HAVCR2

Summary

HAVCR2 (hepatitis A virus cellular receptor 2, HGNC:18437) is a protein-coding gene on chromosome 5q33.3, encoding Hepatitis A virus cellular receptor 2 (Q8TDQ0). Cell surface receptor implicated in modulating innate and adaptive immune responses. In precision oncology, HAVCR2 Overexpression is associated with resistance to PD1 Inhibitor in Lung Non-small Cell Carcinoma (CIViC Level C); 1 further curated variant–drug associations are listed below.

The protein encoded by this gene belongs to the immunoglobulin superfamily, and TIM family of proteins. CD4-positive T helper lymphocytes can be divided into types 1 (Th1) and 2 (Th2) on the basis of their cytokine secretion patterns. Th1 cells are involved in cell-mediated immunity to intracellular pathogens and delayed-type hypersensitivity reactions, whereas, Th2 cells are involved in the control of extracellular helminthic infections and the promotion of atopic and allergic diseases. This protein is a Th1-specific cell surface protein that regulates macrophage activation, and inhibits Th1-mediated auto- and alloimmune responses, and promotes immunological tolerance.

Source: NCBI Gene 84868 — RefSeq curated summary.

At a glance

• Gene–disease (curated): subcutaneous panniculitis-like T-cell lymphoma (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 78 total
• Phenotypes (HPO): 26
• Druggable target: yes
• Precision-oncology evidence (CIViC): 2 curated variant–drug associations
• MANE Select transcript: NM_032782

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18437
Approved symbol	HAVCR2
Name	hepatitis A virus cellular receptor 2
Location	5q33.3
Locus type	gene with protein product
Status	Approved
Aliases	Tim-3, TIM3, FLJ14428, TIMD3, CD366
Ensembl gene	ENSG00000135077
Ensembl biotype	protein_coding
OMIM	606652
Entrez	84868

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 10 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000307851, ENST00000517358, ENST00000521665, ENST00000522593, ENST00000522902, ENST00000524219, ENST00000696897, ENST00000696898, ENST00000696899, ENST00000696900, ENST00000696901, ENST00000696902, ENST00000853244

RefSeq mRNA: 1 — MANE Select: NM_032782 NM_032782

CCDS: CCDS4333

Canonical transcript exons

ENST00000307851 — 7 exons

Exon	Start	End
ENSE00001177812	157085832	157087294
ENSE00002109833	157106627	157106962
ENSE00002110211	157108926	157109044
ENSE00003691168	157098858	157098901
ENSE00003968823	157088941	157088977
ENSE00003968828	157104666	157104749
ENSE00003968829	157095306	157095459

Expression profiles

Bgee: expression breadth ubiquitous, 206 present calls, max score 92.09.

FANTOM5 (CAGE): breadth broad, TPM avg 13.3951 / max 857.2399, expressed in 490 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
64511	9.6119	1721
64502	7.8130	424
64501	1.9930	259
64505	1.5041	270
64500	1.4859	176
64504	0.5992	251

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	92.09	gold quality
leukocyte	CL:0000738	91.75	gold quality
monocyte	CL:0000576	91.72	gold quality
vermiform appendix	UBERON:0001154	88.05	gold quality
kidney epithelium	UBERON:0004819	88.05	gold quality
blood	UBERON:0000178	87.09	gold quality
spleen	UBERON:0002106	85.94	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	85.59	gold quality
lymph node	UBERON:0000029	85.29	gold quality
amniotic fluid	UBERON:0000173	84.76	gold quality
upper lobe of left lung	UBERON:0008952	84.56	gold quality
upper lobe of lung	UBERON:0008948	83.97	gold quality
spinal cord	UBERON:0002240	83.93	gold quality
decidua	UBERON:0002450	83.46	gold quality
gall bladder	UBERON:0002110	83.30	gold quality
adult mammalian kidney	UBERON:0000082	82.68	gold quality
right lung	UBERON:0002167	82.05	gold quality
caecum	UBERON:0001153	80.51	gold quality
lung	UBERON:0002048	80.27	gold quality
germinal epithelium of ovary	UBERON:0001304	80.19	gold quality
right adrenal gland cortex	UBERON:0035827	78.85	gold quality
kidney	UBERON:0002113	78.63	gold quality
left adrenal gland	UBERON:0001234	78.41	gold quality
smooth muscle tissue	UBERON:0001135	78.30	gold quality
right adrenal gland	UBERON:0001233	78.05	gold quality
bone marrow cell	CL:0002092	77.86	gold quality
omental fat pad	UBERON:0010414	77.79	gold quality
subcutaneous adipose tissue	UBERON:0002190	77.77	gold quality
peritoneum	UBERON:0002358	77.73	gold quality
adipose tissue of abdominal region	UBERON:0007808	77.49	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	38.97
E-ANND-3	yes	21.44
E-CURD-112	yes	15.44

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, HAND1, JUN, SMAD2, SMAD4, TBX21, TBXT

miRNA regulators (miRDB)

40 targeting HAVCR2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055
HSA-MIR-4677-3P	99.49	67.91	1246
HSA-MIR-4696	99.48	67.48	1040
HSA-MIR-372-5P	99.41	69.11	2299
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-148A-5P	99.30	68.27	1141
HSA-MIR-133A-3P	99.27	71.53	1270
HSA-MIR-133B	99.27	71.53	1270
HSA-MIR-520E-5P	99.27	68.90	1513
HSA-MIR-196A-3P	99.19	67.34	1204
HSA-MIR-7702	99.06	65.95	698
HSA-MIR-6889-3P	98.84	67.35	1198

Literature-anchored findings (GeneRIF, showing 40)

