NECTIN1

Summary

NECTIN1 (nectin cell adhesion molecule 1, HGNC:9706) is a protein-coding gene on chromosome 11q23.3, encoding Nectin-1 (Q15223). Cell adhesion molecule that promotes cell-cell contacts and plays important roles in the development of the nervous system.

This gene encodes an adhesion protein that plays a role in the organization of adherens junctions and tight junctions in epithelial and endothelial cells. The protein is a calcium(2+)-independent cell-cell adhesion molecule that belongs to the immunoglobulin superfamily and has 3 extracellular immunoglobulin-like loops, a single transmembrane domain (in some isoforms), and a cytoplasmic region. This protein acts as a receptor for glycoprotein D (gD) of herpes simplex viruses 1 and 2 (HSV-1, HSV-2), and pseudorabies virus (PRV) and mediates viral entry into epithelial and neuronal cells. Mutations in this gene cause cleft lip and palate/ectodermal dysplasia 1 syndrome (CLPED1) as well as non-syndromic cleft lip with or without cleft palate (CL/P). Alternative splicing results in multiple transcript variants encoding proteins with distinct C-termini.

Source: NCBI Gene 5818 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cleft lip/palate-ectodermal dysplasia syndrome (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 248 total — 5 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 105
• Druggable target: yes
• MANE Select transcript: NM_002855

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9706
Approved symbol	NECTIN1
Name	nectin cell adhesion molecule 1
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Aliases	PRR, PRR1, PVRR1, SK-12, HIgR, CLPED1, CD111, OFC7, Nectin-1
Ensembl gene	ENSG00000110400
Ensembl biotype	protein_coding
OMIM	600644
Entrez	5818

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 3 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000264025, ENST00000340882, ENST00000341398, ENST00000524429, ENST00000524510, ENST00000531468, ENST00000532197

RefSeq mRNA: 3 — MANE Select: NM_002855 NM_002855, NM_203285, NM_203286

CCDS: CCDS8426, CCDS8427

Canonical transcript exons

ENST00000264025 — 6 exons

Exon	Start	End
ENSE00000748569	119660992	119665297
ENSE00000990385	119728475	119729200
ENSE00003969114	119675159	119675310
ENSE00003969115	119678415	119678765
ENSE00003969116	119677102	119677219
ENSE00003969117	119677555	119677857

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 98.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.9414 / max 198.7090, expressed in 1535 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122753	12.9414	1535

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	98.35	gold quality
skin of abdomen	UBERON:0001416	97.07	gold quality
esophagus mucosa	UBERON:0002469	96.57	gold quality
skin of leg	UBERON:0001511	96.23	gold quality
zone of skin	UBERON:0000014	94.17	gold quality
nipple	UBERON:0002030	93.86	gold quality
pharyngeal mucosa	UBERON:0000355	93.16	gold quality
body of tongue	UBERON:0011876	92.89	gold quality
gingival epithelium	UBERON:0001949	92.87	gold quality
gingiva	UBERON:0001828	92.32	gold quality
lateral nuclear group of thalamus	UBERON:0002736	91.61	gold quality
subthalamic nucleus	UBERON:0001906	91.30	gold quality
mammalian vulva	UBERON:0000997	91.00	gold quality
lateral globus pallidus	UBERON:0002476	90.82	gold quality
vena cava	UBERON:0004087	90.74	silver quality
inferior vagus X ganglion	UBERON:0005363	90.29	gold quality
tongue	UBERON:0001723	90.24	gold quality
substantia nigra pars compacta	UBERON:0001965	90.02	gold quality
prefrontal cortex	UBERON:0000451	89.99	gold quality
substantia nigra pars reticulata	UBERON:0001966	89.99	gold quality
superior surface of tongue	UBERON:0007371	89.88	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.77	gold quality
right frontal lobe	UBERON:0002810	89.67	gold quality
penis	UBERON:0000989	89.60	gold quality
vagina	UBERON:0000996	89.60	gold quality
ventral tegmental area	UBERON:0002691	89.57	gold quality
spinal cord	UBERON:0002240	88.75	gold quality
upper leg skin	UBERON:0004262	88.65	gold quality
dorsal plus ventral thalamus	UBERON:0001897	88.20	gold quality
pons	UBERON:0000988	87.64	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-114	yes	52.98
E-ANND-3	yes	12.37

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

313 targeting NECTIN1, 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-4455	100.00	65.48	1587
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-32-5P	99.98	75.21	1964

Literature-anchored findings (GeneRIF, showing 40)

