NLGN3

Summary

NLGN3 (neuroligin 3, HGNC:14289) is a protein-coding gene on chromosome Xq13.1, encoding Neuroligin-3 (Q9NZ94). Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members.

This gene encodes a member of a family of neuronal cell surface proteins. Members of this family may act as splice site-specific ligands for beta-neurexins and may be involved in the formation and remodeling of central nervous system synapses. Mutations in this gene may be associated with autism and Asperger syndrome. Multiple transcript variants encoding distinct isoforms have been identified for this gene.

Source: NCBI Gene 54413 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked complex neurodevelopmental disorder (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 271 total — 4 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 17
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_181303

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14289
Approved symbol	NLGN3
Name	neuroligin 3
Location	Xq13.1
Locus type	gene with protein product
Status	Approved
Aliases	HNL3, KIAA1480, ASPGX1, AUTSX1
Ensembl gene	ENSG00000196338
Ensembl biotype	protein_coding
OMIM	300336
Entrez	54413

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 18 protein_coding, 5 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000358741, ENST00000374051, ENST00000395855, ENST00000476589, ENST00000536169, ENST00000685718, ENST00000685950, ENST00000687220, ENST00000687470, ENST00000687568, ENST00000688566, ENST00000688950, ENST00000689857, ENST00000689968, ENST00000690133, ENST00000690293, ENST00000691045, ENST00000692338, ENST00000692468, ENST00000692800, ENST00000692905, ENST00000904687, ENST00000939108, ENST00000939109, ENST00000939110, ENST00000957026

RefSeq mRNA: 4 — MANE Select: NM_181303 NM_001166660, NM_001321276, NM_018977, NM_181303

CCDS: CCDS14407, CCDS55441, CCDS55442, CCDS94627

Canonical transcript exons

ENST00000358741 — 8 exons

Exon	Start	End
ENSE00001291712	71148846	71148905
ENSE00001317906	71147550	71148206
ENSE00001319737	71153477	71153536
ENSE00001324655	71144841	71144964
ENSE00003513868	71164143	71164328
ENSE00003561035	71155214	71155363
ENSE00003618221	71167011	71167800
ENSE00003900828	71169254	71171201

Expression profiles

Bgee: expression breadth ubiquitous, 181 present calls, max score 92.74.

FANTOM5 (CAGE): breadth broad, TPM avg 4.9822 / max 434.1932, expressed in 366 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196656	4.6678	361
196657	0.2487	116
196658	0.0657	36

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	92.74	gold quality
ventricular zone	UBERON:0003053	92.73	gold quality
prefrontal cortex	UBERON:0000451	90.54	gold quality
amygdala	UBERON:0001876	89.99	gold quality
right frontal lobe	UBERON:0002810	89.76	gold quality
ganglionic eminence	UBERON:0004023	89.62	gold quality
cingulate cortex	UBERON:0003027	89.23	gold quality
anterior cingulate cortex	UBERON:0009835	89.23	gold quality
nucleus accumbens	UBERON:0001882	88.71	gold quality
caudate nucleus	UBERON:0001873	88.15	gold quality
neocortex	UBERON:0001950	88.07	gold quality
frontal cortex	UBERON:0001870	88.00	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.84	gold quality
putamen	UBERON:0001874	87.67	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	87.59	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.82	gold quality
telencephalon	UBERON:0001893	86.71	gold quality
medial globus pallidus	UBERON:0002477	86.70	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	86.66	gold quality
cerebral cortex	UBERON:0000956	86.52	gold quality
spinal cord	UBERON:0002240	86.12	gold quality
temporal lobe	UBERON:0001871	85.89	gold quality
type B pancreatic cell	CL:0000169	85.87	gold quality
Ammon’s horn	UBERON:0001954	85.54	gold quality
olfactory bulb	UBERON:0002264	85.49	gold quality
cerebellar cortex	UBERON:0002129	85.33	gold quality
cerebellar hemisphere	UBERON:0002245	85.27	gold quality
globus pallidus	UBERON:0001875	85.01	gold quality
inferior olivary complex	UBERON:0002127	85.00	silver quality
hypothalamus	UBERON:0001898	84.68	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	1220.90
E-ANND-3	no	2.63

