TIGIT

Summary

TIGIT (T cell immunoreceptor with Ig and ITIM domains, HGNC:26838) is a protein-coding gene on chromosome 3q13.31, encoding T-cell immunoreceptor with Ig and ITIM domains (Q495A1). Inhibitory receptor that plays a role in the modulation of immune responses.

This gene encodes a member of the PVR (poliovirus receptor) family of immunoglobin proteins. The product of this gene is expressed on several classes of T cells including follicular B helper T cells (TFH). The protein has been shown to bind PVR with high affinity; this binding is thought to assist interactions between TFH and dendritic cells to regulate T cell dependent B cell responses.

Source: NCBI Gene 201633 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 46 total
• Druggable target: yes
• MANE Select transcript: NM_173799

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26838
Approved symbol	TIGIT
Name	T cell immunoreceptor with Ig and ITIM domains
Location	3q13.31
Locus type	gene with protein product
Status	Approved
Aliases	FLJ39873, DKFZp667A205
Ensembl gene	ENSG00000181847
Ensembl biotype	protein_coding
OMIM	612859
Entrez	201633

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000383671, ENST00000461158, ENST00000481065, ENST00000484319, ENST00000485814, ENST00000486257, ENST00000496848, ENST00000891102, ENST00000891103, ENST00000891104

RefSeq mRNA: 1 — MANE Select: NM_173799 NM_173799

CCDS: CCDS2980

Canonical transcript exons

ENST00000383671 — 4 exons

Exon	Start	End
ENSE00003889767	114294028	114294122
ENSE00003889841	114299597	114299703
ENSE00003893273	114307895	114310288
ENSE00003893887	114295545	114295874

Expression profiles

Bgee: expression breadth ubiquitous, 156 present calls, max score 90.93.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.8033 / max 214.7109, expressed in 111 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
37998	1.2237	99
37996	0.3458	58
37995	0.1668	42
37997	0.0669	31

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	90.93	gold quality
lymph node	UBERON:0000029	90.28	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.36	gold quality
vermiform appendix	UBERON:0001154	84.20	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.53	gold quality
spleen	UBERON:0002106	80.94	gold quality
oocyte	CL:0000023	80.41	gold quality
secondary oocyte	CL:0000655	80.33	gold quality
blood	UBERON:0000178	79.44	gold quality
caecum	UBERON:0001153	77.53	gold quality
gall bladder	UBERON:0002110	74.61	gold quality
colonic epithelium	UBERON:0000397	73.13	gold quality
bone marrow cell	CL:0002092	72.65	gold quality
rectum	UBERON:0001052	72.10	gold quality
mucosa of transverse colon	UBERON:0004991	71.51	gold quality
tonsil	UBERON:0002372	71.19	gold quality
small intestine Peyer’s patch	UBERON:0003454	69.84	gold quality
small intestine	UBERON:0002108	67.70	gold quality
ileal mucosa	UBERON:0000331	67.22	gold quality
superficial temporal artery	UBERON:0001614	64.94	silver quality
smooth muscle tissue	UBERON:0001135	64.34	gold quality
epithelium of nasopharynx	UBERON:0001951	62.81	silver quality
upper lobe of left lung	UBERON:0008952	62.65	gold quality
bone marrow	UBERON:0002371	62.25	gold quality
duodenum	UBERON:0002114	61.59	gold quality
right lung	UBERON:0002167	61.35	gold quality
right lobe of liver	UBERON:0001114	61.17	gold quality
upper lobe of lung	UBERON:0008948	61.07	gold quality
omental fat pad	UBERON:0010414	60.43	gold quality
peritoneum	UBERON:0002358	60.41	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-CURD-97	yes	1797.85
E-CURD-95	yes	1329.22
E-MTAB-8142	yes	1229.93
E-CURD-89	yes	1007.49
E-HCAD-29	yes	926.31
E-CURD-88	yes	488.95
E-CURD-122	yes	47.79
E-CURD-120	yes	47.75
E-MTAB-8410	yes	29.23
E-HCAD-1	yes	24.92
E-CURD-46	yes	23.37
E-ANND-3	yes	7.57

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

70 targeting TIGIT, 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-8485	100.00	77.57	4731
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-1255A	99.74	68.09	744
HSA-MIR-1255B-5P	99.74	68.16	741
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-3685	99.62	68.83	1621
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-141-5P	99.57	67.86	897
HSA-MIR-12123	99.52	71.79	2990

Literature-anchored findings (GeneRIF, showing 40)

