NLGN2

Summary

NLGN2 (neuroligin 2, HGNC:14290) is a protein-coding gene on chromosome 17p13.1, encoding Neuroligin-2 (Q8NFZ4). Transmembrane scaffolding 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.

Source: NCBI Gene 57555 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 268 total — 1 likely-pathogenic
• Phenotypes (HPO): 1
• MANE Select transcript: NM_020795

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14290
Approved symbol	NLGN2
Name	neuroligin 2
Location	17p13.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1366
Ensembl gene	ENSG00000169992
Ensembl biotype	protein_coding
OMIM	606479
Entrez	57555

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000302926, ENST00000570940, ENST00000572893, ENST00000575301

RefSeq mRNA: 1 — MANE Select: NM_020795 NM_020795

CCDS: CCDS11103

Canonical transcript exons

ENST00000302926 — 7 exons

Exon	Start	End
ENSE00001143803	7415511	7416107
ENSE00001265562	7414663	7414848
ENSE00001265569	7414344	7414493
ENSE00001265574	7412157	7412207
ENSE00001265582	7407845	7408712
ENSE00001265595	7416926	7419860
ENSE00001265606	7414956	7415148

Expression profiles

Bgee: expression breadth ubiquitous, 138 present calls, max score 96.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.9166 / max 503.9638, expressed in 1663 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
159172	21.8817	1598
159168	5.5177	1386
159175	1.5141	796
159169	1.1745	730
159170	0.6066	357
159171	0.5812	359
159179	0.4300	246
159167	0.4134	225
159166	0.4017	169
159178	0.3997	217

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	96.74	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.77	gold quality
superior frontal gyrus	UBERON:0002661	95.42	gold quality
cerebellum	UBERON:0002037	95.12	gold quality
cerebellar cortex	UBERON:0002129	95.10	gold quality
cerebellar hemisphere	UBERON:0002245	95.06	gold quality
right ovary	UBERON:0002118	94.84	gold quality
primary visual cortex	UBERON:0002436	94.65	gold quality
ganglionic eminence	UBERON:0004023	94.60	gold quality
body of uterus	UBERON:0009853	94.53	gold quality
right frontal lobe	UBERON:0002810	94.52	gold quality
stromal cell of endometrium	CL:0002255	94.50	gold quality
left ovary	UBERON:0002119	94.30	gold quality
nucleus accumbens	UBERON:0001882	94.04	gold quality
frontal cortex	UBERON:0001870	93.79	gold quality
ventricular zone	UBERON:0003053	93.72	gold quality
caudate nucleus	UBERON:0001873	93.63	gold quality
myometrium	UBERON:0001296	93.59	gold quality
left uterine tube	UBERON:0001303	93.48	gold quality
putamen	UBERON:0001874	93.41	gold quality
ovary	UBERON:0000992	93.40	gold quality
prefrontal cortex	UBERON:0000451	93.26	gold quality
cerebral cortex	UBERON:0000956	93.18	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.15	gold quality
endocervix	UBERON:0000458	93.03	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	92.92	gold quality
temporal lobe	UBERON:0001871	92.85	gold quality
amygdala	UBERON:0001876	92.78	gold quality
brain	UBERON:0000955	92.59	gold quality
anterior cingulate cortex	UBERON:0009835	92.58	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.57

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

92 targeting NLGN2, 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-4673	100.00	66.64	1490
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-1207-5P	99.49	69.11	2983

Literature-anchored findings (GeneRIF, showing 10)

