NECTIN2

Summary

NECTIN2 (nectin cell adhesion molecule 2, HGNC:9707) is a protein-coding gene on chromosome 19q13.32, encoding Nectin-2 (Q92692). Modulator of T-cell signaling.

This gene encodes a single-pass type I membrane glycoprotein with two Ig-like C2-type domains and an Ig-like V-type domain. This protein is one of the plasma membrane components of adherens junctions. It also serves as an entry for certain mutant strains of herpes simplex virus and pseudorabies virus, and it is involved in cell to cell spreading of these viruses. Variations in this gene have been associated with differences in the severity of multiple sclerosis. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.

Source: NCBI Gene 5819 — RefSeq curated summary.

At a glance

• GWAS associations: 115
• Clinical variants (ClinVar): 48 total
• Phenotypes (HPO): 1
• MANE Select transcript: NM_001042724

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9707
Approved symbol	NECTIN2
Name	nectin cell adhesion molecule 2
Location	19q13.32
Locus type	gene with protein product
Status	Approved
Aliases	PVRR2, PRR2, CD112, Nectin-2
Ensembl gene	ENSG00000130202
Ensembl biotype	protein_coding
OMIM	600798
Entrez	5819

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 14 protein_coding, 1 retained_intron

ENST00000252483, ENST00000252485, ENST00000585601, ENST00000587386, ENST00000591581, ENST00000592018, ENST00000883535, ENST00000883536, ENST00000883537, ENST00000883538, ENST00000883539, ENST00000883540, ENST00000917943, ENST00000917944, ENST00000945842

RefSeq mRNA: 2 — MANE Select: NM_001042724 NM_001042724, NM_002856

CCDS: CCDS12645, CCDS42576

Canonical transcript exons

ENST00000252483 — 9 exons

Exon	Start	End
ENSE00000711952	44865271	44865660
ENSE00000893918	44882211	44882364
ENSE00000893920	44885937	44886000
ENSE00000893924	44886133	44886219
ENSE00000893930	44888110	44889223
ENSE00001159580	44874330	44874478
ENSE00001159595	44871853	44872149
ENSE00002430369	44873916	44874033
ENSE00002842302	44846297	44846613

Expression profiles

Bgee: expression breadth ubiquitous, 267 present calls, max score 97.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 61.0291 / max 379.1662, expressed in 1751 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176315	59.8123	1751
176316	1.2167	623

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	97.89	gold quality
stromal cell of endometrium	CL:0002255	97.23	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.91	gold quality
apex of heart	UBERON:0002098	96.55	gold quality
right lobe of liver	UBERON:0001114	96.05	gold quality
gall bladder	UBERON:0002110	95.97	gold quality
right testis	UBERON:0004534	95.86	gold quality
left adrenal gland cortex	UBERON:0035825	95.86	gold quality
body of stomach	UBERON:0001161	95.84	gold quality
mucosa of transverse colon	UBERON:0004991	95.82	gold quality
left adrenal gland	UBERON:0001234	95.74	gold quality
upper lobe of left lung	UBERON:0008952	95.58	gold quality
right adrenal gland	UBERON:0001233	95.54	gold quality
metanephros cortex	UBERON:0010533	95.54	gold quality
left testis	UBERON:0004533	95.46	gold quality
right adrenal gland cortex	UBERON:0035827	95.37	gold quality
left lobe of thyroid gland	UBERON:0001120	95.34	gold quality
omental fat pad	UBERON:0010414	95.26	gold quality
adrenal cortex	UBERON:0001235	95.25	gold quality
peritoneum	UBERON:0002358	95.22	gold quality
minor salivary gland	UBERON:0001830	95.05	gold quality
right lobe of thyroid gland	UBERON:0001119	94.91	gold quality
adrenal gland	UBERON:0002369	94.73	gold quality
esophagus mucosa	UBERON:0002469	94.67	gold quality
stomach	UBERON:0000945	94.39	gold quality
left uterine tube	UBERON:0001303	94.34	gold quality
upper lobe of lung	UBERON:0008948	94.31	gold quality
adipose tissue of abdominal region	UBERON:0007808	94.16	gold quality
thyroid gland	UBERON:0002046	94.14	gold quality
islet of Langerhans	UBERON:0000006	94.00	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-7008	yes	449.95
E-MTAB-6075	yes	122.02
E-MTAB-6701	yes	28.03
E-HCAD-10	yes	26.15
E-MTAB-6142	no	159.97
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, FOS, FOXC1, JUN, SP1, SP3

miRNA regulators (miRDB)

9 targeting NECTIN2, 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-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-3196	98.96	63.91	326
HSA-MIR-4691-5P	98.41	66.77	1343
HSA-MIR-6792-3P	98.41	66.86	1359
HSA-MIR-3691-3P	97.90	65.97	791
HSA-MIR-4286	97.20	64.37	1587
HSA-MIR-4764-3P	96.81	67.94	580

