Pathogenic
1098381	NM_021120.4(DLG3):c.1520+1G>T	Likely pathogenic
11518	NM_021120.4(DLG3):c.985+5G>A	Likely pathogenic
1328590	NM_021120.4(DLG3):c.592C>T (p.Arg198Trp)	Likely pathogenic
1334574	NM_021120.4(DLG3):c.1447C>T (p.Gln483Ter)	Likely pathogenic
2237115	NM_021120.4(DLG3):c.158_159insA (p.Tyr54fs)	Likely pathogenic
2429999	NM_021120.4(DLG3):c.1819+1del	Likely pathogenic
2626899	NM_021120.4(DLG3):c.116dup (p.Tyr39Ter)	Likely pathogenic
3770137	NM_021120.4(DLG3):c.131dup (p.Asn45fs)	Likely pathogenic

SpliceAI

3676 predictions. Top by Δscore:

Variant	Effect	Δscore
X:70449685:CACA:C	acceptor_loss	1.0000
X:70449686:ACAG:A	acceptor_gain	1.0000
X:70449687:CAGG:C	acceptor_loss	1.0000
X:70449688:A:AG	acceptor_gain	1.0000
X:70449688:A:T	acceptor_loss	1.0000
X:70449688:AG:A	acceptor_gain	1.0000
X:70449688:AGG:A	acceptor_gain	1.0000
X:70449688:AGGGT:A	acceptor_gain	1.0000
X:70449689:G:GA	acceptor_gain	1.0000
X:70449689:GG:G	acceptor_gain	1.0000
X:70449689:GGG:G	acceptor_gain	1.0000
X:70449689:GGGT:G	acceptor_gain	1.0000
X:70449689:GGGTG:G	acceptor_gain	1.0000
X:70449832:G:GT	donor_gain	1.0000
X:70449857:AAG:A	donor_loss	1.0000
X:70449858:AG:A	donor_loss	1.0000
X:70449859:GGTG:G	donor_loss	1.0000
X:70449860:G:GA	donor_loss	1.0000
X:70450134:T:TA	acceptor_gain	1.0000
X:70450146:A:AG	acceptor_gain	1.0000
X:70450147:C:G	acceptor_gain	1.0000
X:70450152:T:A	acceptor_gain	1.0000
X:70450155:T:TA	acceptor_gain	1.0000
X:70450164:CTCAG:C	acceptor_loss	1.0000
X:70450165:TCAGG:T	acceptor_loss	1.0000
X:70450167:AGGCC:A	acceptor_loss	1.0000
X:70450302:GGCG:G	donor_gain	1.0000
X:70450303:GCGG:G	donor_gain	1.0000
X:70450306:G:GG	donor_gain	1.0000
X:70450635:CTA:C	acceptor_loss	1.0000

AlphaMissense

5375 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:70448956:T:A	L134H	1.000
X:70448956:T:C	L134P	1.000
X:70448962:G:T	R136M	1.000
X:70448963:G:C	R136S	1.000
X:70448963:G:T	R136S	1.000
X:70449368:G:C	G140R	1.000
X:70449368:G:T	G140C	1.000
X:70449369:G:A	G140D	1.000
X:70449372:T:A	L141Q	1.000
X:70449372:T:C	L141P	1.000
X:70449374:G:C	G142R	1.000
X:70449374:G:T	G142C	1.000
X:70449375:G:A	G142D	1.000
X:70449375:G:T	G142V	1.000
X:70449377:T:C	F143L	1.000
X:70449378:T:C	F143S	1.000
X:70449378:T:G	F143C	1.000
X:70449379:C:A	F143L	1.000
X:70449379:C:G	F143L	1.000
X:70449380:A:C	S144R	1.000
X:70449381:G:A	S144N	1.000
X:70449381:G:T	S144I	1.000
X:70449382:T:A	S144R	1.000
X:70449382:T:G	S144R	1.000
X:70449384:T:A	I145N	1.000
X:70449384:T:C	I145T	1.000
X:70449384:T:G	I145S	1.000
X:70449386:G:C	A146P	1.000
X:70449389:G:C	G147R	1.000
X:70449389:G:T	G147C	1.000

