NRXN3

Summary

NRXN3 (neurexin 3, HGNC:8010) is a protein-coding gene on chromosome 14q24.3-q31.1, encoding Neurexin-3-beta (Q9HDB5). Neuronal cell surface protein that may be involved in cell recognition and cell adhesion.

This gene encodes a member of a family of proteins that function in the nervous system as receptors and cell adhesion molecules. Extensive alternative splicing and the use of alternative promoters results in multiple transcript variants and protein isoforms for this gene, but the full-length nature of many of these variants has not been determined. Transcripts that initiate from an upstream promoter encode alpha isoforms, which contain epidermal growth factor-like (EGF-like) sequences and laminin G domains. Transcripts initiating from the downstream promoter encode beta isoforms, which lack EGF-like sequences. Genetic variation at this locus has been associated with a range of behavioral phenotypes, including alcohol dependence and autism spectrum disorder.

Source: NCBI Gene 9369 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autism (Limited, GenCC)
• GWAS associations: 78
• Clinical variants (ClinVar): 207 total — 1 pathogenic
• Phenotypes (HPO): 1
• MANE Select transcript: NM_001330195

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8010
Approved symbol	NRXN3
Name	neurexin 3
Location	14q24.3-q31.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0743
Ensembl gene	ENSG00000021645
Ensembl biotype	protein_coding
OMIM	600567
Entrez	9369

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 14 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000281127, ENST00000335750, ENST00000428277, ENST00000553363, ENST00000553631, ENST00000553803, ENST00000554719, ENST00000554738, ENST00000555073, ENST00000555387, ENST00000556003, ENST00000556088, ENST00000556496, ENST00000557081, ENST00000557594, ENST00000634499, ENST00000635466, ENST00000676811, ENST00000679122

RefSeq mRNA: 7 — MANE Select: NM_001330195 NM_001105250, NM_001272020, NM_001330195, NM_001366425, NM_001366426, NM_004796, NM_138970

CCDS: CCDS45145, CCDS61515, CCDS81831, CCDS91913, CCDS9870, CCDS9871

Canonical transcript exons

ENST00000335750 — 21 exons

Exon	Start	End
ENSE00000808518	79697630	79697937
ENSE00001291831	78810318	78810344
ENSE00001304927	79692173	79692262
ENSE00001312921	78988022	78988141
ENSE00001322483	79805112	79805190
ENSE00002514835	78242391	78243802
ENSE00003460703	78297831	78297860
ENSE00003462275	78967208	78967398
ENSE00003480168	78709217	78709655
ENSE00003543740	78714756	78715139
ENSE00003572890	78957242	78957361
ENSE00003591766	78651165	78651326
ENSE00003602185	79467221	79467402
ENSE00003610211	79663778	79663949
ENSE00003619686	78645120	78645421
ENSE00003631532	78966025	78966406
ENSE00003679808	78803620	78803823
ENSE00003683550	78968173	78968346
ENSE00003786195	78278645	78278662
ENSE00003790415	78170373	78170674
ENSE00003910002	79861342	79868291

Expression profiles

Bgee: expression breadth ubiquitous, 231 present calls, max score 99.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.1979 / max 1530.2193, expressed in 925 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
140796	10.5249	316
140825	6.3286	745
140826	1.4702	415
207315	1.1044	44
140827	0.8905	288
140809	0.5442	102
140824	0.4605	164
140832	0.2170	109
140828	0.2021	104
140805	0.1190	58