Literature-anchored findings (GeneRIF, showing 40)

• Regions of nectin-2 protein important for herpesvirus entry activity and homotypic nectin-nectin interactions are overlapping but not identical. (PMID:12438620)
• Data show that both PVR and Nectin-2 represent specific ligands for the DNAM-1 triggering receptor. (PMID:12913096)
• differences in the N termini of herpes simplex virus type 1 and 2 gDs that influence functional interactions with the human entry receptor Nectin-2 (PMID:12915581)
• Analysis of the ligands for triggering NK receptors revealed the consistent expression of cd155 and cd112 in myeloid leukemias, and less frequent expression in lymphoblastic leukemias (PMID:15536144)
• There is an allelic association of sequence variation in PVRL2 and the severity of multiple sclerosis. (PMID:16738668)
• CD226/CD112 (DNAM-1/Nectin-2) mast cell stimulation has a role in the allergic process (PMID:16831868)
• no statistically significant association between this marker allele and non-syndromic clefting (PMID:17534374)
• identified PVRL2 as a new recurrent partner gene of the TRA@ locus in peripheral T-cell lymphoma (PMID:17696193)
• Crystallization and preliminary X-ray analysis of the V domain of human nectin-2 are reported. (PMID:19478445)
• TIGIT is expressed by all NK cells, it binds PVR and PVRL2 but not PVRL3, and it inhibits NK cytotoxicity (PMID:19815499)
• The authors now show that human cytomegalovirus targets CD112 for proteasome-mediated degradation by 48 h post-infection, thus removing both activating ligands for DNAM-1 from the cell surface during productive infection. (PMID:20410314)
• The CD112 is highly expressed in colon carcinoma tissues and cell lines. (PMID:20617580)
• a possible etiologic role of PRR2 in nonsyndromic cleft lip with or without cleft palate (PMID:20662561)
• Data show that a high expression of CD112 and CD155 (DNAM-1 ligands) on leukemic blasts. (PMID:21383766)
• Structure of Nectin-2 reveals determinants of homophilic and heterophilic interactions that control cell-cell adhesion. (PMID:22927415)
• Chorionic gonadotropin induces vascular endothelial growth factor (VEGFA)-dependent downregulation of nectin 2, which increases the endothelial permeability in the coculture system. (PMID:23465821)
• Nectin-3 trans-interacts with Nectin-2 to promote lymphocyte and monocyte extravasation. (PMID:24116228)
• PVRL2, TOMM40 and APOE might be associated with human longevity. (PMID:24924924)
• Serum levels of nectin-2 may have diagnostic roles for colorectal cancer patients. (PMID:26184725)
• Soluble form of nectin-2 is required for exerting the resistance against HSV-2 infection. (PMID:26982466)
• Chromosomal breakpoints involved the PVRR2 gene in 19q31 is associated with Diffuse Large B-Cell Lymphomas. (PMID:27356265)
• Our data provide important structural and biochemical determinants responsible for the recognition of nectin-2 by TIGIT. (PMID:27978489)
• PVRL2 is a plasma cholesterol-responsive gene acting at endothelial sites of vascular inflammation to regulate transendothelial migration of leukocytes. (PMID:28062492)
• energetic basis for the TIGIT/nectin-2 interaction and revealed that an “aromatic key” of nectin-2 is critical for this interaction, whereas variations in the lock were tolerated. (PMID:28515320)
• In the infection with 3 MLD50 (50 % mouse lethal dose), effective resistance was not observed in transgenic mice expressing nectin-2Ig. (PMID:28671524)
• Nectin-2 mutation in men with severe teratospermia (PMID:28689229)
• Structural analysis of currently available homodimeric structures of both nectin-2 and N-cadherin followed by molecular docking as well as complementary mutagenesis studies revealed the binding interface of this novel interaction. (PMID:30183103)
• we demonstrate that PVRIG and PVRL2 are expressed in human cancers and the PVRIG-PVRL2 and TIGIT-PVR pathways are nonredundant inhibitory signaling pathways. (PMID:30659054)
• Nectin cell adhesion molecule 2 (Nectin-2) expression in ovarian cancer may support tumor cell adhesion, leading to growth and lymph node metastasis. (PMID:30843637)
• ubiquitination of Nectin2 promotes its degradation and is responsible for protein intracellular retention and inhibition of the ubiquitin pathway results in increased Nectin2 surface expression and enhances tumor cell susceptibility to NK cell cytotoxicity (PMID:30888046)
• DNA methylation QTL analysis identifies new regulators of human longevity. (PMID:32160291)
• DNAM-1/CD226 is functionally expressed on acute myeloid leukemia (AML) cells and is associated with favorable prognosis. (PMID:34504191)
• Nectin-2 in general and in the brain. (PMID:34633611)
• Nectin-2 Acts as a Viral Entry Mediated Molecule That Binds to Human Herpesvirus 6B Glycoprotein B. (PMID:35062364)
• Association and interaction of TOMM40 and PVRL2 with plasma amyloid-beta and Alzheimer’s disease among Chinese older adults: a population-based study. (PMID:35093267)
• Nectin2 influences cell apoptosis by regulating ANXA2 expression in neuroblastoma. (PMID:36916296)
• Metabolic Overlap between Alzheimer’s Disease and Metabolic Syndrome Identifies the PVRL2 Gene as a New Modulator of Diabetic Dyslipidemia. (PMID:37108578)
• Relative Expression of BATF and CD112 in PBMC of Patients with Chronic Lymphocytic Leukemia. (PMID:37378949)
• Single-cell RNA sequencing highlights the role of PVR/PVRL2 in the immunosuppressive tumour microenvironment in hepatocellular carcinoma. (PMID:37383234)
• The SNP rs6859 in NECTIN2 gene is associated with underlying heterogeneous trajectories of cognitive changes in older adults. (PMID:38408961)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:113337	ENSDARG00000041998
danio_rerio	si:ch73-22o12.1	ENSDARG00000062831
danio_rerio	pvrl2l	ENSDARG00000063390
danio_rerio	zgc:172122	ENSDARG00000079191
danio_rerio	sc:d189	ENSDARG00000102858
mus_musculus	Nectin2	ENSMUSG00000062300
rattus_norvegicus	Nectin2	ENSRNOG00000018730
drosophila_melanogaster	Fas3	FBGN0000636