• Data identified the R215H mutant as a loss-of-function mutant in inducing GABAergic synaptogenesis. Data also suggests that defects in GABAergic synapse formation in the brain may be an important contributing factor for the onset of schizophrenia. (PMID:21551456)
• Transcellular neuroligin-2 interactions enhance insulin secretion and are integral to pancreatic beta cell function (PMID:22528485)
• Neuroligin-2 was down-regulated in aganglionic colonic segments from Hirschsprung’s disease patients. (PMID:24842555)
• 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)
• This is the first report of an NLGN2 nonsense variant in humans, adding to the accumulating evidence that links synaptic proteins with a spectrum of neurodevelopmental phenotypes. (PMID:27865048)
• MDGAs regulate the formation of neuroligin-neurexin trans-synaptic bridges by sterically blocking access of neurexins to neuroligins. (PMID:28641112)
• nucleus accumbens neuroligin-2 has a role in depression and stress susceptibility (PMID:29339486)
• Neuroligin-2 dependent conformational activation of collybistin reconstituted in supported hybrid membranes. (PMID:33127642)
• Neuroligin-2 as a central organizer of inhibitory synapses in health and disease. (PMID:33443230)
• Expression and structural analysis of human neuroligin 2 and neuroligin 3 implicated in autism spectrum disorders. (PMID:36479216)

Cross-species orthologs

45 orthologs

Organism	Symbol	Gene ID
danio_rerio	nlgn2a	ENSDARG00000077329
mus_musculus	Nlgn2	ENSMUSG00000051790
rattus_norvegicus	Nlgn2	ENSRNOG00000015430
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), CEL (ENSG00000170835), CES4A (ENSG00000172824), CES3 (ENSG00000172828), CES2 (ENSG00000172831), NLGN3 (ENSG00000196338), CES1 (ENSG00000198848)

Protein

Protein identifiers

Neuroligin-2 — Q8NFZ4 (reviewed: Q8NFZ4)

All UniProt accessions (2): Q8NFZ4, I3L498

UniProt curated annotations — full annotation on UniProt →

Function. Transmembrane scaffolding protein involved in cell-cell interactions via its interactions with neurexin family members. Mediates cell-cell interactions both in neurons and in other types of cells, such as Langerhans beta cells. Plays a role in synapse function and synaptic signal transmission, especially via gamma-aminobutyric acid receptors (GABA(A) receptors). Functions by recruiting and clustering synaptic proteins. Promotes clustering of postsynaptic GABRG2 and GPHN. Promotes clustering of postsynaptic LHFPL4. Modulates signaling by inhibitory synapses, and thereby plays a role in controlling the ratio of signaling by excitatory and inhibitory synapses and information processing. Required for normal signal amplitude from inhibitory synapses, but is not essential for normal signal frequency. May promote the initial formation of synapses, but is not essential for this. In vitro, triggers the de novo formation of presynaptic structures. Mediates cell-cell interactions between Langerhans beta cells and modulates insulin secretion.

Subunit / interactions. 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). Interacts with PATJ. Interacts with GPHN. Interacts with MDGA1 and MDGA2. Found in a complex with MAGI2 and IGSF9B, where it interacts with MAGI2 (via WW 1, WW 2 and PDZ 2 domains). Identified in a complex of 720 kDa composed of LHFPL4, NLGN2, GABRA1, GABRB2, GABRG2 and GABRB3. Interacts with LHFPL4; leading to mutual regulation of the protein level and synaptic clustering. Interacts with NLGN2.

Subcellular location. Cell membrane. Postsynaptic cell membrane. Presynaptic cell membrane. Cell projection. Dendritic spine. Dendrite. Synapse.

Tissue specificity. Expressed in the blood vessel walls. Detected in colon, brain and pancreas islets of Langerhans (at protein level). 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.