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar vermis	UBERON:0004720	99.16	gold quality
substantia nigra pars compacta	UBERON:0001965	98.34	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.21	gold quality
pons	UBERON:0000988	97.81	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.76	gold quality
cerebellar cortex	UBERON:0002129	97.51	gold quality
cerebellar hemisphere	UBERON:0002245	97.45	gold quality
cerebellum	UBERON:0002037	97.43	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.91	gold quality
middle temporal gyrus	UBERON:0002771	96.47	gold quality
superior vestibular nucleus	UBERON:0007227	96.37	gold quality
lateral globus pallidus	UBERON:0002476	96.17	gold quality
parietal lobe	UBERON:0001872	95.85	gold quality
superior frontal gyrus	UBERON:0002661	95.77	gold quality
postcentral gyrus	UBERON:0002581	95.76	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.63	gold quality
entorhinal cortex	UBERON:0002728	95.22	gold quality
primary visual cortex	UBERON:0002436	94.83	gold quality
occipital lobe	UBERON:0002021	94.71	gold quality
dorsal root ganglion	UBERON:0000044	93.99	gold quality
sural nerve	UBERON:0015488	93.97	gold quality
trigeminal ganglion	UBERON:0001675	93.46	gold quality
seminal vesicle	UBERON:0000998	92.99	gold quality
ventral tegmental area	UBERON:0002691	92.98	gold quality
prefrontal cortex	UBERON:0000451	92.53	gold quality
germinal epithelium of ovary	UBERON:0001304	92.44	gold quality
medulla oblongata	UBERON:0001896	91.94	gold quality
Brodmann (1909) area 46	UBERON:0006483	91.69	gold quality
frontal cortex	UBERON:0001870	91.04	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	91.04	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	8546.65
E-HCAD-35	yes	8435.05
E-HCAD-30	yes	7005.61
E-MTAB-11268	yes	3234.35
E-CURD-119	yes	42.74
E-HCAD-25	yes	37.11
E-GEOD-93593	yes	19.92
E-ANND-3	yes	6.94
E-GEOD-84465	yes	6.73

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXQ1

miRNA regulators (miRDB)

226 targeting NRXN3, 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-3613-3P	100.00	76.36	7965
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4531	99.99	69.70	3181

Literature-anchored findings (GeneRIF, showing 29)