• TIGIT exerts immunosuppressive effects by binding to poliovirus receptor and modulating cytokine production by dendritic cells. (PMID:19011627)
• a novel immunoreceptor, Washington University Cell Adhesion Molecule, which is expressed on human follicular B helper T cells, was described. (PMID:19197944)
• TIGIT counter inhibits the NK-mediated killing of tumor cells and protects normal cells from NK-mediated cytotoxicity thus providing an “alternative self” mechanism for MHC class I inhibition. (PMID:19815499)
• that soluble Vstm3 attenuates T-cell responses in vitro and in vivo (PMID:21416464)
• data suggest a cis-trans receptor clustering mechanism for cell adhesion and signaling by the TIGIT/PVR complex and provide structural insights into how the PVR family of immunoregulators function (PMID:22421438)
• 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)
• The Tim-3 pathway appears to control regulatory (Treg) and effector T cell balance via altering cell proliferation and apoptosis during hepatitis C virus infection. (PMID:22706088)
• TIGIT is phosphorylated at its cytoplasmic tail after its ligation with PVR. (PMID:23154388)
• TIGIT/PVR ligation signaling mediates suppression of IFN-gamma production via the NF-kappaB pathway. (PMID:24817116)
• Findings suggest that TIGIT is a key checkpoint inhibitor of chronic antiviral and antitumor responses through impairing CD226 function when disrupting its homodimerization. (PMID:25465800)
• The results identify a bacterium-dependent, tumor-immune evasion mechanism in which tumors exploit the Fap2 protein of F. nucleatum to inhibit immune cell activity via TIGIT. (PMID:25680274)
• the TIGIT/FCRL3 combination allows reliable identification of Helios(+) Treg cells even in highly activated conditions in vitro as well as in PBMCs of autoimmune patients. (PMID:25762785)
• TIGIT and PD-1 blockade additively increased proliferation, cytokine production, and degranulation of tumor-antigen-specific CD8 T cells and CD8 TILs. TIGIT and PD-1 regulate the expansion and function of these T cells in melanoma. (PMID:25866972)
• Human regulatory T cells expressing the receptors TIGIT and CD226 display widely divergent phenotypes in regard to expansion and activation. (PMID:25994968)
• a novel mechanism that links TIGIT expression with NK-cell functional heterogeneity, and this mechanism might partially explain why individuals have different susceptibilities to infection, autoimmune disease, and cancer. (PMID:26171588)
• TIGIT-positive circulating follicular helper T cells display robust B-cell help functions: potential role in sickle cell alloimmunization. (PMID:26250578)
• This study shows that HBZ-induced TIGIT plays a pivotal role in attenuating host immune responses and shaping a microenvironment favorable to human T-cell leukemia virus type 1. (PMID:26735971)
• These findings identify TIGIT as a novel marker of dysfunctional HIV-specific T cells (PMID:26741490)
• TIGIT contributes to functional T-cell impairment and associates with poor clinical outcome in acute myelogenous leukemia. The study suggests that blockade of TIGIT to restore T-cell function and antitumor immunity may represent a novel effective leukemia therapeutic. (PMID:26763253)
• implying that TIGIT exerts immunosuppressive effects by competing with DNAM-1 for the same ligand, CD155 (PMID:26842126)
• TIGIT signaling in NK cells after MDSC coculture led to a decrease in the phosphorylation of ZAP70/Syk and ERK1/2. (PMID:27503932)
• High expression of TIGIT and Helios identifies CD4+ T cells with impaired immunological functions, primarily among patients with an advanced stage of Sezary syndrome. (PMID:27592800)
• Our data provide important structural and biochemical determinants responsible for the recognition of nectin-2 by TIGIT. (PMID:27978489)
• Natural killer cells and cytotoxic T cells express both TIGIT and DNAM-1 receptors, and in certain cases their effector functions are dictated by TIGIT or DNAM-1 signaling. Agonist and antagonist antibodies targeting either TIGIT or DNAM-1 present many therapeutic options for diseases spanning from cancer to auto-immunity. (Review) (PMID:28035916)
• These findings highlight the importance of the TIGIT/CD226/PVR axis as an immune checkpoint barrier that could hinder future “cure” strategies requiring potent HIV-specific CD8(+) T cells (PMID:28084312)
• TIGIT is a powerful negative regulator of CD4(+) T cells in systemic lupus erythematosus. (PMID:28108989)
• 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)
• Blockade of TIGIT or CD112R, separately or together, enhances trastuzumab-triggered antitumor response by human NK cells. (PMID:28623459)
• Blimp-1 binds to the promoters of PD-1 and TIGIT and positively regulates their expression in patients with acute myeloid leukemia. (PMID:28629373)
• Data show that gastric cancer cells inhibit T-cell metabolism through CD155/TIGIT signaling. (PMID:28883004)
• high coexpression of PD-1, TIGIT, and KLRG-1 on MiHA-reactive CD8(+) T cells was associated with relapse after allo-SCT. Taken together, these findings indicate that MiHA-specific CD8(+) T cells of relapsed patients have a distinctive coinhibitory expression signature compared with patients who stay in remission. (PMID:29197680)
• Data suggest that T-cell immunoglobulin and ITIM domain (TIGIT) blockade is a relevant strategy for improved immunotherapy in follicular lymphoma (FL). (PMID:29217528)
• Clinical remission of sight-threatening non-infectious uveitis has an immunoregulatory phenotype characterized by upregulation of peripheral Treg, polarized toward T-bet and TIGIT. (PMID:29774027)
• High TIGIT expression is associated with multiple myeloma. (PMID:29986909)
• The activation of PD-1 and TIGIT may exert negative regulatory effects and inhibit the immune response to cancer cells, resulting in immune escape of cancer cells. (PMID:30262800)
• these results highlight the important role of TIGIT in NK cell function and suggest a potential new avenue for the development of therapeutic strategies toward a functional cure for HIV. (PMID:30364127)
• Study results suggest that TIGIT expression on CD4+ T cells in patients with atopic dermatitis (AD) may be increased to suppress chronic cutaneous inflammation. Moreover, TIGIT expression may be impaired in a subset of patients with AD, leading to a deterioration of skin inflammation. (PMID:30402886)
• a novel TIGIT/PVR interaction mode that tumor intrinsic TIGIT delivers inhibitory signals to CD8(+) T cells and NK cells by engaging with PVR. (PMID:30555485)
• associated with a decreased incidence of acute graft-versus-host disease (P=.048) and poor overall (P=.046) and progression-free survival; monitoring TIGIT expression in the BM could be useful for predicting outcome after alloSCT for AML (PMID:30639819)
• HCV-specific CD4+ T cells of patients with acute and chronic HCV infection display high expression of TIGIT and other co-inhibitory molecules. (PMID:31337800)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:113337	ENSDARG00000041998
danio_rerio	si:ch211-222f23.6	ENSDARG00000042880
danio_rerio	si:ch73-22o12.1	ENSDARG00000062831
danio_rerio	pvrl2l	ENSDARG00000063390
danio_rerio	zgc:172122	ENSDARG00000079191
danio_rerio	si:ch211-214p13.3	ENSDARG00000087403
danio_rerio	si:ch211-141e20.2	ENSDARG00000093349
danio_rerio	sc:d189	ENSDARG00000102858
mus_musculus	Tigit	ENSMUSG00000071552
rattus_norvegicus	Tigit	ENSRNOG00000056574
drosophila_melanogaster	Fas3	FBGN0000636