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

RefSeq proteins (1): NP_065846* (*=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 (74 total): strand 25, helix 23, turn 7, compositionally biased region 3, glycosylation site 3, disulfide bond 3, region of interest 3, modified residue 2, topological domain 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
9FAJ	ELECTRON MICROSCOPY	2.6
9FAK	ELECTRON MICROSCOPY	2.6
9FAP	ELECTRON MICROSCOPY	2.8
9FAN	ELECTRON MICROSCOPY	2.9
9FAQ	ELECTRON MICROSCOPY	2.9
9FAR	ELECTRON MICROSCOPY	2.9
9FAW	ELECTRON MICROSCOPY	2.9
9FAX	ELECTRON MICROSCOPY	2.9
9FAU	ELECTRON MICROSCOPY	3.1
5XEQ	X-RAY DIFFRACTION	3.14
9FAV	ELECTRON MICROSCOPY	3.2
8GS4	ELECTRON MICROSCOPY	3.5
9FAM	ELECTRON MICROSCOPY	3.5
9FAT	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NFZ4-F1	78.67	0.60

Antibody-complex structures (SAbDab): 9 — 9FAJ, 9FAK, 9FAM, 9FAP, 9FAQ, 9FAT, 9FAU, 9FAW, 9FAX

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): 713, 718

Disulfide bonds (3): 106–141, 317–328, 487–521

Glycosylation sites (3): 98, 136, 522

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6794361	Neurexins and neuroligins

MSigDB gene sets: 310 (showing top): GOBP_DENDRITE_DEVELOPMENT, GOBP_SYNAPTIC_VESICLE_LOCALIZATION, GOBP_POSITIVE_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, GOBP_BEHAVIOR, GOBP_VESICLE_LOCALIZATION, GOBP_SYNAPSE_ASSEMBLY, GOBP_MEMBRANE_BIOGENESIS, GOBP_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GCANCTGNY_MYOD_Q6, CMYB_01, GOBP_ADULT_BEHAVIOR, SP3_Q3, GOBP_INSULIN_SECRETION, GOBP_REGULATION_OF_RESPIRATORY_SYSTEM_PROCESS

GO Biological Process (39): thigmotaxis (GO:0001966), regulation of respiratory gaseous exchange by nervous system process (GO:0002087), neuron cell-cell adhesion (GO:0007158), synapse assembly (GO:0007416), jump response (GO:0007630), positive regulation of cell population proliferation (GO:0008284), sensory perception of pain (GO:0019233), positive regulation of insulin secretion (GO:0032024), positive regulation of synaptic transmission, GABAergic (GO:0032230), protein localization to cell surface (GO:0034394), social behavior (GO:0035176), protein localization to synapse (GO:0035418), locomotory exploration behavior (GO:0035641), cell-cell junction maintenance (GO:0045217), modulation of chemical synaptic transmission (GO:0050804), synapse organization (GO:0050808), neuromuscular process controlling balance (GO:0050885), synaptic transmission, GABAergic (GO:0051932), positive regulation of synapse assembly (GO:0051965), positive regulation of synaptic transmission, glutamatergic (GO:0051968), positive regulation of dendritic spine development (GO:0060999), terminal button organization (GO:0072553), neurotransmitter-gated ion channel clustering (GO:0072578), postsynaptic membrane assembly (GO:0097104), presynaptic membrane assembly (GO:0097105), gephyrin clustering involved in postsynaptic density assembly (GO:0097116), postsynaptic density protein 95 clustering (GO:0097119), positive regulation of inhibitory postsynaptic potential (GO:0097151), cell-cell adhesion (GO:0098609), presynapse assembly (GO:0099054), insulin metabolic process (GO:1901142), positive regulation of protein localization to synapse (GO:1902474), positive regulation of t-SNARE clustering (GO:1904034), inhibitory synapse assembly (GO:1904862), regulation of presynapse assembly (GO:1905606), positive regulation of excitatory postsynaptic potential (GO:2000463), positive regulation of synaptic vesicle clustering (GO:2000809), cell adhesion (GO:0007155), postsynaptic specialization assembly (GO:0098698)

GO Molecular Function (3): neurexin family protein binding (GO:0042043), identical protein binding (GO:0042802), cell adhesion molecule binding (GO:0050839)