• evidence that nectin-1 confined to adherens junctions in epithelial cells is not very accessible to virus, whereas dissociation of cell junctions releases nectin-1 to serve more efficiently as an entry receptor (PMID:12072519)
• Regions of nectin-1 protein important for herpesvirus entry activity and homotypic nectin-nectin interactions are overlapping but not identical. (PMID:12438620)
• association of HVEM and nectin-1 with lipid rafts during herpes simplex virus entry (PMID:12915568)
• both nectin 1 and HVEM receptors play a role during HSV infection in vivo and both are highly efficient even at low levels of expression (PMID:15110526)
• Nectin-1-Delta2 exhibited a severely reduced ability to mediate HSV entry and accumulated in the endoplasmic reticulum but retained the ability to interact with its HSV ligand, gD. (PMID:15731277)
• trans-interacting nectin inhibits non-trans-interacting E-cadherin endocytosis through afadin, Rap1, and p120ctn and further accumulates non-trans-interacting E-cadherin to the nectin-based cell-cell adhesion sites for the formation of adherens junctions (PMID:15857834)
• mutations at codons 185 and 323, especially the W185X mutation, do not participate in the formation of cleft lip and palate within the Taiwanese population examined (PMID:16497481)
• Mutations within the PVRL1 gene represent risk factors for non-syndromic cleft lip with or without cleft palate. (PMID:16674562)
• Access to nectin-1 contributes to preferential apical infection of human epithelial cells by herpes simplex virus. (PMID:17005657)
• the role of PVRL1 in the sporadic forms of orofacial clefting in multiple populations was studied. (PMID:17089422)
• nectin-1 may be used as a marker to predict the sensitivity of a tumor to herpes oncolytic therapy (PMID:17164781)
• These data suggest that the determinants of gD-mediated internalization of nectin-1 may direct HSV to an endocytic pathway during entry. (PMID:18076965)
• Novel non-synonymous PVRL1 mutation of the substitution of valine by methionine a position 395 in a conserved sequence suggests a possible etiologic role of PVRL1 in non-syndromic CL/P across different populations. (PMID:18356023)
• Western blot analyses demonstrated that accumulation of host nectin-1 is decreased by 85 % at 48 hours post-infection (h.p.i.) in Chlamydia trachomatis serovar E-infected HeLa cells. (PMID:18451037)
• Antibodies against nectin-1, but not HVEM, were able to block HSV-1 infection.Anti-nectin-1 antibodies and F-actin depolymerizers were also successful in blocking the cytoskeletal changes that occur upon HSV-1 entry into cells (PMID:18803666)
• These results indicate that nectin-1 is degraded by chlamydial protease-like activity factor (CPAF) in Chlamydia trachomatis-infected genital epithelial cells, a novel strategy that Chlamydiae may use to aid their dissemination. (PMID:18983929)
• There is no relationship between nonsyndromic cleft lip and/or palate and PVRL1exon3 in Han People. (PMID:19408722)
• Insertional mutations of gB reduced cell fusion activity when PILRalpha was overexpressed much more than nectin-1. (PMID:19457990)
• results suggest that PVRL1 may play a minor role in susceptibility to the occurrence of nsCL/P in some Caucasian populations, and that variation involving the beta (HIgR) isoform might have particular importance for risk of orofacial clefts (PMID:19715471)
• alpha- and gamma-secretase processing of nectin-1 is a Ca(2+)/calmodulin-regulated event that occurs under conditions of activity-dependent synaptic plasticity and ADAM10 and gamma-secretase are responsible for these cleavage events. (PMID:20501653)
• Structure of herpes simplex virus glycoprotein D bound to the human receptor nectin-1. (PMID:21980294)
• alphaVbeta3-integrin relocalizes nectin1 to lipid rafts, independently of herpes simplex virus 1. (PMID:22171266)
• NSCL/P-associated mutations of PVRL1 (PMID:22455396)
• This study demonistated that increased expression of nectin-1 in MS lesions plays a role in the pathogenesis of MS through participation in axonal responses to injury and mediation of altered neuron-glia interactions relevant to myelination. (PMID:22460696)
• Nectin-1 Ig3 induced phosphorylation of FGFR1c in the same manner as the whole nectin-1 ectodomain, and promoted survival of cerebellar granule neurons induced to undergo apoptosis. (PMID:22955284)
• Glycoprotein D (gD) epitope core structure maps to the external surface of herpesvirus (HSV) gD, corresponding to the binding sites of two receptors, herpesvirus entry mediator (HVEM) and nectin-1, which mediate HSV infection. (PMID:24100313)
• These results suggest that HVEM might play more important roles than CD28 in ConA-mediated T cell proliferation (PMID:24163161)
• The conformation of the N-terminus of herpes simplex virus gD is induced by direct binding to HVEM and nectin-1. (PMID:24314649)
• We identified new supportive evidence that the association between PVRL1 gene and nsCL/P in Turkish patients. (PMID:24581844)
• The results showed that the interface between the BV gD and nectin-1 molecule is not geometrically complementary. (PMID:24902525)
• These data provided solid structural and functional evidence that herpes simplex virus 1 and herpes simplex virus 2 gD proteins recognize nectin-1 via the same binding mode. (PMID:25231300)
• Authors show that the same key residues in the BC and FG loops of nectin-4 govern binding to the measles virus attachment protein hemagglutinin (H) and cell entry, nectin-4 homodimerization, and heterodimerization with nectin-1. (PMID:25275122)
• data suggests that E-cadherin regulates assembly of nectin junctions through alpha-catenin-induced remodeling of the actin cytoskeleton around the cadherin clusters. (PMID:25395582)
• Host nectin-1 is required for efficient Chlamydia trachomatis serovar E development. (PMID:25414835)
• mutations in exons 2 and 5 of PVRL1, and T334A, A391T, G1183A in the alpha-spliced transcript, and G1082T in the beta-spliced transcript do not participate in the development of non-syndromic cleft of the lip and/or palate in patients from Guangdong. (PMID:25966106)
• PVRL1 variants make a contribution to non syndromic Cleft Lip with/without Cleft palate in Turkish patients. (PMID:26953873)
• PDZD11 forms a complex with nectin-1 and nectin-3, and its PDZ domain interacts directly with the PDZ-binding motif of nectin-1. (PMID:27044745)
• nectin-1 is expressed in human hair follicles and there is a p63-responsive element in the NECTIN1 promoter (PMID:27516130)
• HSV gD is able to disrupt intercellular homophilic trans-interaction of nectin-1 and induce a rapid redistribution of nectin-1 from cell junctions. (PMID:27723487)
• The viral entry receptor Nectin-1 is also internalized during HSV-1 infection in a Cbl-dependent mechanism, and that increases the opportunity of the virus to spread to uninfected cells. (PMID:28381567)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:dkey-15j16.3	ENSDARG00000042683
danio_rerio	si:dkey-15j16.6	ENSDARG00000042698
danio_rerio	nectin1a	ENSDARG00000069767
danio_rerio	nectin1b	ENSDARG00000086034
mus_musculus	Nectin1	ENSMUSG00000032012
rattus_norvegicus	Nectin1	ENSRNOG00000006403
drosophila_melanogaster	Fas3	FBGN0000636