• Tim-3 gene associated with rheumatoid arthritis (PMID:15325803)
• the -574T > G polymorphism of Tim-3 might be associated with the susceptibility of atopic diseases (PMID:15603868)
• Human Tim-3 can promote HAV entry into target cells but itself may not function as a cellular receptor of HAV. (PMID:16685421)
• Failure to up-regulate T cell expression of TIM3 in inflammatory sites may represent a novel, intrinsic defect that contributes to the pathogenesis of multiple sclerosis and other human autoimmune diseases. (PMID:16754722)
• Stimulation of Tim-3 by its ligand galectin-9 results in increased phosphorylation of Y265, suggesting that this tyrosine residue plays an important role in downstream signalling events regulating T-cell fate. (PMID:17069754)
• Expressed in melanoma cell lines at higher level than in isolated epidermal melanocytes, which can contribute to lower adhering capacity of tumor cells. TIM-3 in TGF-beta-stimulated mast cells and melanoma cells may support survival of this tumor type. (PMID:17096021)
• High expressionof TIM-3 in in acute kidney transplant rejection makes it a promising noninvasive test for its diagnosis. (PMID:17430399)
• T-cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) influences autoimmune diseases, and its role in other inflammatory diseases including allergies and cancer is becoming clear. (PMID:17665973)
• data show that Tim-3 is highly expressed by cells of the innate immune system and that its expression on antigen-presenting cells promotes the secretion of proinflammatory cytokines from monocytes and dendritic cells (PMID:18006747)
• Involved in the pathogenesis of systemic lupus erythematosus. (PMID:18052965)
• multiple sclerosis may function in part by restoring TIM-3 immunoregulation of T cell function (PMID:18354161)
• role of the rs10515746 (A/C), rs1036199 (A/C), and rs10053538 (A/C) SNPs within the TIM-3 gene in 186 German type 1 diabetes families and its interaction with human leukocyte antigen (HLA) high-risk haplotypes (PMID:18401547)
• increase of TIM-3 expression on PBMCs, overproduction of IFN-gamma in the sera, and increased galectin-9 in PBMCs was observed in acquired aplastic anemia patients (PMID:18485114)
• strong linkage disequilibrium between the two SNPs sites in the TIM-3 gene in a Han population from Hubei province (PMID:18785518)
• Data show that blockade of the Tim-3 pathway can enhance HIV-1 - specific T cell responses, and suggest that the Tim-3 pathway plays a critical role in suppressing the overall T cell response to HIV-1. (PMID:19001139)
• Nasopharyngeal carcinoma exosomes induce massive apoptosis in EBV-specific CD4(+) cells used as a model of target T cells. This effect is inhibited by both anti-Tim-3 and antigalectin-9 blocking antibodies. (PMID:19005181)
• The simultaneous expression of galectin-9 and Tim-3 may indicate an immunoregulatory function, during the ongoing cytotoxic response. (PMID:19100864)
• Tim-3 messenger RNA evaluation in renal transplant recipients is a noninvasive method to evaluate graft dysfunction. (PMID:19104436)
• The -1516G>T, -574T>G, and 4259G>T of TIM-3 gene polymorphisms might not play an important role as a genetic risk factor in the pathophysiology of ITP. (PMID:19332093)
• expression is increased on Vdelta T cells of pregnant women (PMID:19395088)
• Tim-3, by virtue of its up-regulation in innate immune cells in pregnant women, enhances both innate and adaptive immune responses (PMID:19414817)
• Reduced TIM-3 expression in the lungs of patients may result in a defective T cell ability to control the Th1 immune response and could thus contribute to the pathogenesis of sarcoidosis. (PMID:19480659)
• haplotypes including TIM-3 genetic variants confer susceptibility to asthma in a Chinese population (PMID:19494522)
• These data suggest that polymorphisms in the TIM3 promoter region are unlikely to play an important role in susceptibility to allergic diseases (PMID:19566956)
• Tim-3 expression correlates with a dysfunctional and senescent phenotype (CD127(low) CD57(high)), a central rather than effector memory profile (CD45RA(negative) CCR7(high)), and reduced Th1/Tc1 cytokine production. (PMID:19587053)
• These results suggest that TIM-3 is a negative regulator of human T cells and regulates Th1 and Th17 cytokine secretion. (PMID:19676072)
• The TIM-3 pathway and the therapeutic potential of modulating the pathway in systemic lupus erythematosus, is reviewed. (PMID:19768575)
• Structural and biologic studies reveal that TIM-3 is a receptor for phosphatidylserine (PtdSer) and that TIM-3 polymorphic variants differ functionally in their recognition of PtdSer and clearance of apoptotic cells. (PMID:20083673)
• Hepatitis B virus infection can up-regulate Tim-3 expression in natural killer cells (NK), which may in turn suppress NK-cell functions in chronic hepatitis B patients. (PMID:20133006)
• Mucin domain-containing molecule 3 (Tim-3) is preferentially expressed in lymphoma-derived endothelial cells. (PMID:20176801)
• The Tim-3/galectin-9 pathway regulates T helper cell type (Th)1 immune responses through at least two mechanisms: directly, by triggering cell death in Th1 cells and indirectly, through the expansion of suppressive CD11b+Ly6G+ cells. (PMID:20574007)
• Histiocytic and dendritic cell neoplasms consistently express TIM-3 and TIM-4 and that these molecules are new markers of neoplasms derived from histiocytic and dendritic cells. (PMID:20656318)
• Tim-3 might participate in the pathogenesis of rheumatoid arthritis by its negative regulation on various T cell subsets. (PMID:20805041)
• three genetic variations within the TIM-3 gene promoter may be associated with the increased susceptibility to gastric cancer, especially among the haplotypes with the risk. (PMID:20811886)
• PD-1(+) NY-ESO-1-specific CD8(+) T cells in patients with advanced melanoma up-regulates Tim-3 expression (PMID:20819923)
• Blockade of either PD-1 or Tim-3 enhanced in vitro proliferation of HCV-specific CTLs to a similar extent, whereas cytotoxicity against a hepatocyte cell line that expressed cognate HCV epitopes was increased exclusively by Tim-3 blockade. (PMID:21084749)
• Both TIM-3 and galectin-9 undergo rapid proteolytic degradation in the cystic fibrosis CF lung, primarily because of neutrophil elastase and proteinase-3 activity. (PMID:21263071)
• The findings suggest that the polymorphisms of TIM gene family might not contribute to systemic lupus erythematosus susceptibility in the Chinese population. (PMID:21367814)
• The elevated expression of Tim-3 on CD8 T cells correlates with functional defects of CD8 T cells and disease severity of pulmonary TB. (PMID:21382414)
• Tim-3 expression on peripheral T cell subsets correlates with disease progression in hepatitis B infection. (PMID:21392402)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
mus_musculus	Havcr2	ENSMUSG00000020399
rattus_norvegicus	Havcr2	ENSRNOG00000031443
caenorhabditis_elegans		WBGENE00018289
caenorhabditis_elegans		WBGENE00020483
caenorhabditis_elegans		WBGENE00020484
caenorhabditis_elegans		WBGENE00020487
caenorhabditis_elegans		WBGENE00020785
caenorhabditis_elegans		WBGENE00021162
caenorhabditis_elegans		WBGENE00077592
caenorhabditis_elegans		WBGENE00195168
caenorhabditis_elegans		WBGENE00206360