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

45 targeting NLGN3, 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-6867-5P	100.00	82.21	3464
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-12130	99.75	65.47	452
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-4762-3P	99.43	69.72	2363
HSA-MIR-1912-3P	99.32	67.40	936
HSA-MIR-3692-5P	99.29	67.04	1421
HSA-MIR-6852-5P	99.17	66.69	2073

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 34)

• report mutations in two X-linked genes encoding neuroligins NLGN3 and NLGN4 in siblings with autism-spectrum disorders (PMID:12669065)
• No structural variants were found in the NLGN3 gene when 96 unrelated patients with autism, 24 ADHD and 24 bipolar disorder patients were analyzed. (PMID:15622415)
• Neuroligin mutations most probably represent rare causes of autism; it is unlikely that the allelic variants in any of these genes would be major risk factors for autism. (PMID:16077734)
• Data indicate that coding mutations in neuroligin 3 are very rarely associated to autism spectrum disorders. (PMID:16508939)
• Splice variants of the NLGN3 gene are associated with autism. (PMID:16648374)
• Syntrophin-gamma2 (SNTG2) is a de novo binding partner of neuroligin 3, which correlates with autism-related mutations. (PMID:17292328)
• no evidence for an involvement of NLGN3 and NLGN4X genetic variants with autism spectrum disorder on high functioning level (PMID:18189281)
• these data support the hypothesis that the autism-associated NL3 mutation affects information processing in neuronal networks by altering network architecture and synchrony (PMID:19406211)
• further characterization of the R451C mutation in NLGN3;role in protein folding (PMID:20227402)
• study provides initial evidence that a common variant in NLGN3 gene may play a role in the etiology of ASDs among affected males in Chinese Han population. (PMID:21569590)
• Data from studies using cross-linking reagents suggest that neuroligins form dimers, including homodimers and, most notably, neuroligin 1/3 heteromers; autism-associated neuroligin mutant (neuroligin 3 R471C) forms heterodimers with neuroligin 1. (PMID:22671294)
• Neuroligins are adhesion proteins that bind to beta-neurexin to form functional synapses. (PMID:23431752)
• Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population. (PMID:23468870)
• The present study explores, for the first time, the contribution of NLGN3 and NLGN4X genetic variants in Greek patients with autistic disorder. (PMID:23851596)
• Our data provided a further evidence for the involvement of NLGN3 and NLGN4X gene in the pathogenesis of autism in Chinese population. (PMID:24570023)
• The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen, and soluble NLGN3 was sufficient and necessary to promote robust high-grade glioma cell proliferation. (PMID:25913192)
• No statistically significant haplotypes have been found associated to autism in the NLGN3 after logistic regression and permutation analysis. (PMID:27782075)
• e found that NLGN3 function at inhibitory synapses in rat CA1 depends on the presence of NLGN2 and identified a domain in the extracellular region that accounted for this functional difference between NLGN2 and 3 specifically at inhibitory synapses. (PMID:27805570)
• Our data suggest that these four previously described neuroligin mutations are not primary risk factors for autism. (PMID:28948087)
• high-grade gliomas growth depends on microenvironmental NLGN3, identify signalling cascades downstream of NLGN3 binding in glioma, and determine a therapeutically targetable mechanism of secretion (PMID:28959975)
• Wnt/beta-catenin signaling targets the trasncription of the autism-associated Neuroligin 3 gene. (PMID:29503438)
• the effects of rs1421589 within NRXN1, rs4844285 and rs11795613 within NLGN3, as well as rs5961397 within NLGX4X on Hirschsprung’s disease phenotypes were also statistically significant. (PMID:29622757)
• NLGN3 protects retinal pigment epithelium (RPE) cells and retinal ganglion cells (RGCs) from H2O2. (PMID:29792861)
• We report gut symptoms in patients with the autism-associated R451C mutation encoding the neuroligin-3 protein. We show that many of the genes implicated in autism are expressed in mouse gut. The neuroligin-3 R451C mutation alters the enteric nervous system, causes gastrointestinal dysfunction, and disrupts gut microbe populations in mice. (PMID:31119867)
• NLGN3 promoted neuroblastoma cell proliferation and growth through activating PI3K/AKT pathway and providing a new target for neuroblastoma therapy (PMID:31150649)
• Our report of two missense variants affecting the normal localization of NLGN3 in a total of five affected individuals reinforces the involvement of the NLGN3 gene in a neurodevelopmental disorder characterized by ID and ASD. (PMID:31184401)
• Evidence for a Contribution of the Nlgn3/Cyfip1/Fmr1 Pathway in the Pathophysiology of Autism Spectrum Disorders. (PMID:31705895)
• Neuronal-driven glioma growth requires Galphai1 and Galphai3. (PMID:34373757)
• Analyses of the autism-associated neuroligin-3 R451C mutation in human neurons reveal a gain-of-function synaptic mechanism. (PMID:36280753)
• Expression and structural analysis of human neuroligin 2 and neuroligin 3 implicated in autism spectrum disorders. (PMID:36479216)
• Autism-linked NLGN3 is a key regulator of gonadotropin-releasing hormone deficiency. (PMID:36810932)
• Neuron-secreted NLGN3 ameliorates ischemic brain injury via activating Galphai1/3-Akt signaling. (PMID:37880221)
• Stabilization of KPNB1 by deubiquitinase USP7 promotes glioblastoma progression through the YBX1-NLGN3 axis. (PMID:38254206)
• Glucocorticoids rescue cell surface trafficking of R451C Neuroligin3 and enhance synapse formation. (PMID:38272450)