GO Cellular Component (19): plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020), axon (GO:0030424), presynaptic membrane (GO:0042734), dendritic shaft (GO:0043198), synapse (GO:0045202), postsynaptic membrane (GO:0045211), excitatory synapse (GO:0060076), inhibitory synapse (GO:0060077), ribbon synapse (GO:0097470), glycinergic synapse (GO:0098690), dopaminergic synapse (GO:0098691), symmetric, GABA-ergic, inhibitory synapse (GO:0098983), postsynaptic specialization membrane (GO:0099634), dendrite (GO:0030425), cell projection (GO:0042995), GABA-ergic synapse (GO:0098982), 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
synapse	7
cellular anatomical structure	4
synaptic membrane	3
behavior	2
positive regulation of synaptic transmission	2
chemical synaptic transmission	2
protein binding	2
neuron projection	2
respiratory gaseous exchange by respiratory system	1
regulation of respiratory system process	1
nervous system process	1
cell-cell adhesion	1
nervous system development	1
cell junction assembly	1
synapse organization	1
adult locomotory behavior	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
sensory perception	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
regulation of synaptic transmission, GABAergic	1
synaptic transmission, GABAergic	1
intracellular protein localization	1
biological process involved in intraspecies interaction between organisms	1
protein localization to cell junction	1
locomotory behavior	1
exploration behavior	1
cell junction maintenance	1
cell-cell junction organization	1
regulation of trans-synaptic signaling	1
cell junction organization	1
musculoskeletal movement	1
neuromuscular process	1
synapse assembly	1
positive regulation of nervous system development	1
regulation of synapse assembly	1

Protein interactions and networks

STRING

1802 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NLGN2	NRXN2	Q9P2S2	999
NLGN2	NRXN1	Q9ULB1	999
NLGN2	DLG4	P78352	995
NLGN2	GPHN	Q9NQX3	968
NLGN2	ARHGEF9	O43307	949
NLGN2	LHFPL4	Q7Z7J7	925
NLGN2	NRXN3	Q9Y4C0	922
NLGN2	LHFPL3	Q86UP9	901
NLGN2	SHANK3	Q9BYB0	864
NLGN2	MDGA1	Q8NFP4	848
NLGN2	SLITRK3	O94933	805
NLGN2	MAGI2	Q86UL8	800
NLGN2	SHANK2	Q9UPX8	739
NLGN2	MDGA2	Q7Z553	721
NLGN2	CADM1	Q9BY67	721

IntAct

178 interactions, top by confidence:

A	B	Type	Score
B3GAT3	GOLIM4	psi-mi:“MI:0914”(association)	0.640
ADCY9	NEMP1	psi-mi:“MI:0914”(association)	0.640
CRISP2	TUBA4A	psi-mi:“MI:0914”(association)	0.530
TTC5	TUBA4A	psi-mi:“MI:0914”(association)	0.530
EVA1B	NRP1	psi-mi:“MI:0914”(association)	0.530
NLGN2	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN2	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN2	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN2	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN2	SHANK1	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN2	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN2	DLG2	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN2	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
GOPC	NLGN2	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN2	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN2	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN2	SNTB1	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN2	TAMALIN	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN2	SNTA1	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN2	SNTG2	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN2	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN2	DLG1	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN2	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
DLG1	NLGN2	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN2	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (79): NLGN2 (Affinity Capture-MS), NLGN2 (Affinity Capture-MS), NLGN2 (Affinity Capture-MS), NLGN2 (Affinity Capture-MS), NLGN2 (Affinity Capture-MS), NLGN2 (Affinity Capture-MS), NLGN2 (Affinity Capture-MS), NLGN2 (Affinity Capture-MS), NLGN2 (Affinity Capture-MS), NLGN2 (Affinity Capture-MS), NLGN2 (Affinity Capture-MS), NLGN2 (Affinity Capture-MS), NLGN2 (Affinity Capture-RNA), NLGN2 (Affinity Capture-RNA), NLGN2 (Reconstituted Complex)