Paralogs (3): HAVCR1 (ENSG00000113249), TIMD4 (ENSG00000145850), MED7 (ENSG00000155868)

Protein

Protein identifiers

Hepatitis A virus cellular receptor 2 — Q8TDQ0 (reviewed: Q8TDQ0)

Alternative names: T-cell immunoglobulin and mucin domain-containing protein 3, T-cell immunoglobulin mucin receptor 3, T-cell membrane protein 3

All UniProt accessions (7): A0A8Q3SIX1, A0A8Q3SJ15, A0A8Q3SJ74, A0A8V8TMM7, E5RFR4, E5RHN3, Q8TDQ0

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface receptor implicated in modulating innate and adaptive immune responses. Generally accepted to have an inhibiting function. Reports on stimulating functions suggest that the activity may be influenced by the cellular context and/or the respective ligand. Regulates macrophage activation. Inhibits T-helper type 1 lymphocyte (Th1)-mediated auto- and alloimmune responses and promotes immunological tolerance. In CD8+ cells attenuates TCR-induced signaling, specifically by blocking NF-kappaB and NFAT promoter activities resulting in the loss of IL-2 secretion. The function may implicate its association with LCK proposed to impair phosphorylation of TCR subunits, and/or LGALS9-dependent recruitment of PTPRC to the immunological synapse. In contrast, shown to activate TCR-induced signaling in T-cells probably implicating ZAP70, LCP2, LCK and FYN. Expressed on Treg cells can inhibit Th17 cell responses. Receptor for LGALS9. Binding to LGALS9 is believed to result in suppression of T-cell responses; the resulting apoptosis of antigen-specific cells may implicate HAVCR2 phosphorylation and disruption of its association with BAG6. Binding to LGALS9 is proposed to be involved in innate immune response to intracellular pathogens. Expressed on Th1 cells interacts with LGALS9 expressed on Mycobacterium tuberculosis-infected macrophages to stimulate antibactericidal activity including IL-1 beta secretion and to restrict intracellular bacterial growth. However, the function as receptor for LGALS9 has been challenged. Also reported to enhance CD8+ T-cell responses to an acute infection such as by Listeria monocytogenes. Receptor for phosphatidylserine (PtSer); PtSer-binding is calcium-dependent. May recognize PtSer on apoptotic cells leading to their phagocytosis. Mediates the engulfment of apoptotic cells by dendritic cells. Expressed on T-cells, promotes conjugation but not engulfment of apoptotic cells. Expressed on dendritic cells (DCs) positively regulates innate immune response and in synergy with Toll-like receptors promotes secretion of TNF. In tumor-imfiltrating DCs suppresses nucleic acid-mediated innate immune repsonse by interaction with HMGB1 and interfering with nucleic acid-sensing and trafficking of nucleid acids to endosomes. Expressed on natural killer (NK) cells acts as a coreceptor to enhance IFN-gamma production in response to LGALS9. In contrast, shown to suppress NK cell-mediated cytotoxicity. Negatively regulates NK cell function in LPS-induced endotoxic shock.

Subunit / interactions. Interacts with HMGB1; impairs HMGB1 binding to B-DNA and likely HMGB1-mediated innate immune response. Interacts with BAG6. Interacts (phosphorylated) with PIK3R1 and PIK3R2. Interacts (not dependent on its phosphorylation status) with FYN. Interacts (in basal state T-cells) with VAV1; AKT1/2, LCP2, ZAP70, SYK, PIK3R1, FYN, SH3BP2 and SH2D2A. Interacts (in activated T-cells) with LCK and PLCG. Interacts with ILF3; this interaction promotes ILF3 ubiquitination and degradation.

Subcellular location. Cell membrane. Cell junction.

Tissue specificity. Expressed in T-helper type 1 (Th1) lymphocytes. Expressed on regulatory T (Treg) cells after TCR stimulation. Expressed in dendritic cells and natural killer (NK) cells. Expressed in epithelial tissues. Expression is increased on CD4+ and CD8+ T-cells in chronic hepatitis C virus (HCV) infection. In progressive HIV-1 infection, expression is up-regulated on HIV-1-specific CD8 T-cells.

Post-translational modifications. O-glycosylated with core 1 or possibly core 8 glycans. Phosphorylated on tyrosine residues; modestly increased after TCR/CD28 stimulation. Can be phosphorylated in the cytoplasmic domain by FYN. Phosphorylation at Tyr-265 is increased by stimulation with ligand LGALS9. Palmitoylated by ZDHHC9 at Cys-296; palmitoylation stabilizes HAVCR2 by preventing binding to E3 ubiquitin ligase SYVN1, thereby suppressing its polyubiquitination and degradation. Ubiquitinated by SYVN1, leading to polyubiquitination and proteasomal degradation.

Disease relevance. May be involved in T-cell exhaustion associated with chronic viral infections such as with human immunodeficiency virus (HIV) and hepatitic C virus (HCV). T-cell lymphoma, subcutaneous panniculitis-like (SPTCL) [MIM:618398] An uncommon form of T-cell non-Hodgkin lymphoma, in which cytotoxic CD8+ T-cells infiltrate subcutaneous adipose tissue, and rimming adipocytes in a lace-like pattern. Affected individuals typically present with multiple subcutaneous nodules, systemic B-cell symptoms, and, in a subset of cases, autoimmune disorders, most commonly systemic lupus erythematosus. A subset of patients develop hemophagocytic lymphohistiocytosis. SPTCL transmission pattern is consistent with autosomal recessive inheritance with incomplete penetrance. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the immunoglobulin superfamily. TIM family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8TDQ0-1	1	yes
Q8TDQ0-2	2

RefSeq proteins (1): NP_116171* (*=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
IPR051669	Immune_Mod/Transcr_Coactivator	Family

Pfam: PF07686

UniProt features (42 total): strand 11, mutagenesis site 5, sequence variant 4, binding site 4, disulfide bond 3, glycosylation site 2, splice variant 2, topological domain 2, helix 2, signal peptide 1, chain 1, modified residue 1, lipid moiety-binding region 1, transmembrane region 1, turn 1, domain 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
7M3Z	X-RAY DIFFRACTION	1.4
7KQL	X-RAY DIFFRACTION	1.49
7M3Y	X-RAY DIFFRACTION	1.69
6DHB	X-RAY DIFFRACTION	1.7
7M41	X-RAY DIFFRACTION	1.79
8TFT	X-RAY DIFFRACTION	2.3
5F71	X-RAY DIFFRACTION	2.4
8TBB	X-RAY DIFFRACTION	2.5
6TXZ	X-RAY DIFFRACTION	3.06
5DZL	X-RAY DIFFRACTION	3.4
8HGJ	ELECTRON MICROSCOPY	4.82

