CD226

Summary

CD226 (CD226 molecule, HGNC:16961) is a protein-coding gene on chromosome 18q22.2, encoding CD226 antigen (Q15762). Cell surface receptor that plays an important role in the immune system, particularly in intercellular adhesion, lymphocyte signaling, cytotoxicity and lymphokine secretion mediated by cytotoxic T-cells and NK cells.

This gene encodes a glycoprotein expressed on the surface of NK cells, platelets, monocytes and a subset of T cells. It is a member of the Ig-superfamily containing 2 Ig-like domains of the V-set. The protein mediates cellular adhesion of platelets and megakaryocytic cells to vascular endothelial cells. The protein also plays a role in megakaryocytic cell maturation. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 10666 — RefSeq curated summary.

At a glance

• GWAS associations: 42
• Clinical variants (ClinVar): 68 total — 1 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_001303618

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16961
Approved symbol	CD226
Name	CD226 molecule
Location	18q22.2
Locus type	gene with protein product
Status	Approved
Aliases	DNAM-1, DNAM1, PTA1, TLiSA1
Ensembl gene	ENSG00000150637
Ensembl biotype	protein_coding
OMIM	605397
Entrez	10666

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 10 protein_coding, 1 nonsense_mediated_decay

ENST00000280200, ENST00000577287, ENST00000578928, ENST00000579496, ENST00000580335, ENST00000581982, ENST00000582621, ENST00000583955, ENST00000851210, ENST00000851211, ENST00000951224

RefSeq mRNA: 3 — MANE Select: NM_001303618 NM_001303618, NM_001303619, NM_006566

CCDS: CCDS11997, CCDS77197

Canonical transcript exons

ENST00000582621 — 6 exons

Exon	Start	End
ENSE00000995709	69867357	69867411
ENSE00002688113	69853274	69864439
ENSE00002734502	69947361	69947873
ENSE00003540091	69895701	69896045
ENSE00003784279	69946734	69947069
ENSE00003786867	69873144	69873246

Expression profiles

Bgee: expression breadth ubiquitous, 173 present calls, max score 92.44.

FANTOM5 (CAGE): breadth broad, TPM avg 5.4942 / max 295.4318, expressed in 340 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172341	1.8569	189
172338	0.9165	94
172342	0.7163	135
172346	0.4812	126
172344	0.4803	84
172348	0.3531	36
172347	0.1621	66
172349	0.1593	30
172340	0.1158	62
172345	0.0955	52

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	92.44	gold quality
mononuclear cell	CL:0000842	91.55	gold quality
leukocyte	CL:0000738	91.41	gold quality
granulocyte	CL:0000094	85.06	gold quality
blood	UBERON:0000178	77.02	gold quality
lymph node	UBERON:0000029	74.91	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	74.31	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.89	gold quality
spleen	UBERON:0002106	72.99	gold quality
vermiform appendix	UBERON:0001154	71.75	gold quality
sural nerve	UBERON:0015488	71.02	gold quality
colonic epithelium	UBERON:0000397	70.69	gold quality
bone marrow cell	CL:0002092	70.42	gold quality
gall bladder	UBERON:0002110	70.10	gold quality
paraflocculus	UBERON:0005351	70.07	silver quality
middle frontal gyrus	UBERON:0002702	69.83	silver quality
calcaneal tendon	UBERON:0003701	68.88	gold quality
rectum	UBERON:0001052	68.70	gold quality
endometrium epithelium	UBERON:0004811	68.46	gold quality
stromal cell of endometrium	CL:0002255	67.32	gold quality
caecum	UBERON:0001153	66.68	gold quality
tendon	UBERON:0000043	66.49	gold quality
upper lobe of left lung	UBERON:0008952	65.96	gold quality
right lung	UBERON:0002167	65.91	gold quality
upper lobe of lung	UBERON:0008948	65.26	gold quality
smooth muscle tissue	UBERON:0001135	65.08	gold quality
bone marrow	UBERON:0002371	63.24	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	63.08	gold quality
tonsil	UBERON:0002372	62.66	gold quality
tendon of biceps brachii	UBERON:0008188	62.39	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.47