ESM2 similar proteins: A2A699, A2XVC2, A8MVW0, B0F2B4, D3ZE55, O09017, O14492, O62763, O95206, P10588, P21836, P22303, P23795, P36196, P37136, P43029, P43136, P50427, Q14003, Q29RK8, Q2QXZ2, Q2RAQ5, Q3U0S6, Q495W5, Q4ACU6, Q5T442, Q5U651, Q5ZMM1, Q62888, Q62889, Q63959, Q69ZK9, Q6UXK2, Q76KP1, Q7FA29, Q7Z4P5, Q80WV3, Q80XF7, Q869C3, Q8BQU6

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

16 interactions.

A	Effect	B	Mechanism
NLGN2	“up-regulates activity”	NRXN1	binding
NLGN2	“up-regulates activity”	NRXN2	binding
NLGN2	“up-regulates activity”	NRXN3	binding
NLGN2	“up-regulates activity”	DLG4	relocalization
GPHN	“up-regulates activity”	NLGN2	binding
NLGN2	up-regulates	Synaptic_plasticity
NLGN2	“up-regulates activity”	MAGI2	binding
NRXN1	“up-regulates activity”	NLGN2	binding
NRXN2	“up-regulates activity”	NLGN2	binding
NRXN3	“up-regulates activity”	NLGN2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 165 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
Ras activation upon Ca2+ influx through NMDA receptor	5	26.4×	1e-04
Unblocking of NMDA receptors, glutamate binding and activation	5	25.2×	1e-04
Negative regulation of NMDA receptor-mediated neuronal transmission	5	25.2×	1e-04
Assembly and cell surface presentation of NMDA receptors	10	23.5×	2e-09
Dopamine Neurotransmitter Release Cycle	5	23.0×	2e-04
Long-term potentiation	5	22.0×	2e-04
Neurexins and neuroligins	12	21.9×	8e-11
Protein-protein interactions at synapses	6	14.8×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	42.6×	6e-13
protein localization to synapse	7	35.8×	3e-07
receptor clustering	7	29.1×	7e-07
regulation of postsynaptic membrane neurotransmitter receptor levels	7	23.1×	3e-06
positive regulation of excitatory postsynaptic potential	5	17.6×	8e-04
establishment of protein localization	5	14.4×	2e-03
establishment of cell polarity	5	12.8×	3e-03
protein-containing complex assembly	11	8.3×	1e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	162
Likely benign	73
Benign	18

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
4537552	NM_020795.4(NLGN2):c.1517A>G (p.Tyr506Cys)	Likely pathogenic

SpliceAI

1589 predictions. Top by Δscore:

Variant	Effect	Δscore
17:7408708:GGACG:G	donor_gain	1.0000
17:7408709:GACGG:G	donor_gain	1.0000
17:7414340:A:AG	acceptor_gain	1.0000
17:7414340:ACAGA:A	acceptor_loss	1.0000
17:7414341:C:G	acceptor_gain	1.0000
17:7414341:CAGA:C	acceptor_loss	1.0000
17:7414342:A:AG	acceptor_gain	1.0000
17:7414342:AGA:A	acceptor_loss	1.0000
17:7414343:G:GG	acceptor_gain	1.0000
17:7414343:G:GT	acceptor_loss	1.0000
17:7414343:GAT:G	acceptor_gain	1.0000
17:7414658:CCCA:C	acceptor_loss	1.0000
17:7414659:CCA:C	acceptor_loss	1.0000
17:7414660:CAG:C	acceptor_loss	1.0000
17:7414661:A:AG	acceptor_gain	1.0000
17:7414662:G:GG	acceptor_gain	1.0000
17:7414844:AGAAG:A	donor_loss	1.0000
17:7414845:GAAG:G	donor_gain	1.0000
17:7414846:AAGGT:A	donor_loss	1.0000
17:7414848:GGTA:G	donor_loss	1.0000
17:7414849:G:T	donor_loss	1.0000
17:7414850:T:A	donor_loss	1.0000
17:7415116:G:GT	donor_gain	1.0000
17:7415132:G:GT	donor_gain	1.0000
17:7415509:A:AG	acceptor_gain	1.0000
17:7415510:G:GA	acceptor_gain	1.0000
17:7415510:GCT:G	acceptor_gain	1.0000
17:7416106:GG:G	donor_gain	1.0000
17:7416107:GG:G	donor_gain	1.0000
17:7416108:G:GG	donor_gain	1.0000