• Identification and characterization of heart-specific splicing of neurexin 3 mRNA (PMID:12379233)
• details of NRXN3’s gene structure and variants, and association of NRXN3 SNPs with alcohol dependence (PMID:17804423)
• Variants in NRXN3 are associated with waist circumference, body mass index and obesity. (PMID:19557197)
• Association of a polymorphism in the NRXN3 gene with the degree of smoking in schizophrenia. (PMID:19658047)
• alpha- and gamma-secretases can sequentially process NRXN3beta, leading to the formation of two final products, an approximately 80-kDa N-terminal extracellular domain of Neurexin-3beta (sNRXN3beta) and an approximately 12-kDa C-terminal intracellular NRXN3beta domain (NRXN3beta-ICD) (PMID:21084300)
• Our results reveal that menopause influences the adipose tissue expression of many genes, especially of neurexin 3, metallothionein 1E, and keratyn 7, which are associated with the alteration of several key biological processes. (PMID:21358552)
• central obesity-associated variants in LYPLAL1, NRXN3, MSRA, and TFAP2B (PMID:21674055)
• Six NRXN3 polymorphisms were genotyped: rs983795, rs11624704, rs917906, rs1004212, rs10146997 and rs8019381 associated with impulsivity and substance abuse. (PMID:21676558)
• NRXN3 single nucleotide polymorphism rs10146997 was significantly (P = 0.0445) associated with higher risk of breast cancer development (OR = 0.66 (95% CI 0.44-0.99)). (PMID:21688152)
• Index cases of autism spectrum were clinically characterized who have rare microdeletions at 14q24.3-31.1, a region that overlaps exons of the alpha and/or beta isoforms of NRXN3. (PMID:22209245)
• By age 7, common variations in FTO, TMEM18 and NRXN3 influence the vulnerability to metabolic complications of sleep deprivation. (PMID:22391885)
• NRXN3 polymorphisms play a role in susceptibility to smoking behavior and are strongly implicated in human genetic vulnerability to addictive behaviors. (PMID:22716474)
• Association of the Graves disease phenotype with two markers, rs12147587 and rs2284720, located within the NRXN3 and TSHR genes, respectively. (PMID:23118423)
• the study finds preliminary evidence for the association of NRXN3 with Borderline Personality Disorder phenotypes. The strongest association with positive screening for BPD was found for SNP rs10083466. (PMID:23245376)
• Our findings suggested that NRXN3 might represent a major susceptibility gene for schizophrenia (PMID:23306218)
• FoxQ1 promotes glioma cell proliferation and migration by down-regulation of NRXN3 expression. (PMID:23383267)
• Neurexin 3-alpha (NRXN3) is a synaptic cell-cell adhesion molecule involved in maintenance of neural connections (such as the maintenance of smoking behavior). (PMID:23909413)
• a positive association between Neurexin 3 and controls in the Han Chinese population, and genetic evidence to support the susceptibility of DEACMP (PMID:24265751)
• The study showed that markers rs2217887 (NRXN3) showed weak associations. (PMID:24444492)
• This study confirmed the genetic heterogeneity of cluster headache, suggesting that a novel rearrangement involving NRXN3 gene might be related to cluster headache in a subset of cases (PMID:24469609)
• The rare variants in NRXN3 were significantly associated with smoking status. (PMID:25450229)
• NRXN2 may play a part in early cortical synaptogenesis, but NRXNs could have diverse roles in development including axon guidance, and intercellular communication between proliferating cells and/or migrating neurons. (PMID:28013231)
• The neurexins are a family of synaptic adhesion proteins encoded by paralogous genes that play key roles in synaptic function. (PMID:29045040)
• Study found that expression and ratio of transmembrane and soluble NRXN3 isoforms were reduced in Alzheimer disease (AD) postmortem brains and inversely correlated with inflammasome component NLRP3 in AD brain regions. (PMID:30902061)
• Modeling a Neurexin-3alpha Human Mutation in Mouse Neurons Identifies a Novel Role in the Regulation of Transsynaptic Signaling and Neurotransmitter Release at Excitatory Synapses. (PMID:31578233)
• Circ_0001367 inhibits glioma proliferation, migration and invasion by sponging miR-431 and thus regulating NRXN3. (PMID:34035217)
• Association of Nicotine Use Disorder with Neurexin 3 Gene Polymorphisms.", trans “Nikotin Kullanim Bozuklugunun Neurexin 3 Gen Polimorfizmi ile Iliskisi. (PMID:34647286)
• N-terminal sequencing of cow neurexin III beta provides evidence for signal peptide (PMID:8163501)
• N-terminal sequencing of rat neurexin III alpha provides evidence for signal peptide (PMID:9856994)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nrxn3a	ENSDARG00000043746
mus_musculus	Nrxn3	ENSMUSG00000066392
rattus_norvegicus	Nrxn3	ENSRNOG00000047574

Paralogs (35): TLL1 (ENSG00000038295), CP (ENSG00000047457), DCBLD2 (ENSG00000057019), HEPH (ENSG00000089472), TLL2 (ENSG00000095587), NRP1 (ENSG00000099250), PCOLCE (ENSG00000106333), CNTNAP3 (ENSG00000106714), CUBN (ENSG00000107611), CNTNAP1 (ENSG00000108797), NRXN2 (ENSG00000110076), MEP1A (ENSG00000112818), NRP2 (ENSG00000118257), CUZD1 (ENSG00000138161), MFGE8 (ENSG00000140545), MEP1B (ENSG00000141434), PDGFC (ENSG00000145431), CNTNAP4 (ENSG00000152910), CNTNAP3B (ENSG00000154529), CNTNAP5 (ENSG00000155052), CDCP2 (ENSG00000157211), PCOLCE2 (ENSG00000163710), EDIL3 (ENSG00000164176), NETO1 (ENSG00000166342), BMP1 (ENSG00000168487), PDGFD (ENSG00000170962), NETO2 (ENSG00000171208), CNTNAP2 (ENSG00000174469), NRXN1 (ENSG00000179915), HEPHL1 (ENSG00000181333), F8 (ENSG00000185010), ASTL (ENSG00000188886), F5 (ENSG00000198734), MFRP (ENSG00000235718), CNTNAP3C (ENSG00000283378)