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TDQ0-F1	71.98	0.28

Antibody-complex structures (SAbDab): 4 — 6TXZ, 7KQL, 8TBB, 8TFT

Functional residue map

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

Ligand- & substrate-binding residues (4): 111; 116; 118; 119

Post-translational modifications (2): 265, 296

Disulfide bonds (3): 38–110, 52–63, 58–109

Glycosylation sites (2): 145, 172

Mutagenesis-validated functional residues (5):

Position	Phenotype
265	abolishes tcr-induced nfat activation; when associated with a-272.
265	no effect on tcr-induced nfat activation (phosphomimetic mutation); when associated with e-272.
272	abolishes tcr-induced nfat activation; when associated with a-265.
272	no effect on tcr-induced nfat activation (phosphomimetic mutation); when associated with e-265.
296	higher amount of polyubiquitination.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-451927	Interleukin-2 family signaling

MSigDB gene sets: 386 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, REACTOME_INTERLEUKIN_2_FAMILY_SIGNALING, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_MACROPHAGE_ACTIVATION, GOBP_TOLERANCE_INDUCTION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_TOLL_LIKE_RECEPTOR_9_SIGNALING_PATHWAY, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_MACROPHAGE_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS

GO Biological Process (46): adaptive immune response (GO:0002250), macrophage activation involved in immune response (GO:0002281), natural killer cell tolerance induction (GO:0002519), regulation of tolerance induction dependent upon immune response (GO:0002652), negative regulation of T-helper 1 type immune response (GO:0002826), negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target (GO:0002859), regulation of transcription by RNA polymerase II (GO:0006357), inflammatory response (GO:0006954), negative regulation of gene expression (GO:0010629), negative regulation of myeloid dendritic cell activation (GO:0030886), obsolete negative regulation of NF-kappaB transcription factor activity (GO:0032088), negative regulation of interferon-alpha production (GO:0032687), negative regulation of type II interferon production (GO:0032689), negative regulation of interleukin-2 production (GO:0032703), negative regulation of interleukin-3 production (GO:0032712), negative regulation of interleukin-6 production (GO:0032715), negative regulation of tumor necrosis factor production (GO:0032720), positive regulation of chemokine production (GO:0032722), positive regulation of type II interferon production (GO:0032729), positive regulation of interleukin-1 production (GO:0032732), positive regulation of interleukin-4 production (GO:0032753), positive regulation of tumor necrosis factor production (GO:0032760), negative regulation of natural killer cell activation (GO:0032815), toll-like receptor 3 signaling pathway (GO:0034138), toll-like receptor 7 signaling pathway (GO:0034154), toll-like receptor 9 signaling pathway (GO:0034162), positive regulation of T cell proliferation (GO:0042102), negative regulation of T cell proliferation (GO:0042130), positive regulation of macrophage activation (GO:0043032), innate immune response (GO:0045087), defense response to Gram-positive bacterium (GO:0050830), maternal process involved in female pregnancy (GO:0060135), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to lipopolysaccharide (GO:0071222), negative regulation of granulocyte colony-stimulating factor production (GO:0071656), negative regulation of defense response to bacterium (GO:1900425), positive regulation of defense response to bacterium (GO:1900426), positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224), negative regulation of immunological synapse formation (GO:2000521), negative regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell (GO:2001189)

GO Molecular Function (3): transmembrane signaling receptor activity (GO:0004888), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (7): immunological synapse (GO:0001772), early endosome (GO:0005769), plasma membrane (GO:0005886), cell surface (GO:0009986), mediator complex (GO:0016592), anchoring junction (GO:0070161), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Signaling by Interleukins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of cytokine production	4
positive regulation of cytokine production	3
cellular anatomical structure	3
immune response	2
type II interferon production	2
regulation of type II interferon production	2
myeloid cell activation involved in immune response	1
leukocyte activation involved in immune response	1
macrophage activation	1
tolerance induction	1
tolerance induction dependent upon immune response	1
regulation of tolerance induction	1
regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
negative regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
regulation of T-helper 1 type immune response	1
T-helper 1 type immune response	1
natural killer cell mediated cytotoxicity directed against tumor cell target	1
negative 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
negative regulation of natural killer cell mediated cytotoxicity	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
defense response	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
myeloid dendritic cell activation	1
negative regulation of leukocyte activation	1
regulation of myeloid dendritic cell activation	1
negative regulation of type I interferon production	1
interferon-alpha production	1
regulation of interferon-alpha production	1
interleukin-2 production	1
regulation of interleukin-2 production	1
interleukin-3 production	1
regulation of interleukin-3 production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1

Protein interactions and networks

STRING

2782 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HAVCR2	LGALS9	O00182	999
HAVCR2	LGALS9B	Q3B8N2	999
HAVCR2	LGALS9C	Q6DKI2	999
HAVCR2	CD274	Q9NZQ7	998
HAVCR2	CEACAM1	P13688	994
HAVCR2	HMGB1	P09429	991
HAVCR2	CADM1	Q9BY67	988
HAVCR2	CD80	P33681	968
HAVCR2	CD86	P42081	965
HAVCR2	PDCD1LG2	Q9BQ51	925
HAVCR2	LAG3	P18627	915
HAVCR2	BAG6	P46379	914
HAVCR2	CTLA4	P16410	891
HAVCR2	TIGIT	Q495A1	885
HAVCR2	PVR	P15151	882

IntAct

23 interactions, top by confidence:

A	B	Type	Score
HAVCR2	CEACAM1	psi-mi:“MI:0915”(physical association)	0.590
TMEM86A	HAVCR2	psi-mi:“MI:0915”(physical association)	0.560
HAVCR2	SEC22A	psi-mi:“MI:0915”(physical association)	0.560
HAVCR2	TCAF2	psi-mi:“MI:0914”(association)	0.530
	HAVCR2	psi-mi:“MI:0915”(physical association)	0.490
HAVCR2	FYN	psi-mi:“MI:0914”(association)	0.460
HAVCR2	LCK	psi-mi:“MI:0914”(association)	0.460
HAVCR2	SYK	psi-mi:“MI:0914”(association)	0.460
ERG28	HAVCR2	psi-mi:“MI:0915”(physical association)	0.400
GSKIP	A2ML1	psi-mi:“MI:0914”(association)	0.350
HAVCR2	MGST3	psi-mi:“MI:0914”(association)	0.350
HAVCR2	LGALS8	psi-mi:“MI:0914”(association)	0.350
SEC22A	HAVCR2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (140): PHLPP1 (Affinity Capture-MS), ZDHHC5 (Affinity Capture-MS), KIAA1804 (Affinity Capture-MS), DIP2B (Affinity Capture-MS), DENND6A (Affinity Capture-MS), CLDND1 (Affinity Capture-MS), AGBL5 (Affinity Capture-MS), EXPH5 (Affinity Capture-MS), GOLGA7 (Affinity Capture-MS), RIPK4 (Affinity Capture-MS), TSPAN7 (Affinity Capture-MS), DIP2A (Affinity Capture-MS), PKN3 (Affinity Capture-MS), KDM1B (Affinity Capture-MS), FAM115C (Affinity Capture-MS)