Cross-species orthologs

45 orthologs

Organism	Symbol	Gene ID
danio_rerio	nlgn3a	ENSDARG00000104786
mus_musculus	Nlgn3	ENSMUSG00000031302
rattus_norvegicus	Nlgn3	ENSRNOG00000003812
drosophila_melanogaster	Est-6	FBGN0000592
drosophila_melanogaster	Est-P	FBGN0000594
drosophila_melanogaster	Glt	FBGN0001114
drosophila_melanogaster	Jhe	FBGN0010052
drosophila_melanogaster	alpha-Est1	FBGN0015568
drosophila_melanogaster	alpha-Est10	FBGN0015569
drosophila_melanogaster	alpha-Est2	FBGN0015570
drosophila_melanogaster	alpha-Est3	FBGN0015571
drosophila_melanogaster	alpha-Est4	FBGN0015572
drosophila_melanogaster	alpha-Est6	FBGN0015574
drosophila_melanogaster	alpha-Est7	FBGN0015575
drosophila_melanogaster	alpha-Est8	FBGN0015576
drosophila_melanogaster	alpha-Est9	FBGN0015577
drosophila_melanogaster	CG4757	FBGN0027584
drosophila_melanogaster	CG9287	FBGN0032057
drosophila_melanogaster	CG9289	FBGN0032058
drosophila_melanogaster	CG3841	FBGN0032131
drosophila_melanogaster	CG4382	FBGN0032132
drosophila_melanogaster	Jhedup	FBGN0034076
drosophila_melanogaster	gas	FBGN0034736
drosophila_melanogaster	alpha-Est5	FBGN0261393
caenorhabditis_elegans		WBGENE00000037
caenorhabditis_elegans		WBGENE00000038
caenorhabditis_elegans		WBGENE00007691
caenorhabditis_elegans		WBGENE00007692
caenorhabditis_elegans		WBGENE00007693
caenorhabditis_elegans		WBGENE00007695
caenorhabditis_elegans		WBGENE00008451
caenorhabditis_elegans		WBGENE00011362
caenorhabditis_elegans		WBGENE00011364
caenorhabditis_elegans		WBGENE00013873
caenorhabditis_elegans		WBGENE00013874
caenorhabditis_elegans		WBGENE00013875
caenorhabditis_elegans		WBGENE00015067
caenorhabditis_elegans		WBGENE00015071
caenorhabditis_elegans		WBGENE00015279
caenorhabditis_elegans		WBGENE00015284
caenorhabditis_elegans		WBGENE00016595
caenorhabditis_elegans		WBGENE00016862
caenorhabditis_elegans		WBGENE00016863
caenorhabditis_elegans	cest-27	WBGENE00018958
caenorhabditis_elegans		WBGENE00020688