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

72 targeting CD226, 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-5692A	100.00	74.40	6850
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-202-5P	99.78	67.65	991
HSA-MIR-4320	99.75	65.80	793
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-1284	99.67	73.56	1353
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-10393-5P	99.65	68.01	1368
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-141-5P	99.57	67.86	897
HSA-MIR-549A-3P	99.54	68.17	825
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-7159-3P	99.51	70.17	1920

Literature-anchored findings (GeneRIF, showing 40)

• CD226 mediates platelet and megakaryocytic cell adhesion to vascular endothelial cells (PMID:12847109)
• Data show that both PVR and Nectin-2 represent specific ligands for the DNAM-1 triggering receptor. (PMID:12913096)
• CD226 is involved in LFA-1-mediated costimulatory signals for triggering naive T cell differentiation and proliferation. (PMID:14676297)
• DNAM-1 regulates monocyte extravasation via its interaction with cd155 protein expressed at endothelial junctions on normal cells. (PMID:15136589)
• PTA-1(CD226 antigen) is localized to membrane rafts and binds the carboxyl-terminal domain of isoforms of the actin-binding protein 4.1G and also can bind human discs large providing the structural basis for a regulated molecular adhesive complex (PMID:15138281)
• CD226 molecules play an important role in maturation of the megakaryocytes in combination with LFA-1 (PMID:15693793)
• Loss of Dnam-1 gene copy number and retention of Cadh-7 might be indicators of worse prognosis, and Dnam-1 deletion might predict for a beneficial response to adjuvant 5-FU-based chemotherapy in patients with colorectal cancer. (PMID:16015041)
• The cytotoxicity of NK cells enhanced by SEA or SEB may be correlation with the increased expression of CD226 molecule, and CD226 may be involved in synapse formation of NK cells at killing stage. (PMID:16388732)
• CD226/CD112 (DNAM-1/Nectin-2) mast cell stimulation has a role in the allergic process (PMID:16831868)
• CD226 promoters P1 and P2 are regulated by Ets-1 and AP-1 (PMID:16887814)
• expression on CD3+, CD4+, and CD8+ T cells and on CD3- CD16+ NK cells of HIV-infected patients was significantly higher than that of normal controls. (PMID:16987076)
• NK cell-mediated killing of myeloma cell lines was dependent on either DNAM-1 or NKG2D but not both molecules. (PMID:17875681)
• EWS tumor cells are recognized and lysed by resting and with higher efficacy by activated NK cells through NKG2D and DNAM-1 dependent pathways. (PMID:18657862)
• CD226 Gly307Ser association with multiple autoimmune diseases is reported. (PMID:18971939)
• CD226 is a multiple sclerosis susceptibility gene. (PMID:18987646)
• CD226-transgenic mice display enlarged thymus lobes resulting from increased thymus cellularity. (PMID:19380793)
• CD226 Gly307Ser polymorphism is associated with Wegener’s granulomatosis and multiple sclerosis. (PMID:19536154)
• In the presence of DC-derived cytokines such as interleukin-12, in both patients & healthy individuals, DNAM-1 can cooperate with NKp30 to induce NK cells to kill DC, release tumor necrosis factor-alpha, & promote DC maturation. (PMID:19580844)
• CD226 gene as a susceptible candidate locus for type 1 diabetes outside the major histocompatibility complex region. (PMID:19624611)
• evidence provided for the contribution of DNAM-1/CD155 interactions to the reduction of DNAM-1 expression, suggesting that chronic receptor-ligand interactions in the tumor environment may induce loss of DNAM-1 on tumor-associated NK cells. (PMID:19801517)
• Data show that pair-wise ligations of 2B4 with DNAM-1 and/or NKG2D lead to increased effector functions of primary CD4(+)CD28(-) T cells to suboptimal levels of anti-CD3 stimulation. (PMID:19904767)
• The rs763361 SNP in the CD226 gene was associated with susceptibility to type 1 diabetes because disease-susceptible minor allele A maintains the wild type ESS sequence. (PMID:20089178)
• CD226 Gly307Ser gene polymorphism is associated with severity of psoriasis (PMID:20399620)
• rs763361 in CD226 confers susceptibility for multiple sclerosis. (PMID:20508602)
• speculate that reduced expression of DNAM-1 on bone marrow natural killer cells may facilitate disease progression in patients with myelodysplastic syndrome (PMID:20613786)
• This study identified an association of CD226 with systemic lupus erythematosus in individuals of European ancestry. (PMID:20669283)
• An association between the Gly307Ser single nucleotide polymorphism (SNP) and susceptibility to systemic lupus erythemtosus was identified (PMID:20887380)
• CD226 as a new systemic sclerosis genetic susceptibility factor underlying the contribution of costimulation pathways in the pathogenesis of systemic sclerosis. (PMID:21162102)
• Demonstrate a genetic association between the CD226 gene and rheumatoid arthritis in a Chinese Han population with a potentially greater genetic effect than in the European population. (PMID:21286723)
• The proportion of circulating CD226positive natural killer (NK) cells is reduced in patients with active systemic lupus erythematosus (SLE). (PMID:21296979)
• Data indicate that NK cells from acute myeloid leukemia (AML) patients younger than 65 years have a reduced expression of DNAM-1 compared with age-matched controls. (PMID:21383766)
• NK cells lysed allogeneic proliferating more efficiently than nonproliferating T lymphocytes, with a mechanism requiring the cooperation between DNAM-1 and NKG2D. (PMID:21406724)
• likely that the 307Ser variant of the CD226 receptor is associated with autoimmune polyendocrinopathy type 2 pathogenesis (PMID:21521299)
• Study provides evidence that (pre)malignant cells themselves can acquire the ability to lyse epithelial cells via DNAM-1. (PMID:21525383)
• CD226 gene polymorphisms may not be associated with rheumatoid arthritis susceptibility. (PMID:22302395)
• TIGIT can inhibit T cell functions by competing with CD226 and can also directly inhibit T cells in a T cell-intrinsic manner. (PMID:22427644)
• CD226 polymorphisms, rs727088, rs34794968 and rs763361 were not involved in giant cell arteritis susceptibility in the Spanish population. (PMID:22512842)
• A CD226 three-variant haplotype is related with genetic predisposition to systemic sclerosis-related pulmonary fibrosis. (PMID:22531499)
• A soluble nectin-2 immunoglobulin-like V-set domain (nectin-2v) has been successfully prepared and demonstrates binding to both soluble ectodomain and cell surface-expressed full-length DNAX accessory molecule (DNAM)-1. (PMID:22547693)
• This demonstrates the CD226 rs763361 polymorphism confers susceptibility to autoimmune disease in Europeans, South Americans and Asians (PMID:22941566)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cd226	ENSDARG00000045391
mus_musculus	Cd226	ENSMUSG00000034028
rattus_norvegicus	Cd226	ENSRNOG00000038197
drosophila_melanogaster	Fas3	FBGN0000636