Paralogs (14): PVR (ENSG00000073008), CD200 (ENSG00000091972), CADM4 (ENSG00000105767), CRTAM (ENSG00000109943), NECTIN1 (ENSG00000110400), NECTIN2 (ENSG00000130202), NECTIN4 (ENSG00000143217), CD226 (ENSG00000150637), CADM3 (ENSG00000162706), SMAGP (ENSG00000170545), CADM2 (ENSG00000175161), NECTIN3 (ENSG00000177707), CADM1 (ENSG00000182985), NCR3 (ENSG00000204475)

Protein

Protein identifiers

T-cell immunoreceptor with Ig and ITIM domains — Q495A1 (reviewed: Q495A1)

Alternative names: V-set and immunoglobulin domain-containing protein 9, V-set and transmembrane domain-containing protein 3

All UniProt accessions (4): Q495A1, A0A0C4DGA4, C9J0B0, C9JZW6

UniProt curated annotations — full annotation on UniProt →

Function. Inhibitory receptor that plays a role in the modulation of immune responses. Suppresses T-cell activation by promoting the generation of mature immunoregulatory dendritic cells. Upon binding to its ligands PVR/CD155 or NECTIN2/CD112, which are expressed on antigen-presenting cells, sends inhibitory signals to the T-cell or NK cell. Mechanistically, interaction with ligand leads to phosphorylation of the cytoplasmic tail by Src family tyrosine kinases such as FYN or LCK, allowing subsequent binding to adapter GRB2 and SHIP1/INPP5D. In turn, inhibits PI3K and MAPK signaling cascades. In addition, associates with beta-arrestin-2/ARRB2 to recruit SHIP1/INPP5D that suppresses autoubiquitination of TRAF6 and subsequently inhibits NF-kappa-B signaling pathway. Also acts as a receptor for NECTIN4 to inhibit NK cell cytotoxicity.