AlphaMissense

5383 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:7408573:C:G	C106W	1.000
17:7408677:G:A	C141Y	1.000
17:7408678:C:G	C141W	1.000
17:7414440:C:A	A202D	1.000
17:7414665:T:A	F221I	1.000
17:7414665:T:C	F221L	1.000
17:7414667:T:A	F221L	1.000
17:7414667:T:G	F221L	1.000
17:7414695:G:C	G231R	1.000
17:7414700:C:A	N232K	1.000
17:7414700:C:G	N232K	1.000
17:7414704:G:T	G234W	1.000
17:7414705:G:A	G234E	1.000
17:7414713:G:C	D237H	1.000
17:7414714:A:T	D237V	1.000
17:7414734:T:A	W244R	1.000
17:7414734:T:C	W244R	1.000
17:7414822:T:C	L273P	1.000
17:7414983:G:T	S291I	1.000
17:7415531:C:A	P353H	1.000
17:7415539:G:C	D356H	1.000
17:7415552:T:A	V360D	1.000
17:7415564:C:A	P364H	1.000
17:7415573:T:C	L367P	1.000
17:7415609:T:C	L379P	1.000
17:7415614:G:C	G381R	1.000
17:7415615:G:A	G381D	1.000
17:7415630:A:T	E386V	1.000
17:7415632:G:C	G387R	1.000
17:7415690:T:G	F406C	1.000

dbSNP variants (sampled 300 via entrez): RS1000084076 (17:7411448 G>GT), RS1000115121 (17:7411259 G>T), RS1000826837 (17:7405982 G>A), RS1001010828 (17:7411501 C>G), RS1001106501 (17:7417904 C>G,T), RS1001122140 (17:7410150 C>T), RS1001511092 (17:7408869 G>A), RS1001543588 (17:7408221 G>A,C,T), RS1001704697 (17:7420350 G>A), RS1001742924 (17:7402779 G>T), RS1001830135 (17:7407193 C>T), RS1001944693 (17:7406961 C>G,T), RS1002038115 (17:7403742 C>T), RS1002112171 (17:7418964 A>G), RS1002125964 (17:7408811 G>A)

Disease associations

OMIM: gene MIM:606479 | disease phenotypes: MIM:209850

GenCC curated gene-disease

Mondo (1): autism (MONDO:0005260)

Orphanet (0):

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000717	Autism

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006462_41	Uterine fibroids	2.000000e-10
GCST010002_119	Refractive error	3.000000e-22
GCST90020029_818	Waist circumference adjusted for body mass index	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases methylation, decreases expression	2
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
kojic acid	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
entinostat	increases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
bisphenol S	decreases methylation	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation, increases methylation	1
Benzo(a)pyrene	affects methylation	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Dexamethasone	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Lead	affects splicing	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With 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
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
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
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00352248	PHASE3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder
NCT00352352	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00355329	PHASE3	COMPLETED	Randomized Control Trial of Using Tongue Acupuncture in Autistic Spectrum Disorder Using PET Scan for Clinical Correlation
NCT00498173	PHASE3	COMPLETED	Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism
NCT00541346	PHASE3	COMPLETED	A Pilot Study of Daytrana TM in Children With Autism Co-Morbid for Attention Deficit Hyperactivity Disorder (ADHD) Symptoms