Paralogs (14): PVR (ENSG00000073008), CD200 (ENSG00000091972), CADM4 (ENSG00000105767), CRTAM (ENSG00000109943), NECTIN2 (ENSG00000130202), NECTIN4 (ENSG00000143217), CD226 (ENSG00000150637), CADM3 (ENSG00000162706), SMAGP (ENSG00000170545), CADM2 (ENSG00000175161), NECTIN3 (ENSG00000177707), TIGIT (ENSG00000181847), CADM1 (ENSG00000182985), NCR3 (ENSG00000204475)

Protein

Protein identifiers

Nectin-1 — Q15223 (reviewed: Q15223)

Alternative names: Herpes virus entry mediator C, Herpesvirus Ig-like receptor, Nectin cell adhesion molecule 1, Poliovirus receptor-related protein 1

All UniProt accessions (2): Q15223, A0A8V8TKI1

UniProt curated annotations — full annotation on UniProt →

Function. Cell adhesion molecule that promotes cell-cell contacts and plays important roles in the development of the nervous system. Acts by forming homophilic or heterophilic trans-dimers. Heterophilic interactions have been detected between NECTIN1 and NECTIN3 and between NECTIN1 and NECTIN4. Involved in axon guidance by promoting contacts between the commissural axons and the floor plate cells. Involved in synaptogegesis. Has some neurite outgrowth-promoting activity. Promotes formation of checkerboard-like cellular pattern of hair cells and supporting cells in the auditory epithelium via heterophilic interaction with NECTIN3: NECTIN1 is present in the membrane of hair cells and associates with NECTIN3 on supporting cells, thereby mediating heterotypic adhesion between these two cell types. Required for enamel mineralization. (Microbial infection) Acts as a receptor for herpes simplex virus 1/HHV-1, herpes simplex virus 2/HHV-2, and pseudorabies virus/PRV. Constitutes the major receptor for herpes simplex virus 1/HHV-1 entry into host cells.