Paralogs (14): PVR (ENSG00000073008), CD200 (ENSG00000091972), CADM4 (ENSG00000105767), CRTAM (ENSG00000109943), NECTIN1 (ENSG00000110400), NECTIN2 (ENSG00000130202), NECTIN4 (ENSG00000143217), CADM3 (ENSG00000162706), SMAGP (ENSG00000170545), CADM2 (ENSG00000175161), NECTIN3 (ENSG00000177707), TIGIT (ENSG00000181847), CADM1 (ENSG00000182985), NCR3 (ENSG00000204475)

Protein

Protein identifiers

CD226 antigen — Q15762 (reviewed: Q15762)

Alternative names: DNAX accessory molecule 1

All UniProt accessions (6): Q15762, J3QKM7, J3QL19, J3QQW1, J3QR77, J3QRQ4

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface receptor that plays an important role in the immune system, particularly in intercellular adhesion, lymphocyte signaling, cytotoxicity and lymphokine secretion mediated by cytotoxic T-cells and NK cells. Functions as a costimulatory receptor upon recognition of target cells, such as virus-infected or tumor cells. Upon binding to its ligands PVR/CD155 or NECTIN2/CD112 on target cells, promotes the cytotoxic activity of NK cells and CTLs, enhancing their ability to kill these cells. Mechanistically, phosphorylation by Src kinases such as LYN of FYN, enables binding to adapter GRB2, leading to activation of VAV1, PI3K and PLCG1. Promotes also activation of kinases ERK and AKT, as well as calcium fluxes.