Paralogs (14): PVR (ENSG00000073008), CD200 (ENSG00000091972), CADM4 (ENSG00000105767), CRTAM (ENSG00000109943), NECTIN1 (ENSG00000110400), NECTIN4 (ENSG00000143217), CD226 (ENSG00000150637), CADM3 (ENSG00000162706), SMAGP (ENSG00000170545), CADM2 (ENSG00000175161), NECTIN3 (ENSG00000177707), TIGIT (ENSG00000181847), CADM1 (ENSG00000182985), NCR3 (ENSG00000204475)

Protein

Protein identifiers

Nectin-2 — Q92692 (reviewed: Q92692)

Alternative names: Herpes virus entry mediator B, Nectin cell adhesion molecule 2, Poliovirus receptor-related protein 2

All UniProt accessions (4): Q92692, K7EK87, K7EKE8, K7ERL3

UniProt curated annotations — full annotation on UniProt →

Function. Modulator of T-cell signaling. Can be either a costimulator of T-cell function, or a coinhibitor, depending on the receptor it binds to. Upon binding to CD226, stimulates T-cell proliferation and cytokine production, including that of IL2, IL5, IL10, IL13, and IFNG. Upon interaction with PVRIG, inhibits T-cell proliferation. These interactions are competitive. Probable cell adhesion protein. (Microbial infection) Acts as a receptor for herpes simplex virus 1 (HHV-1) mutant Rid1, herpes simplex virus 1 (HHV-2) and pseudorabies virus (PRV).

Subunit / interactions. Can form trans-heterodimers with NECTIN3. Interacts with CD226 or with PVRIG; these interactions are competitive and have a differential functional outcome on T-cell activation, either positive or negative, respectively. Binds with low affinity to TIGIT. (Microbial infection) Interacts with herpes simplex virus 1 (HHV-1) mutant Rid1, herpes simplex virus 1 (HHV-2) and pseudorabies virus (PRV) envelope glycoprotein D.

Subcellular location. Cell membrane.

Tissue specificity. Ubiquitous.

Similarity. Belongs to the nectin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q92692-1	Delta	yes
Q92692-2	Alpha

RefSeq proteins (2): NP_001036189, NP_002847 (=MANE)

Domains & families (InterPro)

ID	Name	Type
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
IPR052659	Nectin/PVR	Family

Pfam: PF07686, PF08205

UniProt features (43 total): strand 13, modified residue 4, disulfide bond 3, mutagenesis site 3, helix 3, domain 3, glycosylation site 2, splice variant 2, topological domain 2, turn 2, region of interest 2, signal peptide 1, chain 1, transmembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
3R0N	X-RAY DIFFRACTION	1.3
4HZA	X-RAY DIFFRACTION	1.7
4DFI	X-RAY DIFFRACTION	1.8
4DFH	X-RAY DIFFRACTION	1.85
8X6B	X-RAY DIFFRACTION	2
9E6Y	X-RAY DIFFRACTION	2.2
5V52	X-RAY DIFFRACTION	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92692-F1	75.78	0.51