dbSNP variants (sampled 300 via entrez): RS1000000487 (X:70487046 A>G), RS1000025789 (X:70484297 T>G), RS1000033067 (X:70487470 C>G), RS1000254755 (X:70480442 A>T), RS1000290295 (X:70451334 C>T), RS1000323713 (X:70478070 T>C), RS1000420034 (X:70497650 G>A), RS1000503170 (X:70460686 T>C), RS1000588765 (X:70443096 A>C), RS1000641307 (X:70502614 A>G), RS1000706381 (X:70504711 G>A), RS1000766823 (X:70492243 G>A), RS1000773867 (X:70470525 C>A), RS1000893003 (X:70455312 C>G), RS1000935377 (X:70479996 G>C)

Disease associations

OMIM: gene MIM:300189 | disease phenotypes: MIM:300850

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, X-linked 90	Definitive	X-linked
non-syndromic X-linked intellectual disability	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
non-syndromic X-linked intellectual disability	Definitive	XL

Mondo (5): intellectual disability, X-linked 90 (MONDO:0010452), neurodevelopmental disorder (MONDO:0700092), epilepsy (MONDO:0005027), intellectual disability (MONDO:0001071), non-syndromic X-linked intellectual disability (MONDO:0019181)

Orphanet (2): X-linked non-syndromic intellectual disability (Orphanet:777), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

16 total (16 of 16 shown, HPO-id order):

HPO	Term
HP:0000193	Bifid uvula
HP:0000218	High palate
HP:0000272	Malar flattening
HP:0000486	Strabismus
HP:0000582	Upslanted palpebral fissure
HP:0000750	Delayed speech and language development
HP:0000774	Narrow chest
HP:0000805	Enuresis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001417	X-linked inheritance
HP:0001419	X-linked recessive inheritance
HP:0007018	Attention deficit hyperactivity disorder

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
C564490	Mental Retardation, X-Linked Nonsyndromic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

33 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases methylation	6
trichostatin A	decreases expression, affects cotreatment	3
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	2
Tretinoin	decreases expression, increases expression	2
triphenyl phosphate	affects expression	1
propylparaben	decreases expression	1
sulforaphane	decreases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
aflatoxin B2	increases methylation	1
perfluorodecanoic acid	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression, increases reaction	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	increases expression	1
entinostat	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
licochalcone B	decreases expression	1
jinfukang	increases expression	1
Dimethyl Sulfoxide	increases expression	1
Estradiol	decreases expression	1
Ivermectin	decreases expression	1
Lipopolysaccharides	decreases expression, affects cotreatment, increases reaction	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Melphalan	decreases expression	1
Silicon Dioxide	decreases expression	1
Thiram	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00004637	PHASE4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	PHASE4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	PHASE4	UNKNOWN	Effects on the Diagnostic Accuracy of Magnetic Imaging Angiographies of the Supra-Aortic Vessels by Three Different Magnetic Resonance Contrast Agents in Patients
NCT00133081	PHASE4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	PHASE4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	PHASE4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	PHASE4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	PHASE4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	PHASE4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	PHASE4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	PHASE4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	PHASE4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	PHASE4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	PHASE4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	PHASE4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	PHASE4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	PHASE4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	PHASE4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	PHASE4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	PHASE4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	PHASE4	COMPLETED	RNS® System LTT Study
NCT00610532	PHASE4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	PHASE4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	PHASE4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	PHASE4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	PHASE4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	PHASE4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	PHASE4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	PHASE4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	PHASE4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	PHASE4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	PHASE4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	PHASE4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients
NCT01118455	PHASE4	TERMINATED	Trial to Assess Vagus Nerve Stimulation Therapy vs. Anti-Epileptic Drug (AED) Treatment in Children With Refractory Seizures
NCT01127165	PHASE4	COMPLETED	Low and High Dose Zonisamide in Children as Monotherapy
NCT01127256	PHASE4	COMPLETED	Comparative Study of Zonisamide and Carbamazepine as an Initial Monotherapy: Efficacy and Safety Evaluation
NCT01140867	PHASE4	COMPLETED	Open-label, Multi-center Trial of Zonisamide as Adjunctive Therapy in Patients With Uncontrolled Partial Epilepsy
NCT01175954	PHASE4	COMPLETED	Cognitive and Behavioral Effects of Lacosamide