Paralogs (13): TG (ENSG00000042832), ACHE (ENSG00000087085), BCHE (ENSG00000114200), NLGN4X (ENSG00000146938), CES5A (ENSG00000159398), NLGN4Y (ENSG00000165246), NLGN1 (ENSG00000169760), NLGN2 (ENSG00000169992), CEL (ENSG00000170835), CES4A (ENSG00000172824), CES3 (ENSG00000172828), CES2 (ENSG00000172831), CES1 (ENSG00000198848)

Protein

Protein identifiers

Neuroligin-3 — Q9NZ94 (reviewed: Q9NZ94)

Alternative names: Gliotactin homolog

All UniProt accessions (14): Q9NZ94, A0A8I5KQ26, A0A8I5KSB7, A0A8I5KSW0, A0A8I5KSX7, A0A8I5KTH4, A0A8I5KVP5, A0A8I5QJH8, A0A8I5QJU7, A0A8I5QL38, E7EVK0, X5D2P6, X5D7L6, X5DNV3

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members. Plays a role in synapse function and synaptic signal transmission, and may mediate its effects by clustering other synaptic proteins. May promote the initial formation of synapses, but is not essential for this. May also play a role in glia-glia or glia-neuron interactions in the developing peripheral nervous system.

Subunit / interactions. Homodimer, and heterodimer with NLGN1 and NLGN2. Interacts with neurexins NRXN1, NRXN2 and NRXN3. Interaction with neurexins is mediated by heparan sulfate glycan modification on neurexin. Interacts (via its C-terminus) with DLG4/PSD-95 (via PDZ domain 3).

Subcellular location. Cell membrane. Synapse. Cell projection. Dendrite.

Tissue specificity. Expressed in the blood vessel walls (at protein level). Detected in throughout the brain and in spinal cord. Detected in brain, and at lower levels in pancreas islet beta cells.

Post-translational modifications. N-glycosylated, contains high-mannose, hybrid, complex and sialylated N-glycans. N-glycosylation is essential for localization to synapses, dendrites, and the cell membrane, and enhances its availability for trans-synaptic adhesion. O-glycosylated.

Disease relevance. Autism, X-linked 1 (AUTSX1) [MIM:300425] A complex multifactorial, pervasive developmental disorder characterized by impairments in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, and the presence of developmental abnormalities by 3 years of age. Most individuals with autism also manifest moderate intellectual disability. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the type-B carboxylesterase/lipase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NZ94-1	1, HNL3s	yes
Q9NZ94-2	2, HNL3
Q9NZ94-3	3

RefSeq proteins (4): NP_001160132, NP_001308205, NP_061850, NP_851820* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000460	Nlgn	Family
IPR002018	CarbesteraseB	Domain
IPR019819	Carboxylesterase_B_CS	Conserved_site
IPR029058	AB_hydrolase_fold	Homologous_superfamily
IPR051093	Neuroligin/BSAL	Family

Pfam: PF00135

UniProt features (26 total): sequence variant 5, disulfide bond 3, compositionally biased region 3, modified residue 2, glycosylation site 2, splice variant 2, topological domain 2, sequence conflict 2, region of interest 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8GS3	ELECTRON MICROSCOPY	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZ94-F1	76.80	0.56

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 (2): 745, 792

Disulfide bonds (3): 106–141, 340–351, 510–544

Glycosylation sites (2): 98, 545

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6794361	Neurexins and neuroligins