ESM2 similar proteins: A1KXC4, B2RQL2, B2RTN2, O35188, O55145, O60667, O95196, P06484, P07141, P16382, P24394, P25918, P78423, Q29RT9, Q3SYS8, Q58CT8, Q5BK39, Q5FVQ5, Q5M871, Q5U2P6, Q63257, Q64322, Q68CR7, Q68DV7, Q6AXU5, Q6P1B3, Q6PNM1, Q6RFH4, Q71M36, Q863Z5, Q8BHB3, Q8BHE4, Q8BHW6, Q8BSU2, Q8C708, Q8IXW0, Q8JZQ0, Q8K0B3, Q8NET5, Q8R183

Diamond homologs: O46598, O54947, P0C0K5, Q5FVR0, Q5QNS5, Q6U7R4, Q8R183, Q8TDQ0, Q8VIM0, Q96D42, Q96H15, Q3V3F6, Q6UWV2, A4QPC6, P78310, P97792, Q5R764, Q9R066, Q6ZMC9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ITK	“up-regulates activity”	HAVCR2	phosphorylation

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	43
Likely benign	15
Benign	8

Top pathogenic / likely-pathogenic (0)

SpliceAI

1277 predictions. Top by Δscore:

Variant	Effect	Δscore
5:157087162:G:C	donor_gain	1.0000
5:157087170:A:AC	donor_gain	1.0000
5:157087171:C:CC	donor_gain	1.0000
5:157087174:A:AC	donor_gain	1.0000
5:157087190:T:TA	donor_gain	1.0000
5:157095299:CACTT:C	donor_loss	1.0000
5:157095300:ACTT:A	donor_loss	1.0000
5:157095301:CTTA:C	donor_loss	1.0000
5:157095302:TTACA:T	donor_loss	1.0000
5:157095303:T:TG	donor_loss	1.0000
5:157095304:A:AC	donor_gain	1.0000
5:157095304:ACAT:A	donor_loss	1.0000
5:157095305:C:CC	donor_gain	1.0000
5:157095305:CA:C	donor_gain	1.0000
5:157095305:CAT:C	donor_gain	1.0000
5:157095305:CATT:C	donor_gain	1.0000
5:157095305:CATTT:C	donor_gain	1.0000
5:157095455:ATTTG:A	acceptor_gain	1.0000
5:157095456:TTTG:T	acceptor_gain	1.0000
5:157095457:TTG:T	acceptor_gain	1.0000
5:157095457:TTGC:T	acceptor_loss	1.0000
5:157095458:TG:T	acceptor_gain	1.0000
5:157095458:TGCTA:T	acceptor_loss	1.0000
5:157095460:C:CC	acceptor_gain	1.0000
5:157095461:T:G	acceptor_loss	1.0000
5:157095462:A:C	acceptor_gain	1.0000
5:157106622:CTCA:C	donor_loss	1.0000
5:157106623:TCA:T	donor_loss	1.0000
5:157106624:CA:C	donor_loss	1.0000
5:157106625:A:AC	donor_gain	1.0000

AlphaMissense

1943 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:157106862:C:A	W53C	0.996
5:157106862:C:G	W53C	0.996
5:157106689:C:G	R111P	0.988
5:157106641:A:G	L127S	0.980
5:157106692:C:G	C110S	0.980
5:157106693:A:T	C110S	0.980
5:157106864:A:G	W53R	0.978
5:157106864:A:T	W53R	0.978
5:157106737:A:G	L95P	0.977
5:157106699:A:C	Y108D	0.976
5:157106692:C:T	C110Y	0.970
5:157106691:G:C	C110W	0.969
5:157106698:T:C	Y108C	0.969
5:157106833:C:G	C63S	0.967
5:157106834:A:T	C63S	0.967
5:157106694:G:C	C109W	0.966
5:157106710:T:A	D104V	0.966
5:157106849:A:G	C58R	0.966
5:157106866:C:G	C52S	0.966
5:157106867:A:T	C52S	0.966
5:157106908:C:G	C38S	0.965
5:157106909:A:T	C38S	0.965
5:157106848:C:G	C58S	0.963
5:157106849:A:T	C58S	0.963
5:157106693:A:G	C110R	0.962
5:157106696:A:G	C109R	0.961
5:157106867:A:G	C52R	0.958
5:157106907:G:C	C38W	0.958
5:157106661:A:C	D120E	0.957
5:157106661:A:T	D120E	0.957

dbSNP variants (sampled 300 via entrez): RS1000140896 (5:157095754 C>A,G), RS1000339483 (5:157107581 T>C), RS1000375968 (5:157107863 C>A,G,T), RS1000499475 (5:157108566 A>C), RS1000572958 (5:157108208 C>T), RS1001076754 (5:157106257 A>C,G), RS1001088841 (5:157090662 C>T), RS1001143945 (5:157097164 A>G), RS1001375190 (5:157103708 T>A), RS1001515159 (5:157090331 C>T), RS1001562849 (5:157090427 T>C), RS1001567602 (5:157089928 A>G), RS1001574703 (5:157109713 C>T), RS1001762605 (5:157108751 C>T), RS1001805110 (5:157103330 C>T)

Disease associations

OMIM: gene MIM:606652 | disease phenotypes: MIM:618398

GenCC curated gene-disease

Disease	Classification	Inheritance
subcutaneous panniculitis-like T-cell lymphoma	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
HAVCR2-related cancer predisposition	Moderate	AR

Mondo (1): subcutaneous panniculitis-like T-cell lymphoma (MONDO:0019475)