Protein

Protein identifiers

Neurexin-3-beta — Q9HDB5 (reviewed: Q9HDB5, Q9Y4C0)

Alternative names: Neurexin III-beta

All UniProt accessions (11): A0A0A0MR89, A0A0C4DGK4, A0A0U1RQC5, A0A0U1RRJ0, A0A7I2V2B1, A0A7I2YQT0, Q9HDB5, Q9Y4C0, G3V247, G3V4R9, H0YJL2

UniProt curated annotations — full annotation on UniProt →

Function. Neuronal cell surface protein that may be involved in cell recognition and cell adhesion. May mediate intracellular signaling. Functions as part of a trans-synaptic complex by binding to cerebellins and postsynaptic GRID1. This interaction helps regulate the activity of NMDA and AMPA receptors at hippocampal synapses without affecting synapse formation. NRXN3B-CBLN2-GRID1 complex transduce presynaptic signals into postsynaptic AMPAR response.

Subunit / interactions. Weakly interacts with CBLN1 and CBLN2. Very weak binding, if any, to CBLN4. Specific isoforms bind neuroligins NLGN1, NLGN2 and NLGN3. Interacts with CLSTN3.

Subcellular location. Presynaptic cell membrane.

Tissue specificity. Expressed in the blood vessel walls (at protein level).

Post-translational modifications. Processed by alpha-secretase leading to the formation of an extracellular soluble protein as well as a C-terminal membrane-embedded fragment (CTF). Proteolysis of these CTFs by gamma-secretase releases intracellular domains (ICDs) and extracellular peptides. O-glycosylated; contains heparan sulfate. Heparan sulfate attachment is required for synapse development by mediating interactions with neuroligins.

Miscellaneous. Produced by alternative splicing. Produced by alternative splicing. Produced by alternative splicing.

Similarity. Belongs to the neurexin family.

Isoforms (7)

UniProt ID	Names	Canonical?
Q9HDB5-1	1b	yes
Q9HDB5-2	2b
Q9HDB5-3	3b
Q9HDB5-4	4b
Q9Y4C0-1	1a
Q9Y4C0-3	3a
Q9Y4C0-4	4a

RefSeq proteins (7): NP_001098720, NP_001258949, NP_001317124, NP_001353354, NP_001353355, NP_004787, NP_620426 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001791	Laminin_G	Domain
IPR003585	Neurexin-like	Domain
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR027789	Syndecan/Neurexin_dom	Domain
IPR050372	Neurexin-related_CASP	Family
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain

Pfam: PF01034, PF02210

UniProt features (83 total): binding site 14, splice variant 14, disulfide bond 12, glycosylation site 11, domain 10, region of interest 5, chain 4, compositionally biased region 4, topological domain 4, signal peptide 2, transmembrane region 2, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HDB5-F1	59.75	0.30
AF-Q9Y4C0-F1	75.91	0.48

Functional residue map

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

Q9HDB5 (canonical)

Ligand- & substrate-binding residues (4): 137; 154; 206; 208

Glycosylation sites (4): 184, 252, 296, 312

Q9Y4C0

Ligand- & substrate-binding residues (10): 304; 321; 374; 732; 749; 807; 1142; 1159; 1211; 1213

Disulfide bonds (12): 202–213, 207–222, 224–234, 404–440, 610–639, 647–658, 652–667, 669–679, 1018–1046, 1053–1064, 1058–1073, 1075–1085

Glycosylation sites (7): 58, 105, 757, 1189, 1257, 1301, 1317

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6794361	Neurexins and neuroligins