MSigDB gene sets: 235 (showing top): AHRARNT_01, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_POSITIVE_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_SYNAPSE_ASSEMBLY, GOBP_MEMBRANE_BIOGENESIS, GOBP_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GOBP_ADULT_BEHAVIOR, GOBP_REGULATION_OF_RESPIRATORY_SYSTEM_PROCESS, GOBP_POSITIVE_REGULATION_OF_SYNAPSE_ASSEMBLY, GOBP_GROWTH, GOCC_CELL_SURFACE

GO Biological Process (23): regulation of respiratory gaseous exchange by nervous system process (GO:0002087), receptor-mediated endocytosis (GO:0006898), neuron cell-cell adhesion (GO:0007158), chemical synaptic transmission (GO:0007268), synapse assembly (GO:0007416), learning (GO:0007612), adult behavior (GO:0030534), social behavior (GO:0035176), synaptic vesicle endocytosis (GO:0048488), axon extension (GO:0048675), modulation of chemical synaptic transmission (GO:0050804), synapse organization (GO:0050808), positive regulation of synapse assembly (GO:0051965), positive regulation of synaptic transmission, glutamatergic (GO:0051968), rhythmic synaptic transmission (GO:0060024), inhibitory postsynaptic potential (GO:0060080), vocalization behavior (GO:0071625), postsynaptic membrane assembly (GO:0097104), presynaptic membrane assembly (GO:0097105), presynapse assembly (GO:0099054), positive regulation of glutamate receptor signaling pathway (GO:1900451), positive regulation of excitatory postsynaptic potential (GO:2000463), cell adhesion (GO:0007155)

GO Molecular Function (6): signaling receptor activity (GO:0038023), neurexin family protein binding (GO:0042043), cell adhesion molecule binding (GO:0050839), scaffold protein binding (GO:0097110), cell adhesion mediator activity (GO:0098631), protein binding (GO:0005515)

GO Cellular Component (12): plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020), endocytic vesicle (GO:0030139), dendrite (GO:0030425), synapse (GO:0045202), postsynaptic membrane (GO:0045211), excitatory synapse (GO:0060076), presynapse (GO:0098793), symmetric, GABA-ergic, inhibitory synapse (GO:0098983), asymmetric, glutamatergic, excitatory synapse (GO:0098985), neuron to neuron synapse (GO:0098984)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Protein-protein interactions at synapses	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
behavior	3
cellular anatomical structure	3
synapse	3
synapse assembly	2
membrane assembly	2
protein binding	2
respiratory gaseous exchange by respiratory system	1
regulation of respiratory system process	1
nervous system process	1
endocytosis	1
cell-cell adhesion	1
anterograde trans-synaptic signaling	1
nervous system development	1
cell junction assembly	1
synapse organization	1
learning or memory	1
biological process involved in intraspecies interaction between organisms	1
synaptic vesicle recycling	1
presynaptic endocytosis	1
axonogenesis	1
neuron projection extension	1
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1
cell junction organization	1
positive regulation of nervous system development	1
regulation of synapse assembly	1
positive regulation of cell junction assembly	1
synaptic transmission, glutamatergic	1
positive regulation of synaptic transmission	1
regulation of synaptic transmission, glutamatergic	1
modulation of chemical synaptic transmission	1
regulation of postsynaptic membrane potential	1
chemical synaptic transmission, postsynaptic	1
postsynaptic membrane organization	1
postsynapse assembly	1
presynaptic membrane organization	1
presynapse assembly	1
cellular component assembly	1
presynapse organization	1
molecular transducer activity	1

Protein interactions and networks

STRING

1996 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NLGN3	NRXN1	Q9ULB1	999
NLGN3	NRXN2	Q9P2S2	998
NLGN3	DLG4	P78352	988
NLGN3	SHANK3	Q9BYB0	987
NLGN3	SHANK2	Q9UPX8	920
NLGN3	CNTNAP2	Q9UHC6	904
NLGN3	FMR1	Q06787	809
NLGN3	PTCHD1	Q96NR3	801
NLGN3	SHANK1	Q9Y566	787
NLGN3	NRXN3	Q9Y4C0	776
NLGN3	MAGI2	Q86UL8	758
NLGN3	MECP2	P51608	756
NLGN3	CDH9	Q9ULB4	730
NLGN3	CNTN4	Q8IWV2	715
NLGN3	LRRTM2	O43300	712