Subunit / interactions. Cis- and trans-homodimer. Can form trans-heterodimers with NECTIN3 and with NECTIN4. Interaction between NECTIN1 and NECTIN3 on the pre- and postsynaptic sites, respectively, initiates the formation of puncta adherentia junctions between axons and dendrites. Interacts (via cytoplasmic domain) with AFDN (via PDZ domain); this interaction recruits NECTIN1 to cadherin-based adherens junctions and provides a connection with the actin cytoskeleton. Interacts with integrin alphaV/beta3. Interacts (via Ig-like C2-type domain 2) with FGFR1, FGFR2 and FGFR3. (Microbial infection) Interacts with herpes simplex virus 1/HHV-1, herpes simplex virus 2/HHV-2, and pseudorabies virus/PRV envelope glycoprotein D.

Subcellular location. Cell membrane. Cell junction. Adherens junction. Presynaptic cell membrane Cell membrane Cell membrane Secreted.

Post-translational modifications. (Microbial infection) Ubiquitinated by CBL following infection by herpes simplex virus 1/HHV-1 and association with HHV-1 envelope glycoprotein D, leading to its removal from cell surface.

Disease relevance. Ectodermal dysplasia, Margarita Island type (EDMI) [MIM:225060] An autosomal recessive form of ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. It is a syndrome characterized by the association of cleft lip/palate, ectodermal dysplasia (sparse short and dry scalp hair, sparse eyebrows and eyelashes), and partial syndactyly of the fingers and/or toes. Two thirds of the patients do not manifest oral cleft but present with abnormal teeth and nails. The disease is caused by variants affecting the gene represented in this entry. Non-syndromic orofacial cleft 7 (OFC7) [MIM:225060] A birth defect consisting of cleft lips with or without cleft palate. Cleft lips are associated with cleft palate in two-third of cases. A cleft lip can occur on one or both sides and range in severity from a simple notch in the upper lip to a complete opening in the lip extending into the floor of the nostril and involving the upper gum. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The Ig-like V-type domain is involved in homophilic interaction in cis, a prerequisite for cell adhesion. Ig-like C2-type 2 mediates neurite outgrowth through binding, induction of phosphorylation, and activation of FGFR.

Similarity. Belongs to the nectin family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q15223-1	Delta	yes
Q15223-2	Alpha
Q15223-3	Gamma

RefSeq proteins (3): NP_002846, NP_976030, NP_976031 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013106	Ig_V-set	Domain
IPR013162	CD80_C2-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR041849	Nectin-1_IgV1	Domain
IPR041850	Nectin-1_Ig2	Domain
IPR051427	Nectin/Nectin-like	Family

Pfam: PF07686, PF08205, PF13927

UniProt features (80 total): strand 25, mutagenesis site 16, glycosylation site 8, modified residue 5, splice variant 4, disulfide bond 3, domain 3, helix 3, compositionally biased region 2, topological domain 2, sequence variant 2, turn 2, region of interest 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
3U83	X-RAY DIFFRACTION	2.5
3ALP	X-RAY DIFFRACTION	2.8
3U82	X-RAY DIFFRACTION	3.16
4MYW	X-RAY DIFFRACTION	3.19
4FMF	X-RAY DIFFRACTION	3.2
3SKU	X-RAY DIFFRACTION	4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15223-F1	75.80	0.52

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 (5): 422, 434, 435, 436, 511

Disulfide bonds (3): 51–124, 172–226, 269–316

Glycosylation sites (8): 36, 72, 139, 202, 286, 297, 307, 332

Mutagenesis-validated functional residues (16):