MSigDB gene sets: 259 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, MYAATNNNNNNNGGC_UNKNOWN, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_SYNAPSE_ASSEMBLY, GCANCTGNY_MYOD_Q6, TTTGTAG_MIR520D, GOBP_ADULT_BEHAVIOR, AREB6_01, GTTAAAG_MIR302B, GOBP_NEUROGENESIS, HNF1_Q6, RIZKI_TUMOR_INVASIVENESS_3D_DN, FOXD3_01, GOBP_CELL_CELL_SIGNALING

GO Biological Process (19): angiogenesis (GO:0001525), neuron cell-cell adhesion (GO:0007158), signal transduction (GO:0007165), learning (GO:0007612), adult behavior (GO:0030534), social behavior (GO:0035176), vocalization behavior (GO:0071625), axon guidance (GO:0007411), cell adhesion (GO:0007155), chemical synaptic transmission (GO:0007268), neurotransmitter secretion (GO:0007269), nervous system development (GO:0007399), synapse assembly (GO:0007416), postsynaptic density assembly (GO:0097107), regulation of postsynaptic membrane neurotransmitter receptor levels (GO:0099072), presynaptic modulation of chemical synaptic transmission (GO:0099171), trans-synaptic signaling (GO:0099537), trans-synaptic signaling, modulating synaptic transmission (GO:0099550), neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0099645)

GO Molecular Function (7): transmembrane signaling receptor activity (GO:0004888), metal ion binding (GO:0046872), cell adhesion molecule binding (GO:0050839), neuroligin family protein binding (GO:0097109), signaling receptor activity (GO:0038023), calcium channel regulator activity (GO:0005246), protein binding (GO:0005515)

GO Cellular Component (10): plasma membrane (GO:0005886), presynaptic membrane (GO:0042734), trans-synaptic protein complex (GO:0098820), membrane (GO:0016020), protein-containing complex (GO:0032991), cell projection (GO:0042995), synapse (GO:0045202), presynaptic active zone membrane (GO:0048787), glutamatergic synapse (GO:0098978), GABA-ergic synapse (GO:0098982)

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
presynapse	3
cellular process	2
chemical synaptic transmission	2
modulation of chemical synaptic transmission	2
synaptic membrane	2
cellular anatomical structure	2
synapse	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
cell-cell adhesion	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
learning or memory	1
biological process involved in intraspecies interaction between organisms	1
axonogenesis	1
neuron projection guidance	1
anterograde trans-synaptic signaling	1
neurotransmitter transport	1
establishment of localization in cell	1
signal release from synapse	1
system development	1
nervous system development	1
cell junction assembly	1
synapse organization	1
postsynaptic density organization	1
postsynaptic specialization assembly	1
excitatory synapse assembly	1
regulation of biological quality	1
synaptic signaling	1
trans-synaptic signaling	1
protein-containing complex localization	1
receptor localization to synapse	1
regulation of postsynaptic membrane neurotransmitter receptor levels	1
protein localization to postsynaptic specialization membrane	1
signaling receptor activity	1
cation binding	1
protein binding	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

128 interactions, top by confidence:

A	B	Type	Score
CAMKV	AP3B1	psi-mi:“MI:0914”(association)	0.640
LRRTM4	AP3B1	psi-mi:“MI:0914”(association)	0.530
HADHA	AGRN	psi-mi:“MI:0914”(association)	0.530
TAFA4	NRP1	psi-mi:“MI:0914”(association)	0.530
GPR183	NRP1	psi-mi:“MI:0914”(association)	0.530
CBLN4	C1QL1	psi-mi:“MI:0914”(association)	0.530
TAFA1	ZER1	psi-mi:“MI:0914”(association)	0.530
HTRA1	NRXN3	psi-mi:“MI:0407”(direct interaction)	0.440
NRXN3	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
MPP7	NRXN3	psi-mi:“MI:0407”(direct interaction)	0.440
NRXN3	GRIP2	psi-mi:“MI:0407”(direct interaction)	0.440
NRXN3	HTRA3	psi-mi:“MI:0407”(direct interaction)	0.440
NRXN3	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440
MAGI3	NRXN3	psi-mi:“MI:0407”(direct interaction)	0.440
NRXN3	MPDZ	psi-mi:“MI:0407”(direct interaction)	0.440
NRXN3	RADIL	psi-mi:“MI:0407”(direct interaction)	0.440
NRXN3	GORASP2	psi-mi:“MI:0407”(direct interaction)	0.440
NRXN3	GRIP1	psi-mi:“MI:0407”(direct interaction)	0.440
NRXN3	PDZK1	psi-mi:“MI:0407”(direct interaction)	0.440
NRXN3	PARD3	psi-mi:“MI:0407”(direct interaction)	0.440
NRXN3	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
NRXN3	TIAM2	psi-mi:“MI:0407”(direct interaction)	0.440
NRXN3	FRMPD4	psi-mi:“MI:0407”(direct interaction)	0.440
NRXN3	MPP2	psi-mi:“MI:0407”(direct interaction)	0.440
NRXN3	FRMPD2	psi-mi:“MI:0407”(direct interaction)	0.440
NRXN3	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
NRXN3	GORASP1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (37): NRXN3 (Affinity Capture-MS), NRXN3 (Affinity Capture-MS), NRXN3 (Affinity Capture-MS), NRXN3 (Affinity Capture-MS), NRXN3 (Affinity Capture-MS), NRXN3 (Affinity Capture-MS), NRXN3 (Affinity Capture-MS), NRXN3 (Affinity Capture-MS), NRXN3 (Affinity Capture-MS), DNAJC5 (FRET), NRXN3 (Synthetic Lethality), PAX4 (Two-hybrid), NRXN3 (Two-hybrid), NLGN1 (Reconstituted Complex), NLGN2 (Reconstituted Complex)

ESM2 similar proteins: A1XQX1, A1XQX3, A1XQY0, A8WGA3, C6K2K4, D0PRN2, D0PRN4, D4A1J9, E9PUN2, O13097, O42596, O73612, O73874, P0DI97, P52795, P52796, P58400, P58401, P98172, Q01974, Q0PMD2, Q17QD6, Q28142, Q28143, Q460M5, Q63373, Q63376, Q6NW40, Q6PCX7, Q6PFE7, Q7TQ33, Q80TG9, Q8BNJ6, Q8BXA0, Q8C985, Q8IYR6, Q8NC67, Q91590, Q96B86, Q96NI6

Diamond homologs: A1XQX0, A1XQX1, A1XQX2, A1XQX3, A1XQX8, A1XQY0, A1XQY1, A1XQY3, A6MFK7, D0PRN2, D0PRN3, D0PRN4, E9PUN2, E9Q7X7, P00741, P0DI97, P16294, P16296, P58400, P58401, Q07310, Q28142, Q28143, Q28146, Q3KN41, Q63372, Q63373, Q63374, Q63376, Q6P9K9, Q6SA95, Q8C985, Q9CS84, Q9DDD0, Q9HDB5, Q9P2S2, Q9ULB1, Q9Y4C0, O02768, O19183