Subunit / interactions. Interacts with PVR and NECTIN2. Competes with PVRIG for NECTIN2-binding. Interacts with ITGAL; this interaction mediates CD226 localization to lipid rafts.

Subcellular location. Cell membrane.

Tissue specificity. Expressed by peripheral blood T-lymphocytes.

Post-translational modifications. PKC-mediated phosphorylation at Ser-329 is required for lipid raft recruitment. Phosphorylation of Tyr-322 requires association with lipid rafts and allows GRB2 binding and activation of subsequent signaling.

RefSeq proteins (3): NP_001290547, NP_001290548, NP_006557 (=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
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR042842	CD226	Family

Pfam: PF07686

UniProt features (51 total): strand 16, glycosylation site 8, turn 5, helix 4, disulfide bond 3, mutagenesis site 3, modified residue 2, topological domain 2, domain 2, signal peptide 1, chain 1, sequence variant 1, transmembrane region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6ISB	X-RAY DIFFRACTION	2.5
6O3O	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15762-F1	82.75	0.50

Functional residue map

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

Post-translational modifications (2): 329, 322

Disulfide bonds (3): 37–108, 152–222, 179–199

Glycosylation sites (8): 32, 83, 90, 97, 147, 186, 198, 231

Mutagenesis-validated functional residues (3):

Position	Phenotype
113	significantly reduced nk-cell killing.
322	no loss of association with lipid rafts.
329	loss of association with lipid rafts and loss of phosphorylation by pkc.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 233 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, 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_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOCC_CELL_SURFACE, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_POSITIVE_REGULATION_OF_B_CELL_MEDIATED_IMMUNITY, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY

GO Biological Process (12): positive regulation of natural killer cell cytokine production (GO:0002729), positive regulation of natural killer cell mediated cytotoxicity directed against tumor cell target (GO:0002860), positive regulation of immunoglobulin mediated immune response (GO:0002891), cell adhesion (GO:0007155), signal transduction (GO:0007165), cell recognition (GO:0008037), positive regulation of type II interferon production (GO:0032729), positive regulation of mast cell activation (GO:0033005), natural killer cell mediated cytotoxicity (GO:0042267), positive regulation of natural killer cell mediated cytotoxicity (GO:0045954), positive regulation of T cell receptor signaling pathway (GO:0050862), positive regulation of Fc receptor mediated stimulatory signaling pathway (GO:0060369)

GO Molecular Function (6): integrin binding (GO:0005178), protein kinase binding (GO:0019901), signaling receptor activity (GO:0038023), identical protein binding (GO:0042802), cell adhesion molecule binding (GO:0050839), protein binding (GO:0005515)

GO Cellular Component (5): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), membrane raft (GO:0045121), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Adaptive Immune System	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	3
positive regulation of natural killer cell mediated immunity	2
protein binding	2
cellular anatomical structure	2
natural killer cell cytokine production	1
positive regulation of cytokine production involved in immune response	1
regulation of natural killer cell cytokine production	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 natural killer cell mediated cytotoxicity	1
positive regulation of B cell mediated immunity	1
regulation of immunoglobulin mediated immune response	1
immunoglobulin mediated immune response	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
positive regulation of cytokine production	1
type II interferon production	1
regulation of type II interferon production	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
positive regulation of leukocyte mediated cytotoxicity	1
natural killer cell mediated cytotoxicity	1
regulation of natural killer cell mediated cytotoxicity	1
T cell receptor signaling pathway	1
regulation of T cell receptor signaling pathway	1
positive regulation of antigen receptor-mediated signaling pathway	1
Fc receptor mediated stimulatory signaling pathway	1
positive regulation of signal transduction	1
positive regulation of immune response	1
regulation of Fc receptor mediated stimulatory signaling pathway	1
signaling receptor binding	1
protein-containing complex binding	1
cell adhesion molecule binding	1
kinase binding	1