IntAct

18 interactions, top by confidence:

A	B	Type	Score
NLGN3	MT-CO2	psi-mi:“MI:0914”(association)	0.430
NLGN3	MT-CO2	psi-mi:“MI:0403”(colocalization)	0.430
FLNA	NLGN3	psi-mi:“MI:0403”(colocalization)	0.430
EEF1A1	NLGN3	psi-mi:“MI:0403”(colocalization)	0.430
TGFBR1	NLGN3	psi-mi:“MI:0915”(physical association)	0.400
TLE5	NLGN3	psi-mi:“MI:0915”(physical association)	0.370
AKT1	NLGN3	psi-mi:“MI:0915”(physical association)	0.370
APC2	NLGN3	psi-mi:“MI:0915”(physical association)	0.370
ATXN1	NLGN3	psi-mi:“MI:0915”(physical association)	0.370
COBL	NLGN3	psi-mi:“MI:0915”(physical association)	0.370
EFEMP1	NLGN3	psi-mi:“MI:0915”(physical association)	0.370
HIVEP1	NLGN3	psi-mi:“MI:0915”(physical association)	0.370
PICK1	NLGN3	psi-mi:“MI:0915”(physical association)	0.370
RBFOX2	NLGN3	psi-mi:“MI:0915”(physical association)	0.370
TDRD7	NLGN3	psi-mi:“MI:0915”(physical association)	0.370
NLGN3	PRDX2	psi-mi:“MI:0915”(physical association)	0.370
NLGN3	TMEM131L	psi-mi:“MI:0914”(association)	0.350

BioGRID (108): TGFBR1 (Affinity Capture-MS), CGB (Two-hybrid), CYP11A1 (Two-hybrid), FKBP1A (Two-hybrid), PLCB4 (Two-hybrid), PSAP (Two-hybrid), NFATC4 (Two-hybrid), C1orf122 (Two-hybrid), GUK1 (Two-hybrid), SSR4 (Two-hybrid), AP2A2 (Two-hybrid), EEF1A1 (Two-hybrid), FLNA (Two-hybrid), ALPP (Two-hybrid), ATF4 (Two-hybrid)

ESM2 similar proteins: A0A8M2B818, A0A8M9PFP2, A1XQX3, A1XQY0, A1XQY3, B0S5G3, D0PRN4, F1N4M2, L7VG99, O35158, O35464, O61307, Q01083, Q14DG7, Q24322, Q3KN41, Q3UHK6, Q3UN70, Q568T5, Q58EG3, Q5R7F5, Q62765, Q62889, Q66IV1, Q76KF0, Q7T2X6, Q8BMA3, Q8N2Q7, Q8NFY4, Q8VDA1, Q90Z04, Q91713, Q96LU7, Q9DER5, Q9ER65, Q9H2E6, Q9H4D0, Q9HDB5, Q9NT68, Q9NZ94

Diamond homologs: A0A0E4AET8, A0A0G3FWY4, B0F2B4, D4ASH1, G3V7J5, I6Y9F7, O00748, O08710, O16168, O16173, O46421, P06882, P0C6R3, P10959, P12337, P16303, P16854, P17573, P19835, P22394, P23141, P23953, P24484, P25726, P25727, P35501, P35502, P37967, P71668, P79066, P86325, P96402, P9WK86, P9WK87, Q01470, Q07085, Q1PET6, Q29550, Q47M62, Q50681

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
NLGN3	“up-regulates activity”	NRXN1	binding
NLGN3	“up-regulates activity”	NRXN2	binding
NLGN3	“up-regulates activity”	NRXN3	binding
NLGN3	“up-regulates activity”	DLG4	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	8
Uncertain significance	162
Likely benign	33
Benign	4