Subunit / interactions. Homodimer in cis; binds with high affinity to PVR, forming a heterotetrameric assembly of two TIGIT and two PVR molecules. Binds with lower affinity to NECTIN2 and NECTIN3. Interacts with GRB2. Interacts with NECTIN4.

Subcellular location. Cell membrane.

Tissue specificity. Expressed at low levels on peripheral memory and regulatory CD4+ T-cells and NK cells and is up-regulated following activation of these cells (at protein level).

Domain organisation. Contains 1 copy of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM). This motif is involved in modulation of cellular responses. The phosphorylated ITIM motif can bind the SH2 domain of several SH2-containing phosphatases.

Isoforms (2)

UniProt ID	Names	Canonical?
Q495A1-1	1	yes
Q495A1-2	2

RefSeq proteins (1): NP_776160* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
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
IPR042948	TIGIT	Family

Pfam: PF07686

UniProt features (37 total): strand 11, mutagenesis site 5, glycosylation site 2, splice variant 2, topological domain 2, sequence conflict 2, turn 2, helix 2, signal peptide 1, chain 1, disulfide bond 1, sequence variant 1, transmembrane region 1, domain 1, region of interest 1, short sequence motif 1, modified residue 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
8VTD	X-RAY DIFFRACTION	1.23
7VYT	X-RAY DIFFRACTION	1.53
3Q0H	X-RAY DIFFRACTION	1.7
8JEO	X-RAY DIFFRACTION	2.06
8VTE	X-RAY DIFFRACTION	2.29
8SZY	X-RAY DIFFRACTION	2.31
8JEL	X-RAY DIFFRACTION	2.45
3UCR	X-RAY DIFFRACTION	2.63
3RQ3	X-RAY DIFFRACTION	2.7
8JEN	X-RAY DIFFRACTION	2.71
3UDW	X-RAY DIFFRACTION	2.9
5V52	X-RAY DIFFRACTION	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q495A1-F1	74.82	0.49

Antibody-complex structures (SAbDab): 7 — 7VYT, 8JEL, 8JEN, 8JEO, 8SZY, 8VTD, 8VTE

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 (1): 225

Disulfide bonds (1): 45–108

Glycosylation sites (2): 101, 32

Mutagenesis-validated functional residues (5):

Position	Phenotype
42	abrogates interaction with pvr, cell clustering and pvr signaling.
225	complete loss of phosphorylation.
227	complete loss of binding to grb2.
231	no loss of phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 139 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, GOCC_CELL_SURFACE, GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, GOBP_NEGATIVE_REGULATION_OF_NATURAL_KILLER_CELL_MEDIATED_IMMUNITY, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_CELL_CELL_ADHESION, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY

GO Biological Process (5): negative regulation of interleukin-12 production (GO:0032695), positive regulation of interleukin-10 production (GO:0032733), negative regulation of natural killer cell mediated cytotoxicity (GO:0045953), negative regulation of T cell activation (GO:0050868), natural killer cell mediated cytotoxicity (GO:0042267)

GO Molecular Function (4): signaling receptor binding (GO:0005102), signaling receptor activity (GO:0038023), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	2
cellular anatomical structure	2
negative regulation of cytokine production	1
interleukin-12 production	1
regulation of interleukin-12 production	1
positive regulation of cytokine production	1
interleukin-10 production	1
regulation of interleukin-10 production	1
negative regulation of leukocyte mediated cytotoxicity	1
negative regulation of natural killer cell mediated immunity	1
natural killer cell mediated cytotoxicity	1
regulation of natural killer cell mediated cytotoxicity	1
T cell activation	1
regulation of T cell activation	1
negative regulation of lymphocyte activation	1
negative regulation of leukocyte cell-cell adhesion	1
leukocyte mediated cytotoxicity	1
natural killer cell mediated immunity	1
molecular transducer activity	1
binding	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1592 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TIGIT	NECTIN2	Q92692	999
TIGIT	PVR	P15151	997
TIGIT	NECTIN3	Q9NQS3	994
TIGIT	CD226	Q15762	979
TIGIT	NECTIN1	Q15223	978
TIGIT	LGALS9	O00182	974
TIGIT	CD274	Q9NZQ7	973
TIGIT	CD96	P40200	967
TIGIT	LGALS9B	Q3B8N2	950
TIGIT	LGALS9C	Q6DKI2	950
TIGIT	LAG3	P18627	924
TIGIT	CD80	P33681	901
TIGIT	CTLA4	P16410	889
TIGIT	HAVCR2	Q8TDQ0	885
TIGIT	INPP5D	Q92835	880