Functional residue map

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

Post-translational modifications (4): 410, 433, 465, 470

Disulfide bonds (3): 54–140, 183–238, 283–329

Glycosylation sites (2): 137, 324

Mutagenesis-validated functional residues (3):

Position	Phenotype
81	abolishes homodimerization.
89	loss of entry of hhv-1/rid1 and hsv-2. no effect on prv entry.
89	increased entry of hhv-1/rid1 and hsv-2.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-418990	Adherens junctions interactions
R-HSA-420597	Nectin/Necl trans heterodimerization
R-HSA-1280218	Adaptive Immune System
R-HSA-1500931	Cell-Cell communication
R-HSA-168256	Immune System
R-HSA-421270	Cell-cell junction organization
R-HSA-446728	Cell junction organization

MSigDB gene sets: 355 (showing top): GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_VESICLE_ORGANIZATION, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_MEDIATED_IMMUNITY, GOZGIT_ESR1_TARGETS_DN, ROVERSI_GLIOMA_COPY_NUMBER_UP, GOBP_MEMBRANE_FUSION, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN

GO Biological Process (27): acrosome assembly (GO:0001675), positive regulation of natural killer cell mediated cytotoxicity directed against tumor cell target (GO:0002860), positive regulation of immunoglobulin mediated immune response (GO:0002891), cytoskeleton organization (GO:0007010), homophilic cell-cell adhesion (GO:0007156), spermatid development (GO:0007286), spermatid nucleus differentiation (GO:0007289), fertilization (GO:0009566), fusion of virus membrane with host plasma membrane (GO:0019064), sperm mitochondrion organization (GO:0030382), positive regulation of mast cell activation (GO:0033005), natural killer cell mediated cytotoxicity (GO:0042267), susceptibility to natural killer cell mediated cytotoxicity (GO:0042271), adhesion of symbiont to host (GO:0044406), cilium organization (GO:0044782), negative regulation of natural killer cell mediated cytotoxicity (GO:0045953), positive regulation of natural killer cell mediated cytotoxicity (GO:0045954), regulation of viral entry into host cell (GO:0046596), coreceptor-mediated virion attachment to host cell (GO:0046814), positive regulation of T cell receptor signaling pathway (GO:0050862), establishment of localization in cell (GO:0051649), establishment of mitochondrion localization (GO:0051654), susceptibility to T cell mediated cytotoxicity (GO:0060370), cell adhesion (GO:0007155), signal transduction (GO:0007165), cellular anatomical entity morphogenesis (GO:0032989), symbiont entry into host cell (GO:0046718)

GO Molecular Function (7): virus receptor activity (GO:0001618), coreceptor activity (GO:0015026), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), receptor ligand activity (GO:0048018), cell adhesion molecule binding (GO:0050839), protein binding (GO:0005515)

GO Cellular Component (9): plasma membrane (GO:0005886), cell-cell junction (GO:0005911), zonula adherens (GO:0005915), focal adhesion (GO:0005925), cell surface (GO:0009986), membrane (GO:0016020), apical junction complex (GO:0043296), cell-cell contact zone (GO:0044291), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-6 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
spermatid development	2
positive regulation of natural killer cell mediated cytotoxicity	2
organelle organization	2
natural killer cell mediated cytotoxicity	2
regulation of natural killer cell mediated cytotoxicity	2
symbiont entry into host cell	2
protein binding	2
cellular anatomical structure	2
cell-cell junction	2
developmental process involved in reproduction	1
cellular component assembly involved in morphogenesis	1
cellular process involved in reproduction in multicellular organism	1
secretory granule organization	1
organelle assembly	1
natural killer cell mediated cytotoxicity directed against tumor cell target	1
positive regulation of natural killer cell mediated immune response to tumor cell	1
regulation of natural killer cell mediated cytotoxicity directed against tumor cell target	1
positive regulation of B cell mediated immunity	1
regulation of immunoglobulin mediated immune response	1
immunoglobulin mediated immune response	1
cell-cell adhesion	1
germ cell development	1
spermatid differentiation	1
nucleus organization	1
sexual reproduction	1
reproductive process	1
membrane fusion involved in viral entry into host cell	1
membrane fusion	1
mitochondrion organization	1
positive regulation of leukocyte activation	1
regulation of mast cell activation	1
mast cell activation	1
leukocyte mediated cytotoxicity	1
natural killer cell mediated immunity	1
biological process involved in interaction with host	1
plasma membrane bounded cell projection organization	1
negative regulation of leukocyte mediated cytotoxicity	1
negative regulation of natural killer cell mediated immunity	1
positive regulation of leukocyte mediated cytotoxicity	1
positive regulation of natural killer cell mediated immunity	1