Orphanet (1): Subcutaneous panniculitis-like T-cell lymphoma (Orphanet:86884)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000282	Facial edema
HP:0001433	Hepatosplenomegaly
HP:0001744	Splenomegaly
HP:0001824	Weight loss
HP:0001876	Pancytopenia
HP:0001903	Anemia
HP:0001945	Fever
HP:0002155	Hypertriglyceridemia
HP:0002960	Autoimmunity
HP:0003256	Abnormality of the coagulation cascade
HP:0003281	Increased circulating ferritin concentration
HP:0003584	Late onset
HP:0003596	Middle age onset
HP:0003621	Juvenile onset
HP:0011462	Young adult onset
HP:0011463	Childhood onset
HP:0011900	Hypofibrinogenemia
HP:0012156	Hemophagocytosis
HP:0012378	Fatigue
HP:0012490	Panniculitis
HP:0025143	Chills
HP:0025474	Erythematous plaque
HP:0030350	Erythematous papule
HP:0034403	Subcutaneous panniculitis-like T-cell lymphoma
HP:0200042	Skin ulcer

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001905_8	Hypertriglyceridemia	3.000000e-06
GCST006585_1486	Blood protein levels	7.000000e-104
GCST007742_19	Iris heterochromicity	4.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0009764	eye colour measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537503	Subcutaneous panniculitis-like T-cell lymphoma (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630879 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 2 predictive associations from 2 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
HAVCR2 Overexpression	PD1 Inhibitor	Lung Non-small Cell Carcinoma	Resistance	CIViC C	EID1150
HAVCR2 Overexpression	PD1 Inhibitor + Anti-TIM-3 Monoclonal Antibody	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC D	EID1151

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1036199	HAVCR2		0.00	0
rs10515746	HAVCR2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — CD molecules

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
sabatolimab	Binding	9.78	pKd

ChEMBL bioactivities

53 potent at pChembl≥5 of 84 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.24	Kd	0.58	nM	CHEMBL5431861
7.16	Ki	70	nM	CHEMBL4863322
6.96	Ki	110	nM	CHEMBL4857707
6.81	Ki	156	nM	CHEMBL4863017
6.80	Kd	160	nM	CHEMBL5571782
6.79	Ki	164	nM	CHEMBL4862554
6.69	Ki	204	nM	CHEMBL4873816
6.66	Kd	217	nM	CHEMBL5571782
6.60	Kd	250	nM	CHEMBL4873902
6.57	Kd	270	nM	CHEMBL5575871
6.54	Ki	287	nM	CHEMBL4846481
6.48	Kd	330	nM	CHEMBL5575027
6.41	Kd	390	nM	CHEMBL5567449
6.36	Ki	440	nM	CHEMBL4854153
6.30	Ki	500	nM	CHEMBL4875904
6.26	Ki	550	nM	CHEMBL4873816
6.21	Kd	610	nM	CHEMBL5431861
6.12	Ki	750	nM	CHEMBL4863017
6.12	Kd	750	nM	CHEMBL5573426
6.01	Ki	970	nM	CHEMBL4868118
6.01	Kd	980	nM	CHEMBL5428118
5.89	Ki	1300	nM	CHEMBL4875904
5.89	Kd	1280	nM	CHEMBL5436299
5.87	Kd	1350	nM	CHEMBL5437490
5.82	Ki	1500	nM	CHEMBL4874818
5.82	Ki	1500	nM	CHEMBL4846039
5.80	Ki	1600	nM	CHEMBL4859588
5.79	Kd	1630	nM	CHEMBL5428825
5.75	Ki	1800	nM	CHEMBL4851756
5.72	Kd	1900	nM	CHEMBL5542747
5.70	Kd	2000	nM	CHEMBL4848599
5.70	Kd	2010	nM	CHEMBL5417245
5.68	Ki	2100	nM	CHEMBL4860976
5.66	Ki	2200	nM	CHEMBL4872496
5.64	Ki	2300	nM	CHEMBL4876721
5.61	Kd	2470	nM	CHEMBL5395251
5.58	Ki	2600	nM	CHEMBL4864303
5.57	Kd	2700	nM	CHEMBL5562869
5.51	Kd	3120	nM	CHEMBL5419656
5.39	Kd	4100	nM	CHEMBL5549921
5.32	Kd	4800	nM	CHEMBL5574715
5.31	Ki	4900	nM	CHEMBL4863477
5.31	Ki	4900	nM	CHEMBL4852144
5.24	IC50	5800	nM	CHEMBL4873816
5.22	Kd	6040	nM	CHEMBL5418365
5.14	Kd	7300	nM	CHEMBL6173519
5.08	Kd	8320	nM	CHEMBL5396005
5.03	Kd	9450	nM	CHEMBL5440144
5.01	Kd	9700	nM	CHEMBL5575353
5.00	Kd	1e+04	nM	CHEMBL4863477