Protein interactions and networks

STRING

2640 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CD226	NECTIN2	Q92692	999
CD226	PVR	P15151	999
CD226	NECTIN1	Q15223	992
CD226	TIGIT	Q495A1	979
CD226	NCR3	O14931	941
CD226	KLRK1	P26718	934
CD226	NCR1	O76036	925
CD226	ULBP1	Q9BZM6	910
CD226	KLRD1	Q13241	881
CD226	KLRC1	P26715	866
CD226	KLRC2	P26717	860
CD226	SLAMF6	Q96DU3	848
CD226	IL2RB	P14784	832
CD226	CD48	P09326	827
CD226	ULBP2	Q9BZM5	816

IntAct

127 interactions, top by confidence:

A	B	Type	Score
PVR	CD226	psi-mi:“MI:0407”(direct interaction)	0.860
CD226	PVR	psi-mi:“MI:0407”(direct interaction)	0.860
CD226	PVR	psi-mi:“MI:0915”(physical association)	0.860
PVR	CD226	psi-mi:“MI:0915”(physical association)	0.860
CD226	CD226	psi-mi:“MI:0915”(physical association)	0.610
CD226	CD226	psi-mi:“MI:0407”(direct interaction)	0.610
CD226	NECTIN2	psi-mi:“MI:0915”(physical association)	0.610
NECTIN2	CD226	psi-mi:“MI:0407”(direct interaction)	0.610
CD226	TIGIT	psi-mi:“MI:0915”(physical association)	0.560
TIGIT	CD226	psi-mi:“MI:2364”(proximity)	0.560
CD226	MEN1	psi-mi:“MI:0914”(association)	0.530
MAGI2	CD226	psi-mi:“MI:0407”(direct interaction)	0.440
CD226	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
CD226	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.440
CD226	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
CD226	GOPC	psi-mi:“MI:0407”(direct interaction)	0.440
CD226	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
CD226	TJP2	psi-mi:“MI:0407”(direct interaction)	0.440
CD226	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
CD226	NOS1	psi-mi:“MI:0407”(direct interaction)	0.440
CD226	GRID2IP	psi-mi:“MI:0407”(direct interaction)	0.440
CD226	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
CD226	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
CD226	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.440
CD226	SHANK1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (52): PVR (Reconstituted Complex), PVRL2 (Reconstituted Complex), MBLAC2 (Affinity Capture-MS), ATP13A1 (Affinity Capture-MS), TSC2 (Affinity Capture-MS), INTS7 (Affinity Capture-MS), NCAPH2 (Affinity Capture-MS), TBC1D22B (Affinity Capture-MS), ZDHHC6 (Affinity Capture-MS), EIF2B5 (Affinity Capture-MS), EIF2B2 (Affinity Capture-MS), EIF2B4 (Affinity Capture-MS), TTC7B (Affinity Capture-MS), KLHL23 (Affinity Capture-MS), DSTYK (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IGV4, A0A8M2B818, A0JM41, A2VD98, B0CLX4, B6ZK77, D3YX43, F1LW30, O00241, O18906, O54901, O88775, O95256, P00545, P04218, P0C673, P10522, P13369, P17948, P21995, P27931, P35916, P35917, P35969, P37301, P42071, P42703, P53767, Q08DK1, Q15762, Q58EG3, Q5DX21, Q5FWR8, Q5R412, Q5U2P2, Q5VJ70, Q6GMZ9, Q6PCB8, Q6X936, Q7TSN7

Diamond homologs: O18906, Q15762, Q8K4F0, Q9JKF6

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
PVR	“up-regulates activity”	CD226	binding
NECTIN2	“up-regulates activity”	CD226	binding
CD226	up-regulates	“AL/b2 integrin”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 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
Dopamine Neurotransmitter Release Cycle	5	45.1×	4e-06
Assembly and cell surface presentation of NMDA receptors	9	41.5×	6e-11
Neurexins and neuroligins	10	35.8×	3e-11
Protein-protein interactions at synapses	7	33.8×	9e-08
RHOB GTPase cycle	5	14.0×	5e-04
RHOC GTPase cycle	5	13.3×	6e-04
RHOA GTPase cycle	6	8.1×	1e-03
Neuronal System	7	5.6×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	75.5×	2e-14
receptor clustering	7	56.7×	7e-09
protein localization to synapse	5	49.7×	5e-06
regulation of postsynaptic membrane neurotransmitter receptor levels	5	32.2×	3e-05
cell-cell adhesion	9	11.9×	6e-06
protein-containing complex assembly	8	11.8×	3e-05
establishment of localization in cell	5	10.4×	2e-03
regulation of small GTPase mediated signal transduction	5	9.3×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	50
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
2427508	NC_000018.9:g.(?67578932)(67872894_?)del	Pathogenic
3062371	GRCh37/hg19 18q21.32-22.3(chr18:58508272-70495604)x3	Likely pathogenic