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
1710287	NM_181303.2(NLGN3):c.611T>C (p.Val204Ala)	Pathogenic
2443311	NM_181303.2(NLGN3):c.366G>A (p.Trp122Ter)	Pathogenic
520912	NM_181303.2(NLGN3):c.214dup (p.Val72fs)	Pathogenic
631481	NM_181303.2(NLGN3):c.1600C>T (p.Pro534Ser)	Pathogenic
1326919	NM_181303.2(NLGN3):c.913+1G>A	Likely pathogenic
1327915	NM_181303.2(NLGN3):c.1672A>G (p.Met558Val)	Likely pathogenic
1745802	NM_181303.2(NLGN3):c.577+1G>A	Likely pathogenic
1806399	NM_181303.2(NLGN3):c.2222T>G (p.Leu741Arg)	Likely pathogenic
235850	NM_181303.2(NLGN3):c.1849C>T (p.Arg617Trp)	Likely pathogenic
3376622	NM_181303.2(NLGN3):c.1978C>T (p.Arg660Cys)	Likely pathogenic
4082285	NM_181303.2(NLGN3):c.622G>A (p.Gly208Arg)	Likely pathogenic
4292970	NM_181303.2(NLGN3):c.422_423del (p.Cys141fs)	Likely pathogenic

SpliceAI

1267 predictions. Top by Δscore:

Variant	Effect	Δscore
X:71146503:T:G	acceptor_gain	1.0000
X:71153448:T:A	acceptor_gain	1.0000
X:71155209:TGCA:T	acceptor_loss	1.0000
X:71155210:GCA:G	acceptor_loss	1.0000
X:71155211:CA:C	acceptor_loss	1.0000
X:71155213:GAC:G	acceptor_gain	1.0000
X:71164325:GAGG:G	donor_gain	1.0000
X:71164327:GG:G	donor_gain	1.0000
X:71164328:GG:G	donor_gain	1.0000
X:71167006:TGTA:T	acceptor_loss	1.0000
X:71167010:G:A	acceptor_loss	1.0000
X:71144960:AACAG:A	donor_loss	0.9900
X:71144965:G:GA	donor_loss	0.9900
X:71146499:C:G	acceptor_gain	0.9900
X:71148202:GGATG:G	donor_gain	0.9900
X:71148203:GATG:G	donor_gain	0.9900
X:71148203:GATGG:G	donor_gain	0.9900
X:71148204:ATGG:A	donor_loss	0.9900
X:71148205:TGG:T	donor_loss	0.9900
X:71148208:T:TC	donor_loss	0.9900
X:71148209:GA:G	donor_loss	0.9900
X:71148844:A:AG	acceptor_gain	0.9900
X:71148845:G:GG	acceptor_gain	0.9900
X:71153438:T:TA	acceptor_gain	0.9900
X:71153443:T:TA	acceptor_gain	0.9900
X:71153445:T:TA	acceptor_gain	0.9900
X:71155212:A:AG	acceptor_gain	0.9900
X:71155213:G:GT	acceptor_gain	0.9900
X:71155213:GA:G	acceptor_gain	0.9900
X:71155213:GACA:G	acceptor_gain	0.9900

AlphaMissense

5545 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:71148065:T:C	C106R	1.000
X:71148066:G:A	C106Y	1.000
X:71148067:C:G	C106W	1.000
X:71148170:T:C	C141R	1.000
X:71148171:G:A	C141Y	1.000
X:71148172:T:G	C141W	1.000
X:71148180:T:C	L144P	1.000
X:71155348:C:G	R238G	1.000
X:71155349:G:C	R238P	1.000
X:71155363:G:C	G243R	1.000
X:71164143:G:A	G243D	1.000
X:71164145:T:C	F244L	1.000
X:71164147:C:A	F244L	1.000
X:71164147:C:G	F244L	1.000
X:71164175:G:C	G254R	1.000
X:71164175:G:T	G254C	1.000
X:71164176:G:A	G254D	1.000
X:71164176:G:T	G254V	1.000
X:71164180:C:A	N255K	1.000
X:71164180:C:G	N255K	1.000
X:71164184:G:T	G257W	1.000
X:71164185:G:A	G257E	1.000
X:71164188:T:C	L258P	1.000
X:71164193:G:C	D260H	1.000
X:71164194:A:T	D260V	1.000
X:71164209:T:C	L265P	1.000
X:71164214:T:A	W267R	1.000
X:71164214:T:C	W267R	1.000
X:71164298:A:C	S295R	1.000
X:71164300:C:A	S295R	1.000