PubChem BioAssay actives

48 with measured affinity, of 85 total; 41 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-(2,4-dimethoxyphenyl)-2-[3-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]phenoxy]acetamide	2011218: Binding affinity to His-tagged recombinant human TIM3 expressed in HEK293 cells assessed as dissociation constant by MST assay	kd	0.0006	uM
N-[4-(8-chloro-2-methyl-5-oxo-6H-[1,2,4]triazolo[1,5-c]quinazolin-9-yl)-3-methylphenyl]-1H-imidazole-2-sulfonamide	1785235: Displacement of FITC-labelled SP2 probe from human TIM-3 IgV domain (residues 22 to 130) expressed in Escherichia coli BL21 (DE3) by FPA competition assay	ki	0.0700	uM
N-[4-(8-chloro-2-methyl-5-oxo-6H-[1,2,4]triazolo[1,5-c]quinazolin-9-yl)-3-methylphenyl]-2,4-dimethoxybenzenesulfonamide	1785235: Displacement of FITC-labelled SP2 probe from human TIM-3 IgV domain (residues 22 to 130) expressed in Escherichia coli BL21 (DE3) by FPA competition assay	ki	0.1100	uM
N-[4-(8-chloro-2-methyl-5-oxo-6H-[1,2,4]triazolo[1,5-c]quinazolin-9-yl)-3-methylphenyl]methanesulfonamide	1785235: Displacement of FITC-labelled SP2 probe from human TIM-3 IgV domain (residues 22 to 130) expressed in Escherichia coli BL21 (DE3) by FPA competition assay	ki	0.1560	uM
(3S,6S,9S,12R,15S,18S,21S,24S,27R,30S,33S)-33-benzyl-21-[(2S)-butan-2-yl]-3,6,9,18,30-pentakis(hydroxymethyl)-15,24-bis[(4-hydroxyphenyl)methyl]-12,27-bis(sulfanylmethyl)-1,4,7,10,13,16,19,22,25,28,31,34-dodecazacyclohexatriacontane-2,5,8,11,14,17,20,23,26,29,32,35-dodecone	2094819: Binding affinity to recombinant His-tagged human TIM-3 expressed in HEK293 assessed as dissociation constant by SPR analysis	kd	0.1600	uM
8-chloro-2-methyl-9-[2-methyl-4-(methylsulfamoylamino)phenyl]-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one	1785235: Displacement of FITC-labelled SP2 probe from human TIM-3 IgV domain (residues 22 to 130) expressed in Escherichia coli BL21 (DE3) by FPA competition assay	ki	0.1640	uM
N-[3-chloro-4-(8-chloro-2-methyl-5-oxo-6H-[1,2,4]triazolo[1,5-c]quinazolin-9-yl)phenyl]methanesulfonamide	1785235: Displacement of FITC-labelled SP2 probe from human TIM-3 IgV domain (residues 22 to 130) expressed in Escherichia coli BL21 (DE3) by FPA competition assay	ki	0.2040	uM
5-[[8-chloro-9-[2-chloro-4-(methanesulfonamido)phenyl]-5-oxo-6H-[1,2,4]triazolo[1,5-c]quinazolin-2-yl]methylcarbamothioylamino]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1785232: Binding affinity to human TIM-3 IgV domain (residues 22 to 130) expressed in Escherichia coli BL21 (DE3) by 1H-15N SOFAST-HMQC spectroscopic analysis	kd	0.2500	uM
(3S,6S,9S,12R,15S,18S,21S,24S,27S,30S,33S)-33-benzyl-21-[(2S)-butan-2-yl]-12,27-bis[(1R)-1-hydroxyethyl]-6,9,18,30-tetrakis(hydroxymethyl)-24-[(4-hydroxyphenyl)methyl]-15-(1H-indol-3-ylmethyl)-3-methyl-1,4,7,10,13,16,19,22,25,28,31,34-dodecazacyclohexatriacontane-2,5,8,11,14,17,20,23,26,29,32,35-dodecone	2094819: Binding affinity to recombinant His-tagged human TIM-3 expressed in HEK293 assessed as dissociation constant by SPR analysis	kd	0.2700	uM
N-[4-(8-chloro-2-methyl-5-oxo-6H-[1,2,4]triazolo[1,5-c]quinazolin-9-yl)-3-fluorophenyl]methanesulfonamide	1785235: Displacement of FITC-labelled SP2 probe from human TIM-3 IgV domain (residues 22 to 130) expressed in Escherichia coli BL21 (DE3) by FPA competition assay	ki	0.2870	uM
(3S,6S,9S,12R,15S,18S,21S,24S,27R,30S,33S)-21-[(2S)-butan-2-yl]-6,9,18,30-tetrakis(hydroxymethyl)-15,24-bis[(4-hydroxyphenyl)methyl]-3-methyl-33-(2-methylpropyl)-12,27-bis(sulfanylmethyl)-1,4,7,10,13,16,19,22,25,28,31,34-dodecazacyclohexatriacontane-2,5,8,11,14,17,20,23,26,29,32,35-dodecone	2094819: Binding affinity to recombinant His-tagged human TIM-3 expressed in HEK293 assessed as dissociation constant by SPR analysis	kd	0.3300	uM
(3S,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S)-15-benzyl-21-[(2S)-butan-2-yl]-12,27-bis[(1R)-1-hydroxyethyl]-6,9,18,30-tetrakis(hydroxymethyl)-24,33-bis[(4-hydroxyphenyl)methyl]-3-methyl-1,4,7,10,13,16,19,22,25,28,31,34-dodecazacyclohexatriacontane-2,5,8,11,14,17,20,23,26,29,32,35-dodecone	2094819: Binding affinity to recombinant His-tagged human TIM-3 expressed in HEK293 assessed as dissociation constant by SPR analysis	kd	0.3900	uM
8-chloro-9-[4-(1H-imidazol-2-ylmethylamino)-2-methylphenyl]-2-methyl-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one	1785235: Displacement of FITC-labelled SP2 probe from human TIM-3 IgV domain (residues 22 to 130) expressed in Escherichia coli BL21 (DE3) by FPA competition assay	ki	0.4400	uM
N-[4-(8-chloro-2-methyl-5-oxo-6H-[1,2,4]triazolo[1,5-c]quinazolin-9-yl)phenyl]methanesulfonamide	1785235: Displacement of FITC-labelled SP2 probe from human TIM-3 IgV domain (residues 22 to 130) expressed in Escherichia coli BL21 (DE3) by FPA competition assay	ki	0.5000	uM
(3S,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S)-33-benzyl-21-[(2S)-butan-2-yl]-12,27-bis[(1R)-1-hydroxyethyl]-3,6,9,18,30-pentakis(hydroxymethyl)-15,24-bis[(4-hydroxyphenyl)methyl]-1,4,7,10,13,16,19,22,25,28,31,34-dodecazacyclohexatriacontane-2,5,8,11,14,17,20,23,26,29,32,35-dodecone	2094819: Binding affinity to recombinant His-tagged human TIM-3 expressed in HEK293 assessed as dissociation constant by SPR analysis	kd	0.7500	uM
N-[4-(8-chloro-2-methyl-5-oxo-6H-[1,2,4]triazolo[1,5-c]quinazolin-9-yl)-2-methoxyphenyl]methanesulfonamide	1785234: Displacement of FITC-labelled 5-(((8-Chloro-9-(3-methylpyridin-4-yl)-5-oxo-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)methyl)carbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid probe from human TIM-3 IgV domain (residues 22 to 130) expressed in Escherichia coli BL21 (DE3) by FPA competition assay	ki	0.9700	uM
N-(2,5-dimethoxyphenyl)-2-[3-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]phenoxy]acetamide	2011217: Binding affinity to His-tagged recombinant human TIM3 expressed in HEK293 cells assessed as dissociation constant by sensor chip immobilization based SPR analysis	kd	0.9800	uM
N-(4-ethoxyphenyl)-2-[3-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]phenoxy]acetamide	2011217: Binding affinity to His-tagged recombinant human TIM3 expressed in HEK293 cells assessed as dissociation constant by sensor chip immobilization based SPR analysis	kd	1.2800	uM