SpliceAI

2044 predictions. Top by Δscore:

Variant	Effect	Δscore
18:69864317:A:C	donor_gain	1.0000
18:69867421:A:C	acceptor_gain	1.0000
18:69896042:CTAT:C	acceptor_gain	1.0000
18:69946899:T:TA	donor_gain	1.0000
18:69839658:G:GT	donor_gain	0.9900
18:69841238:CTCTA:C	acceptor_loss	0.9900
18:69841239:TCTA:T	acceptor_loss	0.9900
18:69841240:CTAG:C	acceptor_loss	0.9900
18:69841241:TAGG:T	acceptor_loss	0.9900
18:69841243:G:A	acceptor_loss	0.9900
18:69864315:TAA:T	donor_gain	0.9900
18:69864316:AAA:A	donor_gain	0.9900
18:69864316:AAACT:A	donor_gain	0.9900
18:69864365:AT:A	donor_gain	0.9900
18:69864366:T:TA	donor_gain	0.9900
18:69867420:CA:C	acceptor_gain	0.9900
18:69867426:CAA:C	acceptor_gain	0.9900
18:69867427:A:T	acceptor_gain	0.9900
18:69896043:TAT:T	acceptor_gain	0.9900
18:69896044:ATCTG:A	acceptor_loss	0.9900
18:69896045:TCTGA:T	acceptor_loss	0.9900
18:69896046:C:CC	acceptor_gain	0.9900
18:69896046:CTG:C	acceptor_loss	0.9900
18:69896047:T:A	acceptor_loss	0.9900
18:69946829:C:CT	acceptor_gain	0.9900
18:69946829:C:T	acceptor_gain	0.9900
18:69839695:G:GT	donor_gain	0.9800
18:69841242:A:AG	acceptor_gain	0.9800
18:69841243:G:GG	acceptor_gain	0.9800
18:69841243:GGTC:G	acceptor_gain	0.9800

AlphaMissense

2209 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:69946968:A:G	W50R	0.986
18:69946968:A:T	W50R	0.986
18:69895933:C:A	W165C	0.984
18:69895933:C:G	W165C	0.984
18:69895770:A:C	Y220D	0.982
18:69946966:C:A	W50C	0.981
18:69946966:C:G	W50C	0.981
18:69946793:C:G	C108S	0.978
18:69946794:A:T	C108S	0.978
18:69895935:A:G	W165R	0.977
18:69895935:A:T	W165R	0.977
18:69946800:A:C	Y106D	0.977
18:69946794:A:G	C108R	0.969
18:69946935:C:G	A61P	0.969
18:69895766:C:G	R221P	0.967
18:69946792:G:C	C108W	0.966
18:69946838:A:T	L93H	0.965
18:69946934:G:T	A61D	0.963
18:69947007:A:G	C37R	0.963
18:69946793:C:T	C108Y	0.957
18:69946832:A:G	F95S	0.957
18:69947006:C:G	C37S	0.954
18:69947007:A:T	C37S	0.954
18:69947012:A:G	L35P	0.951
18:69895979:A:G	L150P	0.945
18:69946805:C:A	G104V	0.945
18:69895769:T:G	Y220S	0.943
18:69946799:T:C	Y106C	0.940
18:69946797:A:G	S107P	0.939
18:69946976:T:G	Q47P	0.938

dbSNP variants (sampled 300 via entrez): RS1000004508 (18:69925740 C>T), RS1000028958 (18:69958889 T>C), RS1000046211 (18:69925595 T>C), RS1000047751 (18:69919560 AAGG>A), RS1000048186 (18:69946460 G>A,C), RS1000067223 (18:69859746 C>T), RS1000085599 (18:69866130 G>A), RS1000094213 (18:69905368 T>C), RS1000190206 (18:69854334 A>G), RS1000223449 (18:69896527 TTTTTTG>T), RS1000241026 (18:69922275 T>A), RS1000255802 (18:69902137 C>T), RS1000272392 (18:69942857 C>G), RS1000276595 (18:69889022 G>A,C,T), RS1000287110 (18:69860747 T>C)