Position	Phenotype
61	does not affect interaction with herpes simplex virus 1/hhv-1 and herpes simplex virus 2/hhv-2 glycoprotein d.
63–64	impaired homophilic interaction in cis and cell adhsion activity; when associated with a-125 and a-133.
63	does not affect interaction with herpes simplex virus 1/hhv-1 and herpes simplex virus 2/hhv-2 glycoprotein d.
64	does not affect interaction with herpes simplex virus 1/hhv-1 and herpes simplex virus 2/hhv-2 glycoprotein d.
76	does not affect interaction with herpes simplex virus 1/hhv-1 and herpes simplex virus 2/hhv-2 glycoprotein d.
77	decreased interaction with herpes simplex virus 1/hhv-1, herpes simplex virus 2/hhv-2 and pseudorabies virus glycoprotei
80	decreased interaction with herpes simplex virus 1/hhv-1 and herpes simplex virus 2/hhv-2 glycoprotein d.
82	does not affect interaction with herpes simplex virus 1/hhv-1 and herpes simplex virus 2/hhv-2 glycoprotein d.
82	impairs interaction with herpes simplex glycoprotein d. decreases susceptibility to infection by herpes simplex virus.
84	impairs interaction with herpes simplex glycoprotein d. decreases susceptibility to infection by herpes simplex virus.
85	decreased interaction with herpes simplex virus 1/hhv-1, herpes simplex virus 2/hhv-2 and pseudorabies virus glycoprotei
90	does not affect interaction with herpes simplex virus 1/hhv-1 and herpes simplex virus 2/hhv-2 glycoprotein d.
125	does not affect interaction with herpes simplex virus 1/hhv-1 and herpes simplex virus 2/hhv-2 glycoprotein d. impaired
129	abolished interaction with herpes simplex and pseudorabies glycoprotein d. decreases susceptibility to infection by herp
130	does not affect interaction with herpes simplex virus 1/hhv-1 and herpes simplex virus 2/hhv-2 glycoprotein d.
133	does not affect interaction with herpes simplex virus 1/hhv-1 and herpes simplex virus 2/hhv-2 glycoprotein d. impaired

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-418990	Adherens junctions interactions
R-HSA-420597	Nectin/Necl trans heterodimerization
R-HSA-1500931	Cell-Cell communication
R-HSA-421270	Cell-cell junction organization
R-HSA-446728	Cell junction organization

MSigDB gene sets: 551 (showing top): RNGTGGGC_UNKNOWN, E2F_Q4, MYAATNNNNNNNGGC_UNKNOWN, E2F_Q4_01, GOBP_HETEROPHILIC_CELL_CELL_ADHESION, GOBP_SYNAPSE_ASSEMBLY, GOBP_TRANSITION_METAL_ION_TRANSPORT, SP3_Q3, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, MODULE_16, GOBP_TOOTH_MINERALIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GGGTGGRR_PAX4_03, GOBP_IRON_ION_TRANSPORT

GO Biological Process (17): lens morphogenesis in camera-type eye (GO:0002089), desmosome organization (GO:0002934), iron ion transport (GO:0006826), immune response (GO:0006955), cell adhesion (GO:0007155), homophilic cell-cell adhesion (GO:0007156), heterophilic cell-cell adhesion (GO:0007157), axon guidance (GO:0007411), symbiont entry into host cell (GO:0046718), regulation of synapse assembly (GO:0051963), retina development in camera-type eye (GO:0060041), enamel mineralization (GO:0070166), cochlea morphogenesis (GO:0090103), cell-cell adhesion (GO:0098609), protein localization to cell junction (GO:1902414), camera-type eye morphogenesis (GO:0048593), regulation of synapse organization (GO:0050807)

GO Molecular Function (11): virus receptor activity (GO:0001618), coreceptor activity (GO:0015026), carbohydrate binding (GO:0030246), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein-containing complex binding (GO:0044877), virion binding (GO:0046790), cell adhesion molecule binding (GO:0050839), cell adhesion mediator activity (GO:0098631), protein binding (GO:0005515), signaling receptor activity (GO:0038023)

GO Cellular Component (15): extracellular region (GO:0005576), plasma membrane (GO:0005886), adherens junction (GO:0005912), membrane (GO:0016020), dendrite (GO:0030425), growth cone membrane (GO:0032584), apical junction complex (GO:0043296), cell-cell contact zone (GO:0044291), presynaptic active zone membrane (GO:0048787), hippocampal mossy fiber to CA3 synapse (GO:0098686), axon (GO:0030424), presynaptic membrane (GO:0042734), cell projection (GO:0042995), synapse (GO:0045202), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Cell-cell junction organization	1
Adherens junctions interactions	1
Cell junction organization	1
Cell-Cell communication	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
binding	3
protein binding	3
cell-cell junction	3
cell-cell adhesion	2
camera-type eye development	2
cell adhesion	2
neuron projection	2
synaptic membrane	2
cell junction	2
lens development in camera-type eye	1
anatomical structure morphogenesis	1
camera-type eye morphogenesis	1
cell-cell junction organization	1
transition metal ion transport	1
immune system process	1
response to stimulus	1
cellular process	1
axonogenesis	1
neuron projection guidance	1
viral life cycle	1
symbiont entry into host	1
synapse assembly	1
regulation of synapse organization	1
regulation of cell junction assembly	1
anatomical structure development	1
tooth mineralization	1
amelogenesis	1
inner ear morphogenesis	1
embryonic morphogenesis	1
cochlea development	1
intracellular protein localization	1
eye morphogenesis	1
regulation of synapse structure or activity	1
synapse organization	1
regulation of cellular component organization	1
symbiont entry into host cell	1
exogenous protein binding	1
signaling receptor activity	1
identical protein binding	1