dbSNP variants (sampled 300 via entrez): RS1000105541 (X:71148386 C>T), RS1000186539 (X:71152603 G>A), RS1000238989 (X:71152005 TG>T), RS1000398551 (X:71164418 G>A), RS1000463966 (X:71168901 A>G), RS1000746586 (X:71164879 A>G), RS1000792879 (X:71173592 T>C), RS1000815037 (X:71168406 G>C), RS1000895959 (X:71159872 G>A), RS1001157565 (X:71151200 T>C,G), RS1001270614 (X:71149087 G>A,C), RS1001357110 (X:71161806 C>G), RS1001410422 (X:71174352 A>G), RS1001674436 (X:71159004 A>G), RS1001727976 (X:71149785 T>C)

Disease associations

OMIM: gene MIM:300336 | disease phenotypes: MIM:300425, MIM:147950, MIM:120970

GenCC curated gene-disease

Disease	Classification	Inheritance
autism, susceptibility to, X-linked 1	Strong	X-linked
X-linked complex neurodevelopmental disorder	Strong	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
X-linked complex neurodevelopmental disorder	Moderate	XL

Mondo (6): autism, susceptibility to, X-linked 1 (MONDO:0010321), intellectual disability (MONDO:0001071), autism spectrum disorder (MONDO:0005258), hypogonadotropic hypogonadism (MONDO:0018555), X-linked complex neurodevelopmental disorder (MONDO:0100148), cone-rod dystrophy (MONDO:0015993)

Orphanet (4): Normosmic congenital hypogonadotropic hypogonadism (Orphanet:432), Cone rod dystrophy (Orphanet:1872), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

17 total (18 of 17 shown, HPO-id order):

HPO	Term
HP:0000717	Autism
HP:0000721	Lack of spontaneous play
HP:0000723	Restrictive behavior
HP:0000728	Reduced ability to form peer relationships
HP:0000732	Inflexible adherence to routines
HP:0000733	Motor stereotypy
HP:0000750	Delayed speech and language development
HP:0000758	Abnormal nonverbal communicative behavior
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001417	X-linked inheritance
HP:0001426	Non-Mendelian inheritance
HP:0002332	Lack of peer relationships
HP:0002353	EEG abnormality
HP:0003144	Increased serum serotonin
HP:0003745	Sporadic
HP:0011463	Childhood onset
HP:0000044	Hypogonadotropic hypogonadism

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002606_22	Prostate cancer	1.000000e-09
GCST002606_41	Prostate cancer	9.000000e-08
GCST90002390_295	Mean corpuscular hemoglobin	1.000000e-09
GCST90002392_241	Mean corpuscular volume	3.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
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: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	2
belinostat	decreases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Valproic Acid	decreases expression	2
Particulate Matter	increases methylation, affects methylation, decreases expression, decreases reaction	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
ethyl-p-hydroxybenzoate	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
Decitabine	decreases expression, decreases reaction, increases methylation	1
Sunitinib	decreases expression	1
Vorinostat	decreases expression	1
Acetylcysteine	decreases expression, decreases reaction, increases methylation	1
Air Pollutants	increases abundance, affects expression	1
Azacitidine	increases expression	1
Cadmium	decreases expression, increases abundance	1
Cisplatin	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Endosulfan	decreases expression	1

Clinical trials (associated diseases)

300 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
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
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
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)