Protein interactions and networks

STRING

1018 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NECTIN2	CD96	P40200	999
NECTIN2	CD226	Q15762	999
NECTIN2	TIGIT	Q495A1	999
NECTIN2	PVRIG	Q6DKI7	993
NECTIN2	ACKR1	Q16570	986
NECTIN2	AFDN	P55196	982
NECTIN2	KLRK1	P26718	980
NECTIN2	NCR3	O14931	959
NECTIN2	NECTIN3	Q9NQS3	953
NECTIN2	CTLA4	P16410	931
NECTIN2	TOMM40	O96008	890
NECTIN2	NCR1	O76036	852
NECTIN2	TNFRSF14	Q92956	822
NECTIN2	KLRC1	P26715	809
NECTIN2	HAVCR2	Q8TDQ0	809

IntAct

135 interactions, top by confidence:

A	B	Type	Score
NECTIN2	NECTIN2	psi-mi:“MI:0407”(direct interaction)	0.920
NECTIN2	NECTIN2	psi-mi:“MI:0915”(physical association)	0.920
TIGIT	NECTIN2	psi-mi:“MI:0407”(direct interaction)	0.840
TIGIT	NECTIN2	psi-mi:“MI:0915”(physical association)	0.840
NECTIN2	NECTIN3	psi-mi:“MI:0915”(physical association)	0.790
NECTIN2	NECTIN3	psi-mi:“MI:0407”(direct interaction)	0.790
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
MDFI	NECTIN2	psi-mi:“MI:0915”(physical association)	0.670
NECTIN2	MDFI	psi-mi:“MI:0915”(physical association)	0.670
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
SLC17A5	LGALS8	psi-mi:“MI:0914”(association)	0.640
CD226	NECTIN2	psi-mi:“MI:0915”(physical association)	0.610

BioGRID (246): PVRL2 (Two-hybrid), PVRL2 (Two-hybrid), SIAH1 (Two-hybrid), KRTAP10-7 (Two-hybrid), KRTAP10-1 (Two-hybrid), KRTAP10-5 (Two-hybrid), KRTAP10-3 (Two-hybrid), NOTCH2NL (Two-hybrid), PVRL2 (Affinity Capture-MS), PVRL2 (Affinity Capture-MS), PVRL2 (Affinity Capture-MS), PVRL2 (Affinity Capture-MS), PVRL2 (Affinity Capture-MS), PVRL2 (Two-hybrid), PVRL2 (Proximity Label-MS)

ESM2 similar proteins: A0JNA2, A4FUY1, C0HL12, O14514, O19131, O60241, O75325, P0C5H6, P15151, P32506, P32507, P70225, P98095, Q05BQ1, Q13477, Q14626, Q14CZ8, Q29RN8, Q3UHD1, Q4V9Z5, Q53EL9, Q5DRQ8, Q5R7Y0, Q5RF19, Q5STE3, Q63148, Q64385, Q6AX42, Q6BAA4, Q6MZW2, Q6UWL2, Q6UWL6, Q6UXD5, Q6WN34, Q7TSK2, Q7TSU7, Q8BHA1, Q8BQC3, Q8CGM1, Q8IVU1

Diamond homologs: A0A8M2B818, B0JYH6, P15151, P32506, P32507, Q15223, Q5FWR8, Q92692, Q9GL76, Q9JKF6, B4KPU0, P06731, P20273, P31997, Q9JLB9, Q9N1E4, Q9N1E5, Q9N1E6, Q9NQS3, P41217, Q5ZPR3, Q7TPB4, Q8VE98, P28685, Q58EG3, Q5E9Z9, Q00889, Q8R007, Q96NY8, Q8VD31, Q9BX59, Q5RAL8

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
NECTIN2	“up-regulates activity”	CD226	binding
SRC	unknown	NECTIN2	phosphorylation

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
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	65.3×	2e-09
Activation of BAD and translocation to mitochondria	5	52.9×	4e-06
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	46.6×	6e-06
Activation of BH3-only proteins	5	34.5×	2e-05
RHO GTPases activate PKNs	5	22.0×	1e-04
Intrinsic Pathway for Apoptosis	5	20.3×	1e-04
Transcriptional and post-translational regulation of MITF-M expression and activity	6	14.9×	1e-04
Apoptosis	6	14.0×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	6
Likely benign	22
Benign	10

Top pathogenic / likely-pathogenic (0)

SpliceAI

1097 predictions. Top by Δscore:

Variant	Effect	Δscore
19:44865659:AGG:A	donor_loss	1.0000
19:44871851:A:AG	acceptor_gain	1.0000
19:44871852:G:GG	acceptor_gain	1.0000
19:44871852:GCCA:G	acceptor_gain	1.0000
19:44871852:GCCAA:G	acceptor_gain	1.0000
19:44872147:GCT:G	donor_gain	1.0000
19:44872150:G:GG	donor_gain	1.0000
19:44873890:T:A	acceptor_gain	1.0000
19:44873911:CCCA:C	acceptor_loss	1.0000
19:44873912:CCA:C	acceptor_loss	1.0000
19:44873913:CA:C	acceptor_loss	1.0000
19:44873914:A:AG	acceptor_gain	1.0000
19:44873914:AGA:A	acceptor_loss	1.0000
19:44873915:G:GT	acceptor_gain	1.0000
19:44873915:GA:G	acceptor_gain	1.0000
19:44873915:GAC:G	acceptor_gain	1.0000
19:44873915:GACC:G	acceptor_gain	1.0000
19:44873915:GACCC:G	acceptor_gain	1.0000
19:44874029:AGCAC:A	donor_gain	1.0000
19:44874030:GCAC:G	donor_gain	1.0000
19:44874030:GCACG:G	donor_gain	1.0000
19:44874032:AC:A	donor_gain	1.0000
19:44874034:G:GG	donor_gain	1.0000
19:44865661:G:GG	donor_gain	0.9900
19:44865662:T:G	donor_loss	0.9900
19:44871848:CCCA:C	acceptor_loss	0.9900
19:44871849:CCA:C	acceptor_loss	0.9900
19:44871850:CAGC:C	acceptor_loss	0.9900
19:44871851:AG:A	acceptor_loss	0.9900
19:44871852:GC:G	acceptor_gain	0.9900

AlphaMissense

3432 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:44873987:T:A	C283S	0.999
19:44873988:G:C	C283S	0.999
19:44874028:G:C	W296C	0.999
19:44874028:G:T	W296C	0.999
19:44874421:T:A	C329S	0.999
19:44874422:G:C	C329S	0.999
19:44865392:G:C	W70C	0.998
19:44865392:G:T	W70C	0.998
19:44873956:G:C	W272C	0.998
19:44873956:G:T	W272C	0.998
19:44873988:G:A	C283Y	0.998
19:44874026:T:A	W296R	0.998
19:44874026:T:C	W296R	0.998
19:44874421:T:C	C329R	0.998
19:44874422:G:A	C329Y	0.998
19:44874423:C:G	C329W	0.998
19:44874435:T:A	N333K	0.998
19:44874435:T:G	N333K	0.998
19:44882268:C:A	A367D	0.998
19:44865496:T:G	F105C	0.997
19:44871921:T:A	C183S	0.997
19:44871922:G:C	C183S	0.997
19:44871962:G:C	W196C	0.997
19:44871962:G:T	W196C	0.997
19:44873954:T:A	W272R	0.997
19:44873954:T:C	W272R	0.997
19:44873987:T:C	C283R	0.997
19:44865342:T:A	C54S	0.996
19:44865343:G:C	C54S	0.996
19:44865600:T:A	C140S	0.996

dbSNP variants (sampled 300 via entrez): RS1000036120 (19:44862610 C>T), RS1000043449 (19:44879120 C>T), RS1000144131 (19:44856896 G>A), RS1000145354 (19:44879971 G>A), RS1000150404 (19:44887513 C>T), RS1000235970 (19:44845415 C>A,G,T), RS1000297038 (19:44850443 G>A), RS1000347120 (19:44844956 G>C,T), RS1000449012 (19:44844934 C>T), RS1000455712 (19:44851050 C>T), RS1000517461 (19:44858052 G>A), RS1000695499 (19:44864164 G>C,T), RS1000828196 (19:44866552 G>A,T), RS1000829473 (19:44884426 A>G), RS1000936474 (19:44869093 C>T)

Disease associations

OMIM: gene MIM:600798 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): cerebral palsy (MONDO:0006497)

Orphanet (0):

HPO phenotypes

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

HPO	Term
HP:0100021	Cerebral palsy

GWAS associations

115 associations (top):