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
NLGN3	“up-regulates activity”	NRXN3	binding
NLGN4Y	“up-regulates activity”	NRXN3	binding
NLGN1	“up-regulates activity”	NRXN3	binding
NLGN4X	“up-regulates activity”	NRXN3	binding
NLGN2	“up-regulates activity”	NRXN3	binding
DGC	“up-regulates activity”	NRXN3	binding
NRXN3	“up-regulates activity”	NLGN2	binding
NRXN3	“up-regulates activity”	DAG1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 99 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	43.9×	6e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	41.8×	6e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	41.8×	6e-06
Long-term potentiation	5	36.6×	1e-05
Neurexins and neuroligins	11	33.3×	5e-12
Protein-protein interactions at synapses	8	32.7×	2e-08
Assembly and cell surface presentation of NMDA receptors	8	31.2×	2e-08
RND3 GTPase cycle	5	20.0×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	66.6×	3e-15
receptor clustering	8	52.0×	6e-10
protein localization to synapse	6	47.9×	5e-07
regulation of postsynaptic membrane neurotransmitter receptor levels	6	31.0×	5e-06
protein-containing complex assembly	9	10.7×	1e-05
cell-cell adhesion	9	9.5×	3e-05
chemical synaptic transmission	8	6.4×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	131
Likely benign	43
Benign	12

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
375395	NM_001330195.2(NRXN3):c.1315A>G (p.Lys439Glu)	Pathogenic

SpliceAI

5259 predictions. Top by Δscore:

Variant	Effect	Δscore
14:78645116:A:AG	acceptor_gain	1.0000
14:78645117:T:G	acceptor_gain	1.0000
14:78645117:TA:T	acceptor_loss	1.0000
14:78645118:A:AG	acceptor_gain	1.0000
14:78645118:AGCT:A	acceptor_loss	1.0000
14:78645118:AGCTC:A	acceptor_gain	1.0000
14:78645119:G:GG	acceptor_gain	1.0000
14:78645119:GCT:G	acceptor_gain	1.0000
14:78645119:GCTC:G	acceptor_gain	1.0000
14:78645119:GCTCG:G	acceptor_gain	1.0000
14:78651151:T:G	acceptor_gain	1.0000
14:78651324:GAG:G	donor_gain	1.0000
14:78651324:GAGGT:G	donor_loss	1.0000
14:78651325:AGG:A	donor_loss	1.0000
14:78651327:G:C	donor_loss	1.0000
14:78651328:T:G	donor_loss	1.0000
14:78170671:AAAG:A	donor_loss	0.9900
14:78170673:AGGTA:A	donor_loss	0.9900
14:78170675:GTAA:G	donor_loss	0.9900
14:78170676:T:G	donor_loss	0.9900
14:78261082:A:T	donor_gain	0.9900
14:78278435:G:GT	donor_gain	0.9900
14:78278628:T:A	acceptor_gain	0.9900
14:78278637:T:A	acceptor_gain	0.9900
14:78278640:CACAG:C	acceptor_loss	0.9900
14:78278642:CA:C	acceptor_loss	0.9900
14:78278643:A:AG	acceptor_gain	0.9900
14:78278644:G:GG	acceptor_gain	0.9900
14:78279093:G:GT	donor_gain	0.9900
14:78291572:A:G	acceptor_gain	0.9900

AlphaMissense

5861 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000000901 (14:79642752 C>T), RS1000002978 (14:78642384 AT>A), RS1000005878 (14:78232280 A>G), RS1000009659 (14:79418672 A>G), RS1000011845 (14:79202036 C>G,T), RS1000015761 (14:79495582 A>C), RS1000016321 (14:79476192 A>G), RS1000019355 (14:78684877 TATC>T), RS1000020280 (14:79514168 T>A), RS1000024413 (14:78513485 G>A,T), RS1000029360 (14:79499959 G>A), RS1000031412 (14:79520169 G>A,T), RS1000033569 (14:78775844 C>A), RS1000034883 (14:79160480 A>G), RS1000035186 (14:79708284 A>G)

Disease associations

OMIM: gene MIM:600567 | disease phenotypes: MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
autism	Limited	Autosomal dominant

Mondo (2): autism spectrum disorder (MONDO:0005258), autism (MONDO:0005260)

Orphanet (1): NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

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

HPO	Term
HP:0000717	Autism

GWAS associations

78 associations (top):