IntAct

35 interactions, top by confidence:

A	B	Type	Score
TIGIT	NECTIN2	psi-mi:“MI:0407”(direct interaction)	0.840
TIGIT	NECTIN2	psi-mi:“MI:0915”(physical association)	0.840
TIGIT	PVR	psi-mi:“MI:0407”(direct interaction)	0.790
PVR	TIGIT	psi-mi:“MI:0915”(physical association)	0.790
TIGIT	PVR	psi-mi:“MI:0915”(physical association)	0.790
NECTIN3	TIGIT	psi-mi:“MI:0915”(physical association)	0.610
NECTIN3	TIGIT	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
TIGIT	PLLP	psi-mi:“MI:0915”(physical association)	0.560
MAL	TIGIT	psi-mi:“MI:0915”(physical association)	0.560
TIGIT	TIGIT	psi-mi:“MI:0407”(direct interaction)	0.540
TIGIT	TIGIT	psi-mi:“MI:0915”(physical association)	0.540
TIGIT	PVR	psi-mi:“MI:0407”(direct interaction)	0.440
NECTIN4	TIGIT	psi-mi:“MI:0915”(physical association)	0.400
FCGR2A	TIGIT	psi-mi:“MI:0915”(physical association)	0.400
TIGIT	FAM171A2	psi-mi:“MI:0914”(association)	0.350
TIGIT	PTPRF	psi-mi:“MI:0914”(association)	0.350
RASL11A	MBL2	psi-mi:“MI:0914”(association)	0.350

BioGRID (27): TIGIT (Two-hybrid), TIGIT (Two-hybrid), D2HGDH (Affinity Capture-MS), ATP8B2 (Affinity Capture-MS), UFSP2 (Affinity Capture-MS), CDC6 (Affinity Capture-MS), FAM171A2 (Affinity Capture-MS), RHOBTB3 (Affinity Capture-MS), C1orf27 (Affinity Capture-MS), ZDHHC6 (Affinity Capture-MS), ITCH (Affinity Capture-MS), ZRANB3 (Affinity Capture-MS), GET4 (Affinity Capture-MS), DDR1 (Affinity Capture-MS), PTPRD (Affinity Capture-MS)

ESM2 similar proteins: A6NJW9, O02757, P01730, P01731, P01732, P05541, P07725, P09793, P0DSE1, P10300, P10747, P10966, P15530, P16003, P16004, P16410, P30433, P30434, P31041, P31042, P31043, P31783, P33705, P33706, P40259, P41688, P42069, P42072, P50283, P79184, P79336, Q08338, Q08340, Q28071, Q2YFS1, Q2YFS2, Q2YFS3, Q3LRV9, Q495A1, Q5JXA9

Diamond homologs: P86176, Q495A1, P32507, Q96NY8

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PVR	“up-regulates activity”	TIGIT	binding
TIGIT	“up-regulates activity”	ARRB2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	31
Likely benign	8
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

630 predictions. Top by Δscore:

Variant	Effect	Δscore
3:114299591:CTCTA:C	acceptor_loss	1.0000
3:114299592:TCTA:T	acceptor_loss	1.0000
3:114299593:CTAGT:C	acceptor_loss	1.0000
3:114299594:TA:T	acceptor_loss	1.0000
3:114299595:A:AG	acceptor_gain	1.0000
3:114299595:AGT:A	acceptor_gain	1.0000
3:114299595:AGTG:A	acceptor_gain	1.0000
3:114299596:G:GA	acceptor_gain	1.0000
3:114299596:GT:G	acceptor_gain	1.0000
3:114299596:GTG:G	acceptor_gain	1.0000
3:114299596:GTGG:G	acceptor_gain	1.0000
3:114299596:GTGGC:G	acceptor_gain	1.0000
3:114307893:A:AG	acceptor_gain	1.0000
3:114307894:G:GG	acceptor_gain	1.0000
3:114291293:G:GT	donor_gain	0.9900
3:114291294:A:T	donor_gain	0.9900
3:114294412:G:GT	donor_gain	0.9900
3:114295795:G:GT	donor_gain	0.9900
3:114295795:G:T	donor_gain	0.9900
3:114299700:AAAG:A	donor_loss	0.9900
3:114299701:AAGG:A	donor_loss	0.9900
3:114299704:G:GA	donor_loss	0.9900
3:114299705:T:A	donor_loss	0.9900
3:114307894:GA:G	acceptor_gain	0.9900
3:114307894:GAA:G	acceptor_gain	0.9900
3:114307894:GAAGA:G	acceptor_gain	0.9900
3:114291188:G:T	donor_gain	0.9800
3:114294488:G:GT	donor_gain	0.9800
3:114294489:A:T	donor_gain	0.9800
3:114299699:GAAAG:G	donor_gain	0.9800