Study	Trait	p-value
GCST000237_1	Alzheimer’s disease	6.000000e-14
GCST000808_3	Alzheimer’s disease (late onset)	1.000000e-07
GCST001237_6	HDL cholesterol	8.000000e-11
GCST001280_7	Alzheimer’s disease (age of onset)	1.000000e-12
GCST001342_10	Alzheimer’s disease	5.000000e-07
GCST001814_21	Age-related macular degeneration	1.000000e-06
GCST001814_31	Age-related macular degeneration	1.000000e-06
GCST001868_2	Alzheimer’s disease biomarkers	1.000000e-10
GCST001947_2	Alzheimer’s disease (late onset)	5.000000e-39
GCST002422_1	Alzheimer’s disease	9.000000e-116
GCST002588_1	Cerebral amyloid angiopathy	3.000000e-21
GCST002592_1	Neuritic plaque	3.000000e-47
GCST002592_33	Neuritic plaque	2.000000e-27
GCST002593_23	Dementia and core Alzheimer’s disease neuropathologic changes	2.000000e-62
GCST002593_49	Dementia and core Alzheimer’s disease neuropathologic changes	3.000000e-38
GCST002594_1	Neurofibrillary tangles	5.000000e-47
GCST002594_37	Neurofibrillary tangles	5.000000e-44
GCST002701_42	Verbal declarative memory	4.000000e-13
GCST002701_6	Verbal declarative memory	4.000000e-13
GCST002960_5	Frontotemporal dementia	8.000000e-06
GCST003073_10	Cerebral amyloid deposition (PET imaging)	8.000000e-32
GCST003077_1	Cerebral amyloid deposition positivity (PET imaging)	5.000000e-20
GCST003818_17	Resting heart rate	5.000000e-11
GCST004069_9	Cerebrospinal fluid AB1-42 levels	5.000000e-94
GCST004070_13	Cerebrospinal P-tau181p levels	5.000000e-33
GCST004071_5	Cerebrospinal T-tau levels	4.000000e-29
GCST004584_2	Waist-to-hip circumference ratio (smoking years interaction)	4.000000e-06
GCST004599_153	Mean platelet volume	6.000000e-10
GCST004827_1	Verbal memory performance (immediate recall change)	8.000000e-10
GCST004829_2	Verbal memory performance (residualized delayed recall level)	3.000000e-12

EFO canonical traits (32, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004847	age at onset
EFO:0005194	amyloid-beta measurement
EFO:0006798	neuritic plaque measurement
EFO:0006801	Alzheimer’s disease neuropathologic change
EFO:0006797	neurofibrillary tangles measurement
EFO:0004874	memory performance
EFO:0006806	paragraph delayed recall measurement
EFO:0007707	cerebral amyloid deposition measurement
EFO:0004670	beta-amyloid 1-42 measurement
EFO:0004763	p-tau measurement
EFO:0004760	t-tau measurement
EFO:0004343	waist-hip ratio
EFO:0006941	grip strength measurement
EFO:0004340	body mass index
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0005035	hippocampal volume
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0009268	family history of Alzheimer’s disease
EFO:0009932	HMG CoA reductase inhibitor use measurement
EFO:0007626	emphysema imaging measurement
EFO:0010130	health study participation
EFO:0004531	urate measurement
EFO:0004530	triglyceride measurement
EFO:0008111	diet measurement
EFO:0004615	apolipoprotein B measurement
EFO:0004842	eosinophil count
EFO:0004587	lymphocyte count
EFO:0004527	mean corpuscular hemoglobin

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D002547	Cerebral Palsy	C10.228.140.140.254

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, increases expression	4
Valproic Acid	affects cotreatment, decreases expression, increases expression	4
bisphenol A	decreases methylation, increases expression, decreases expression	3
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
trichostatin A	decreases expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Benztropine	decreases expression	1
Caffeine	decreases phosphorylation	1
Clozapine	decreases expression	1
Coumestrol	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects expression	1
Gasoline	affects cotreatment, increases abundance, increases expression	1
Ivermectin	decreases expression	1
Lipopolysaccharides	affects response to substance, increases expression	1
Methotrexate	affects response to substance	1
Nickel	increases expression	1