Study	Trait	p-value
GCST000427_4	Waist circumference	5.000000e-08
GCST000614_4	Brain structure (temporal lobe volume)	8.000000e-06
GCST000830_5	Body mass index	3.000000e-11
GCST001057_8	Obesity	3.000000e-09
GCST001629_5	Response to platinum-based chemotherapy in non-small-cell lung cancer	4.000000e-06
GCST001663_8	Amyotrophic lateral sclerosis (age of onset)	6.000000e-06
GCST001953_31	Obesity	1.000000e-17
GCST001953_61	Obesity	3.000000e-09
GCST002569_1	Underweight status	1.000000e-06
GCST002587_24	Blood pressure (smoking interaction)	3.000000e-07
GCST002587_25	Blood pressure (smoking interaction)	1.000000e-07
GCST002587_26	Blood pressure (smoking interaction)	1.000000e-07
GCST002706_12	Electrodermal activity	5.000000e-06
GCST002706_9	Electrodermal activity	8.000000e-06
GCST002783_158	Body mass index	1.000000e-14
GCST002783_211	Body mass index	9.000000e-15
GCST002783_462	Body mass index	1.000000e-11
GCST002783_563	Body mass index	6.000000e-08
GCST003161_3	Objective response to lithium treatment in bipolar disorder	4.000000e-06
GCST003248_3	Body mass index	2.000000e-06
GCST003560_16	Coronary artery aneurysm in Kawasaki disease	6.000000e-06
GCST004032_9	JT interval (sulfonylurea treatment interaction)	1.000000e-06
GCST004064_36	Waist-hip ratio	3.000000e-08
GCST004064_53	Waist-hip ratio	9.000000e-07
GCST004065_101	Waist circumference	2.000000e-07
GCST004065_68	Waist circumference	9.000000e-16
GCST004065_75	Waist circumference	7.000000e-13
GCST004066_122	Hip circumference	9.000000e-13
GCST004066_47	Hip circumference	2.000000e-11
GCST004495_64	BMI (adjusted for smoking behaviour)	5.000000e-12

EFO canonical traits (27, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004847	age at onset
EFO:0005936	underweight body mass index status
EFO:0006335	systolic blood pressure
EFO:0006525	cigarettes per day measurement
EFO:0006526	pack-years measurement
EFO:0004318	smoking behavior
EFO:0006527	smoking status measurement
EFO:0007885	JT interval
EFO:0007922	response to sulfonylurea
EFO:0004343	waist-hip ratio
EFO:0008002	physical activity measurement
EFO:0009180	rosacea severity measurement
EFO:0007702	hip bone mineral density
EFO:0009751	facial asymmetry measurement
EFO:0008328	chronotype measurement
EFO:0004338	body weight
EFO:0010091	tea consumption measurement
EFO:0009282	sodium measurement
EFO:0008354	cognitive function measurement
EFO:0004644	TPE interval measurement
EFO:0007768	response to exercise
EFO:0007874	gut microbiome measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0007828	daytime rest measurement
EFO:0005670	smoking initiation
EFO:0004502	adiponectin measurement

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

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation, increases expression	7
sodium arsenite	increases abundance, increases expression, affects methylation, affects cotreatment, decreases expression	3
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	3
Aflatoxin B1	increases methylation, decreases expression, decreases methylation	3
bisphenol A	affects cotreatment, decreases methylation, decreases expression, increases methylation	2
trichostatin A	decreases expression, increases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
Vorinostat	affects cotreatment, decreases expression	2
Progesterone	increases expression, decreases expression, affects cotreatment	2
Tretinoin	increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
sulforaphane	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	increases expression	1
aflatoxin B2	increases methylation	1
perfluorooctane sulfonic acid	decreases 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
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects cotreatment, increases methylation, decreases methylation	1
jinfukang	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Dasatinib	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	decreases expression	1
Fulvestrant	decreases methylation, increases methylation, affects cotreatment	1

Clinical trials (associated diseases)

394 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