Protein interactions and networks

STRING

1380 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NECTIN1	AFDN	P55196	999
NECTIN1	ACKR1	Q16570	994
NECTIN1	CDH17	Q12864	992
NECTIN1	CD96	P40200	992
NECTIN1	CD226	Q15762	992
NECTIN1	TIGIT	Q495A1	978
NECTIN1	CDH1	P12830	936
NECTIN1	CTNNB1	P35222	890
NECTIN1	TNFRSF14	Q92956	887
NECTIN1	NECTIN3	Q9NQS3	869
NECTIN1	CTNND1	O60716	862
NECTIN1	CDH5	P33151	842
NECTIN1	ERVW-1	Q9UQF0	825
NECTIN1	IRF6	O14896	760
NECTIN1	PARD3	Q8TEW0	757

IntAct

183 interactions, top by confidence:

A	B	Type	Score
NECTIN1	NECTIN1	psi-mi:“MI:0407”(direct interaction)	0.840
NECTIN3	NECTIN1	psi-mi:“MI:0915”(physical association)	0.840
NECTIN1	NECTIN1	psi-mi:“MI:0915”(physical association)	0.840
NECTIN1	NECTIN3	psi-mi:“MI:0915”(physical association)	0.840
NECTIN1	NECTIN3	psi-mi:“MI:0407”(direct interaction)	0.840
NECTIN1	NECTIN4	psi-mi:“MI:0407”(direct interaction)	0.760
NECTIN1	NECTIN4	psi-mi:“MI:0915”(physical association)	0.760
NECTIN4	NECTIN1	psi-mi:“MI:0915”(physical association)	0.760
SDCBP	NECTIN1	psi-mi:“MI:0407”(direct interaction)	0.650
SDCBP	NECTIN1	psi-mi:“MI:0915”(physical association)	0.650
SDCBP	NECTIN1	psi-mi:“MI:0403”(colocalization)	0.650
GRIP2	NECTIN1	psi-mi:“MI:0915”(physical association)	0.590
PICK1	NECTIN1	psi-mi:“MI:0915”(physical association)	0.590
GRIP2	NECTIN1	psi-mi:“MI:0407”(direct interaction)	0.590
NECTIN1	MPP2	psi-mi:“MI:0407”(direct interaction)	0.590

BioGRID (34): PVRL1 (Two-hybrid), PVRL1 (Affinity Capture-MS), PVRL1 (Affinity Capture-MS), FGFR1 (Reconstituted Complex), FGFR2 (Reconstituted Complex), FGFR3 (Reconstituted Complex), PVRL1 (Proximity Label-MS), PVRL1 (Affinity Capture-MS), PVRL1 (Affinity Capture-MS), PVRL1 (Affinity Capture-Western), PVRL1 (Affinity Capture-Western), CBL (Affinity Capture-Western), PVRL1 (Reconstituted Complex), PVRL1 (Proximity Label-MS), PVRL1 (Proximity Label-MS)

ESM2 similar proteins: A0A1B0GW64, A2AFR3, A4IFL2, A6QLZ5, A8MVS5, A8MWV9, E1BBQ2, E9Q2Z6, O54693, O73612, P01134, P0C8R9, P18519, P48030, P52795, P52796, P98172, Q0VAQ4, Q0VBP7, Q14CM0, Q15223, Q3MHZ5, Q4FZH1, Q4R566, Q5JRV8, Q5R8M2, Q5RB29, Q5T1S8, Q5T292, Q5VX71, Q6AYP5, Q7TPF1, Q8BHW5, Q8BR63, Q8CA71, Q8IVY1, Q8R5M8, Q91WM6, Q91XV6, Q96DD7

Diamond homologs: A0A140LHF2, P0DP72, P11464, P16573, P31809, P31997, P35329, Q00887, Q15223, Q15746, Q16557, Q58EX2, Q6V4S5, Q96FE5, Q9D1T0, Q9GL76, Q9N008, A0A8M2B818, B0JYH6, P15151, P32506, P32507, Q5FWR8, Q92692, Q9JKF6, B4KPU0, P06731, P20273, Q9JLB9, Q9N1E4, Q9N1E5, Q9N1E6, Q9NQS3, P41217, Q5ZPR3, Q7TPB4, Q8VE98, A0JM41, O60487, O60939