Disease associations

OMIM: gene MIM:605397 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

42 associations (top):

Study	Trait	p-value
GCST000038_2	Type 1 diabetes	1.000000e-08
GCST000497_3	Mean platelet volume	1.000000e-10
GCST001191_13	Type 1 diabetes	1.000000e-09
GCST001335_1	Mean platelet volume	3.000000e-11
GCST001725_59	Inflammatory bowel disease	5.000000e-09
GCST002318_148	Rheumatoid arthritis	9.000000e-10
GCST002318_63	Rheumatoid arthritis	1.000000e-08
GCST004030_9	Primary sclerosing cholangitis	7.000000e-12
GCST004599_134	Mean platelet volume	4.000000e-117
GCST004599_135	Mean platelet volume	9.000000e-13
GCST004607_12	Plateletcrit	2.000000e-17
GCST004616_36	Platelet distribution width	2.000000e-59
GCST004628_28	Immature fraction of reticulocytes	4.000000e-11
GCST005536_17	Type 1 diabetes	2.000000e-11
GCST005537_41	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	2.000000e-08
GCST006670_1	Primary sclerosing cholangitis	3.000000e-08
GCST006959_178	Rheumatoid arthritis	2.000000e-06
GCST006959_91	Rheumatoid arthritis	2.000000e-06
GCST007932_87	Medication use (thyroid preparations)	9.000000e-10
GCST008167_5	Mean platelet volume	3.000000e-11
GCST009597_57	Multiple sclerosis	3.000000e-08
GCST010397_43	Gut microbiota (bacterial taxa, rank normal transformation method)	2.000000e-06
GCST010571_72	Autoimmune thyroid disease	5.000000e-11
GCST011956_110	Systemic lupus erythematosus	6.000000e-10
GCST90002381_559	Eosinophil count	4.000000e-12
GCST90002385_293	High light scatter reticulocyte count	4.000000e-17
GCST90002386_91	High light scatter reticulocyte percentage of red cells	3.000000e-17
GCST90002387_215	Immature fraction of reticulocytes	4.000000e-24
GCST90002389_252	Lymphocyte percentage of white cells	1.000000e-12
GCST90002390_558	Mean corpuscular hemoglobin	2.000000e-10

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0007985	platelet crit
EFO:0007984	platelet component distribution width
EFO:0007986	reticulocyte count
EFO:0009933	Thyroid preparation use measurement
EFO:0007874	gut microbiome measurement
EFO:0004842	eosinophil count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0004527	mean corpuscular hemoglobin
EFO:0004833	neutrophil count
EFO:0004309	platelet count
EFO:0010099	chronic widespread pain

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — CD molecules

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression	2
Aflatoxin B1	increases methylation	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects methylation	1
terbufos	increases methylation	1
CGP 52608	affects binding, increases reaction	1
clothianidin	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Fonofos	increases methylation	1
Mercury	increases expression	1
Nickel	increases expression	1
Parathion	increases methylation	1
Progesterone	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Zinc	decreases expression	1
Antirheumatic Agents	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8CX	Abcam HCT 116 CD226 KO	Cancer cell line	Male
CVCL_B9F5	Abcam A-549 CD226 KO	Cancer cell line	Male
CVCL_D2E7	Abcam MCF-7 CD226 KO	Cancer cell line	Female
CVCL_E6PC	Genomeditech CHO-K1 H_CD226	Spontaneously immortalized cell line	Female
CVCL_E6VZ	Genomeditech Jurkat H_TIGIT+CD226 Reporter	Cancer cell line	Male
CVCL_SH58	HAP1 CD226 (-) 1	Cancer cell line	Male
CVCL_SH59	HAP1 CD226 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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