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 2 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8LB	Abcam HCT 116 NECTIN2 KO	Cancer cell line	Male
CVCL_B9NH	Abcam A-549 NECTIN2 KO	Cancer cell line	Male
CVCL_D2GM	Abcam MCF-7 NECTIN2 KO	Cancer cell line	Female
CVCL_E5IN	CHO-K1/CD112	Spontaneously immortalized cell line	Female
CVCL_E6RC	Genomeditech CHO-K1 H_NECTIN2(CD112) aAPC	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00154830	PHASE4	COMPLETED	Alterations of Functional Activities and Leg Stiffness After Hamstring Lengthening in Cerebral Palsy Children
NCT00432055	PHASE4	COMPLETED	Effects of Botulinum Toxin Type A in Adults With Cerebral Palsy
NCT00549471	PHASE4	TERMINATED	Improvement After Botulinum Toxin Injections to the Arms in Children With Cerebral Palsy
NCT00752934	PHASE4	TERMINATED	Does Oral Baclofen Improve Care and Comfort in Spastic Children in Nursing Homes?
NCT00964639	PHASE4	COMPLETED	Postoperative Pain in Children With Cerebral Palsy After Pelvic and Femoral Osteotomies
NCT01386255	PHASE4	WITHDRAWN	Placebo Controlled Study of Baclofen for GERD in Children With Cerebral Palsy
NCT02546999	PHASE4	COMPLETED	Does Botulinum Toxin A Make Walking Easier in Children With Cerebral Palsy?
NCT02633241	PHASE4	COMPLETED	A Pilot Study of Dexmedetomidine-Propofol in Children Undergoing Magnetic Resonance Imaging
NCT03117322	PHASE4	COMPLETED	Synbiotic, Prebiotics and Probiotics in Children With Cerebral Palsy and Constipation
NCT03648658	PHASE4	UNKNOWN	Paracetamol Study in Patients With Low Muscle Mass
NCT04074265	PHASE4	COMPLETED	Peri-operative Use of a Pain Injection in Pediatric Patients With Cerebral Palsy
NCT04273737	PHASE4	TERMINATED	Amantadine in Treating Cognitive & Motor Impairments in Adolescents and Adults With Cerebral Palsy
NCT04523935	PHASE4	COMPLETED	Excessive Crying in Children With Cerebral Palsy and Communication Deficits
NCT05887765	PHASE4	COMPLETED	Effect of Systematic Dexamethasone on the Duration of Popliteal Nerve Block for Anesthesia After Pediatric Ankle Surgery
NCT06176430	PHASE4	UNKNOWN	Comparison of Twice Weekly Versus Daily Iron Therapy in Treating Anemia in Children With Cerebral Palsy
NCT06189781	PHASE4	RECRUITING	Pain Injection Versus Epidural Anesthesia for Hip Surgery in Pediatric Patients With Cerebral Palsy
NCT00014989	PHASE3	COMPLETED	Beneficial Effects of Antenatal Magnesium Sulfate (BEAM Trial)
NCT00065949	PHASE3	UNKNOWN	Magnesium Sulfate to Prevent Brain Injury in Premature Infants
NCT00367068	PHASE3	COMPLETED	Dutch National ITB Study in Children With Cerebral Palsy
NCT00491894	PHASE3	COMPLETED	Safety and Efficacy Study of Oral Glycopyrrolate Liquid for the Treatment of Pathologic (Chronic Moderate to Severe) Drooling in Pediatric Patients 3 to 18 Years of Age With Cerebral Palsy or Other Neurologic Conditions
NCT00632528	PHASE3	COMPLETED	MEOPA to Improve Physical Therapy Results After Multilevel Surgery
NCT00822029	PHASE3	TERMINATED	Use of Oral Bisphosphonates in the Treatment of Osteoporosis of Non-walking Children With Cerebral Palsy
NCT00922077	PHASE3	COMPLETED	Individualized Neurodevelopmental Treatment
NCT01249417	PHASE3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Study
NCT01251380	PHASE3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Follow-on Study
NCT01437644	PHASE3	COMPLETED	The Post-Operative Pain in Cerebral Palsy (POPPIES) Trial
NCT01492608	PHASE3	COMPLETED	Magnesium Sulphate for Preterm Birth (MASP Study)
NCT01603602	PHASE3	COMPLETED	BOTOX® Treatment in Pediatric Upper Limb Spasticity
NCT01603615	PHASE3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Upper Limb Spasticity
NCT01603628	PHASE3	COMPLETED	BOTOX® Treatment in Pediatric Lower Limb Spasticity
NCT01603641	PHASE3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Lower Limb Spasticity
NCT01633736	PHASE3	UNKNOWN	Targeted Hip Strength Training in Children With Cerebral Palsy (CP)
NCT01898520	PHASE3	COMPLETED	A Safety, Efficacy and Tolerability Study of Sativex for the Treatment of Spasticity in Children Aged 8 to 18 Years
NCT01929434	PHASE3	COMPLETED	Efficacy of Stem Cell Transplantation Compared to Rehabilitation Treatment of Patients With Cerebral Paralysis
NCT02002884	PHASE3	COMPLETED	Dose-response Study of Efficacy and Safety of Botulinum Toxin Type A to Treat Spasticity of the Arm(s) or of Arm(s) and Leg(s) in Cerebral Palsy
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02839785	PHASE3	TERMINATED	Analgesia and Physiotherapy in Children With Cerebral Palsy (ANTALKINECP)
NCT03110341	PHASE3	UNKNOWN	Effect of Erythropoietin in Premature Infants on White Matter Lesions and Neurodevelopmental Outcome
NCT03302871	PHASE3	COMPLETED	Integrated Management Enhances Functional Gains in Children With Cerebral Palsy Treated by BoNT-A
NCT03306212	PHASE3	COMPLETED	Efficacy of Intermittent Serial Casting on Spastic Wrist Flexion Deformity