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 106 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	8	66.2×	5e-11
Unblocking of NMDA receptors, glutamate binding and activation	5	39.4×	9e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	39.4×	9e-06
Long-term potentiation	5	34.5×	1e-05
Assembly and cell surface presentation of NMDA receptors	9	33.1×	5e-10
Neurexins and neuroligins	10	28.5×	2e-10
Protein-protein interactions at synapses	6	23.1×	9e-06
RHOB GTPase cycle	5	11.2×	8e-04

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	65.2×	3e-15
protein localization to synapse	6	46.9×	4e-07
receptor clustering	7	44.6×	5e-08
regulation of postsynaptic membrane neurotransmitter receptor levels	7	35.4×	2e-07
bicellular tight junction assembly	5	16.9×	5e-04
Ras protein signal transduction	6	12.6×	4e-04
cell-cell adhesion	11	11.4×	4e-07
protein-containing complex assembly	9	10.5×	1e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	3
Uncertain significance	143
Likely benign	56
Benign	13

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
1697231	NM_002855.5(NECTIN1):c.400C>T (p.Arg134Ter)	Pathogenic
2857719	NM_002855.5(NECTIN1):c.283G>T (p.Glu95Ter)	Pathogenic
8969	NM_002855.5(NECTIN1):c.554G>A (p.Trp185Ter)	Pathogenic
8970	NM_002855.5(NECTIN1):c.556del (p.Glu186fs)	Pathogenic
8971	NM_002855.5(NECTIN1):c.969dup (p.Thr324fs)	Pathogenic
3061953	NM_002855.5(NECTIN1):c.226C>T (p.Gln76Ter)	Likely pathogenic
4278246	NM_002855.5(NECTIN1):c.1544G>A (p.Trp515Ter)	Likely pathogenic
984386	NM_002855.5(NECTIN1):c.472C>T (p.Arg158Ter)	Likely pathogenic

SpliceAI

1287 predictions. Top by Δscore:

Variant	Effect	Δscore
11:119675153:TCCTA:T	donor_loss	1.0000
11:119675154:CCTA:C	donor_loss	1.0000
11:119675155:CTAC:C	donor_loss	1.0000
11:119675156:TA:T	donor_loss	1.0000
11:119675158:C:CA	donor_loss	1.0000
11:119677100:A:AC	donor_gain	1.0000
11:119677101:C:CC	donor_gain	1.0000
11:119677215:CTCAT:C	acceptor_gain	1.0000
11:119677217:CAT:C	acceptor_gain	1.0000
11:119677220:C:CC	acceptor_gain	1.0000
11:119677553:A:AC	donor_gain	1.0000
11:119677554:C:CC	donor_gain	1.0000
11:119677554:CA:C	donor_gain	1.0000
11:119677554:CACTG:C	donor_gain	1.0000
11:119677578:T:TA	donor_gain	1.0000
11:119678410:CTTA:C	donor_loss	1.0000
11:119678411:TTA:T	donor_loss	1.0000
11:119678412:TAC:T	donor_loss	1.0000
11:119678413:A:AC	donor_gain	1.0000
11:119678413:AC:A	donor_gain	1.0000
11:119678413:ACCCA:A	donor_loss	1.0000
11:119678414:C:CC	donor_gain	1.0000
11:119678414:CC:C	donor_gain	1.0000
11:119678414:CCCA:C	donor_gain	1.0000
11:119664756:CCA:C	donor_gain	0.9900
11:119675173:TCC:T	donor_gain	0.9900
11:119675311:C:CC	acceptor_gain	0.9900
11:119675311:C:T	acceptor_loss	0.9900
11:119675312:T:C	acceptor_loss	0.9900
11:119677095:CACT:C	donor_loss	0.9900

AlphaMissense

3373 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:119675202:G:C	N320K	1.000
11:119675202:G:T	N320K	1.000
11:119675215:C:G	C316S	1.000
11:119675216:A:T	C316S	1.000
11:119677107:C:A	W282C	1.000
11:119677107:C:G	W282C	1.000
11:119677109:A:G	W282R	1.000
11:119677109:A:T	W282R	1.000
11:119677147:C:G	C269S	1.000
11:119677148:A:G	C269R	1.000
11:119677148:A:T	C269S	1.000
11:119677153:A:G	L267P	1.000
11:119677611:C:G	C226S	1.000
11:119677612:A:G	C226R	1.000
11:119677612:A:T	C226S	1.000
11:119677733:C:A	W185C	1.000
11:119677733:C:G	W185C	1.000
11:119677735:A:G	W185R	1.000
11:119677735:A:T	W185R	1.000
11:119677772:G:C	C172W	1.000
11:119677773:C:G	C172S	1.000
11:119677773:C:T	C172Y	1.000
11:119677774:A:G	C172R	1.000
11:119677774:A:T	C172S	1.000
11:119678426:A:G	L140P	1.000
11:119678458:G:C	F129L	1.000
11:119678458:G:T	F129L	1.000
11:119678459:A:C	F129C	1.000
11:119678460:A:G	F129L	1.000
11:119678473:G:C	C124W	1.000