AlphaMissense

1569 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:114295660:G:C	W59C	0.995
3:114295660:G:T	W59C	0.995
3:114295800:A:G	Y106C	0.982
3:114295658:T:A	W59R	0.981
3:114295658:T:C	W59R	0.981
3:114295805:T:A	C108S	0.981
3:114295806:G:C	C108S	0.981
3:114295659:G:C	W59S	0.976
3:114295799:T:C	Y106H	0.976
3:114295616:T:A	C45S	0.975
3:114295617:G:C	C45S	0.975
3:114295806:G:A	C108Y	0.975
3:114295799:T:G	Y106D	0.974
3:114295611:T:C	L43S	0.973
3:114295800:A:C	Y106S	0.973
3:114295805:T:C	C108R	0.968
3:114295807:C:G	C108W	0.968
3:114295616:T:C	C45R	0.965
3:114295650:A:C	Q56P	0.963
3:114295788:A:T	D102V	0.963
3:114295811:T:G	Y110D	0.960
3:114308072:T:C	F226L	0.953
3:114308074:C:A	F226L	0.953
3:114308074:C:G	F226L	0.953
3:114295829:G:T	G116W	0.952
3:114295788:A:C	D102A	0.950
3:114295830:G:T	G116V	0.946
3:114295788:A:G	D102G	0.937
3:114295806:G:T	C108F	0.936
3:114295682:G:C	A67P	0.935

dbSNP variants (sampled 300 via entrez): RS1000289861 (3:114302881 G>T), RS1000472252 (3:114309035 G>A), RS1000520785 (3:114297388 T>G), RS1000710683 (3:114309726 G>A), RS1001099678 (3:114303503 A>G,T), RS1001205010 (3:114302271 A>G), RS1001228297 (3:114309227 C>T), RS1001259357 (3:114308962 A>G), RS1001259454 (3:114304570 A>G), RS1001290360 (3:114308583 G>A), RS1001402890 (3:114310645 T>A), RS1001950345 (3:114298021 C>T), RS1002204914 (3:114299186 T>G), RS1002312813 (3:114310107 C>T), RS1002335383 (3:114305462 T>C)

Disease associations

OMIM: gene MIM:612859 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630878 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — Immunoglobulin like domain containing proteins

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects cotreatment, increases methylation	2
perfluorooctanoic acid	affects cotreatment, decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
Nickel	increases expression	2
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
monomethylpropion	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	affects cotreatment, decreases expression	1
perfluorohexanesulfonic acid	decreases expression, affects cotreatment	1
Fulvestrant	affects cotreatment, increases methylation	1
Atrazine	increases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression, affects cotreatment	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	increases expression	1

Cellosaurus cell lines

8 cell lines: 4 cancer cell line, 3 spontaneously immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A8AF	Raji-hTIGIT	Cancer cell line	Male
CVCL_D2TE	CHO/hTIGIT	Spontaneously immortalized cell line	Female
CVCL_E6RZ	Genomeditech CHO-K1 H_TIGIT	Spontaneously immortalized cell line	Female
CVCL_E6VZ	Genomeditech Jurkat H_TIGIT+CD226 Reporter	Cancer cell line	Male
CVCL_KA05	CHO-K1/TIGIT	Spontaneously immortalized cell line	Female
CVCL_TS35	HAP1 TIGIT (-) 1	Cancer cell line	Male
CVCL_TS36	HAP1 TIGIT (-) 2	Cancer cell line	Male
CVCL_UE50	293T human TIGIT	Transformed cell line	Female

Clinical trials (associated diseases)

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