dbSNP variants (sampled 300 via entrez): RS1000022474 (11:119681396 A>G), RS1000059429 (11:119709764 G>A,T), RS1000073825 (11:119724932 GT>G,GTT), RS1000090388 (11:119657913 C>A), RS1000102889 (11:119657893 C>T), RS1000145815 (11:119689880 C>T), RS1000183940 (11:119665434 G>A), RS1000197224 (11:119652167 C>G), RS1000247216 (11:119697937 T>G), RS1000249754 (11:119660067 A>G), RS1000257482 (11:119646619 A>C,G), RS1000266279 (11:119714034 T>C), RS1000274656 (11:119662790 G>A), RS1000350863 (11:119684574 C>A), RS1000352267 (11:119654538 A>G)

Disease associations

OMIM: gene MIM:600644 | disease phenotypes: MIM:225060

GenCC curated gene-disease

Disease	Classification	Inheritance
cleft lip/palate-ectodermal dysplasia syndrome	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
cleft lip/palate-ectodermal dysplasia syndrome	Definitive	AR

Mondo (2): cleft lip/palate-ectodermal dysplasia syndrome (MONDO:0009151), orofacial cleft 7 (MONDO:0700251)

Orphanet (2): Cleft lip/palate-ectodermal dysplasia syndrome (Orphanet:3253), OBSOLETE: Cleft lip/palate-ectodermal dysplasia syndrome (Orphanet:320317)

HPO phenotypes

105 total (30 of 105 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000046	Small scrotum
HP:0000069	Abnormality of the ureter
HP:0000135	Hypogonadism
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000202	Orofacial cleft
HP:0000204	Cleft upper lip
HP:0000220	Velopharyngeal insufficiency
HP:0000271	Abnormality of the face
HP:0000272	Malar flattening
HP:0000288	Abnormality of the philtrum
HP:0000325	Triangular face
HP:0000327	Hypoplasia of the maxilla
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000389	Chronic otitis media
HP:0000400	Macrotia
HP:0000403	Recurrent otitis media
HP:0000405	Conductive hearing impairment
HP:0000411	Protruding ear
HP:0000419	Abnormal nasal septum morphology
HP:0000431	Wide nasal bridge
HP:0000494	Downslanted palpebral fissures
HP:0000653	Sparse eyelashes
HP:0000664	Synophrys
HP:0000668	Hypodontia
HP:0000670	Carious teeth
HP:0000674	Anodontia
HP:0000682	Abnormal dental enamel morphology

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002682_11	Tourette’s syndrome or obsessive-compulsive disorder	1.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4742295 (PROTEIN-PROTEIN INTERACTION)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, decreases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
Cadmium Chloride	decreases expression	2
FR900359	increases phosphorylation	1
terbufos	increases methylation	1
sodium arsenite	increases expression	1
ochratoxin A	increases expression, increases acetylation	1
4-hydroxy-2-nonenal	decreases expression	1
ferrous chloride	decreases expression	1
bisphenol S	decreases methylation	1
Decitabine	affects expression	1
Leflunomide	decreases expression	1
Air Pollutants	increases expression, increases abundance	1
Cisplatin	affects expression	1
Doxorubicin	decreases expression	1
Fonofos	increases methylation	1
Estradiol	increases expression	1
Hydrogen Peroxide	affects expression	1
Mustard Gas	increases phosphorylation	1
N-Nitrosopyrrolidine	increases expression	1
Oxygen	decreases expression	1
Parathion	increases methylation	1
Smoke	decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Okadaic Acid	increases expression	1
Copper Sulfate	increases expression	1
Lactic Acid	increases expression	1
Acrylamide	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4713775	Binding	Protac activity at CRBN/Nectin-1 in human BxPC-3 cells assessed as Nectin-1 degradation incubated for 16 hrs by proteomic analysis	Discovery of a Napabucasin PROTAC as an Effective Degrader of the E3 Ligase ZFP91. — J Med Chem

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_H568	GM14817	Transformed cell line	Male
CVCL_H569	GM14818	Finite cell line	Male

Clinical trials (associated diseases)

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