N-(4-ethoxyphenyl)-2-[3-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]phenoxy]acetamide	2011217: Binding affinity to His-tagged recombinant human TIM3 expressed in HEK293 cells assessed as dissociation constant by sensor chip immobilization based SPR analysis	kd	1.3500	uM
9-(4-amino-2-methylphenyl)-8-chloro-2-methyl-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one	1785234: Displacement of FITC-labelled 5-(((8-Chloro-9-(3-methylpyridin-4-yl)-5-oxo-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)methyl)carbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid probe from human TIM-3 IgV domain (residues 22 to 130) expressed in Escherichia coli BL21 (DE3) by FPA competition assay	ki	1.5000	uM
8-chloro-9-(3-methoxy-4-pyridinyl)-2-methyl-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one	1785234: Displacement of FITC-labelled 5-(((8-Chloro-9-(3-methylpyridin-4-yl)-5-oxo-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)methyl)carbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid probe from human TIM-3 IgV domain (residues 22 to 130) expressed in Escherichia coli BL21 (DE3) by FPA competition assay	ki	1.5000	uM
8-chloro-2-methyl-9-(2-methylphenyl)-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one	1785234: Displacement of FITC-labelled 5-(((8-Chloro-9-(3-methylpyridin-4-yl)-5-oxo-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)methyl)carbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid probe from human TIM-3 IgV domain (residues 22 to 130) expressed in Escherichia coli BL21 (DE3) by FPA competition assay	ki	1.6000	uM
N-(3-methoxyphenyl)-2-[3-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]phenoxy]acetamide	2011217: Binding affinity to His-tagged recombinant human TIM3 expressed in HEK293 cells assessed as dissociation constant by sensor chip immobilization based SPR analysis	kd	1.6300	uM
8-chloro-9-(1H-indol-4-yl)-2-methyl-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one	1785234: Displacement of FITC-labelled 5-(((8-Chloro-9-(3-methylpyridin-4-yl)-5-oxo-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)methyl)carbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid probe from human TIM-3 IgV domain (residues 22 to 130) expressed in Escherichia coli BL21 (DE3) by FPA competition assay	ki	1.8000	uM
(3S,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S)-33-[(2S)-butan-2-yl]-12,27-bis[(1R)-1-hydroxyethyl]-6,9,18,30-tetrakis(hydroxymethyl)-15,24-bis[(4-hydroxyphenyl)methyl]-3-methyl-21-propan-2-yl-1,4,7,10,13,16,19,22,25,28,31,34-dodecazacyclohexatriacontane-2,5,8,11,14,17,20,23,26,29,32,35-dodecone	2094819: Binding affinity to recombinant His-tagged human TIM-3 expressed in HEK293 assessed as dissociation constant by SPR analysis	kd	1.9000	uM
5-[[8-chloro-9-(3-methyl-4-pyridinyl)-5-oxo-6H-[1,2,4]triazolo[1,5-c]quinazolin-2-yl]methylcarbamoyl]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1785232: Binding affinity to human TIM-3 IgV domain (residues 22 to 130) expressed in Escherichia coli BL21 (DE3) by 1H-15N SOFAST-HMQC spectroscopic analysis	kd	2.0000	uM
2-[3-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]phenoxy]-N-pyridin-4-ylacetamide	2011217: Binding affinity to His-tagged recombinant human TIM3 expressed in HEK293 cells assessed as dissociation constant by sensor chip immobilization based SPR analysis	kd	2.0100	uM
8-chloro-2-methyl-9-pyridin-4-yl-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one	1785234: Displacement of FITC-labelled 5-(((8-Chloro-9-(3-methylpyridin-4-yl)-5-oxo-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)methyl)carbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid probe from human TIM-3 IgV domain (residues 22 to 130) expressed in Escherichia coli BL21 (DE3) by FPA competition assay	ki	2.1000	uM
8-chloro-2-methyl-9-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one	1785234: Displacement of FITC-labelled 5-(((8-Chloro-9-(3-methylpyridin-4-yl)-5-oxo-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)methyl)carbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid probe from human TIM-3 IgV domain (residues 22 to 130) expressed in Escherichia coli BL21 (DE3) by FPA competition assay	ki	2.2000	uM
8-chloro-2-methyl-9-(5-methyl-1H-indazol-4-yl)-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one	1785234: Displacement of FITC-labelled 5-(((8-Chloro-9-(3-methylpyridin-4-yl)-5-oxo-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)methyl)carbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid probe from human TIM-3 IgV domain (residues 22 to 130) expressed in Escherichia coli BL21 (DE3) by FPA competition assay	ki	2.3000	uM
2-[3-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]phenoxy]-N-(6-methyl-3-pyridinyl)acetamide	2011217: Binding affinity to His-tagged recombinant human TIM3 expressed in HEK293 cells assessed as dissociation constant by sensor chip immobilization based SPR analysis	kd	2.4700	uM
9-(4-aminophenyl)-8-chloro-2-methyl-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one	1785234: Displacement of FITC-labelled 5-(((8-Chloro-9-(3-methylpyridin-4-yl)-5-oxo-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)methyl)carbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid probe from human TIM-3 IgV domain (residues 22 to 130) expressed in Escherichia coli BL21 (DE3) by FPA competition assay	ki	2.6000	uM
(3S,6S,9S,12R,15S,18S,21S,24S,27R,30S,33S)-21-[(2S)-butan-2-yl]-6,9,18,30-tetrakis(hydroxymethyl)-15,24-bis[(4-hydroxyphenyl)methyl]-33-(1H-imidazol-5-ylmethyl)-3-methyl-12,27-bis(sulfanylmethyl)-1,4,7,10,13,16,19,22,25,28,31,34-dodecazacyclohexatriacontane-2,5,8,11,14,17,20,23,26,29,32,35-dodecone	2094819: Binding affinity to recombinant His-tagged human TIM-3 expressed in HEK293 assessed as dissociation constant by SPR analysis	kd	2.7000	uM
2-[3-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]phenoxy]-N-(3-methylphenyl)acetamide	2011217: Binding affinity to His-tagged recombinant human TIM3 expressed in HEK293 cells assessed as dissociation constant by sensor chip immobilization based SPR analysis	kd	3.1200	uM
(3S,6S,9S,12R,15S,18S,21S,24S,27R,30S,33S)-21-[(2S)-butan-2-yl]-3,6,9,18,30-pentakis(hydroxymethyl)-24-[(4-hydroxyphenyl)methyl]-33-(1H-imidazol-5-ylmethyl)-15-(1H-indol-3-ylmethyl)-12,27-bis(sulfanylmethyl)-1,4,7,10,13,16,19,22,25,28,31,34-dodecazacyclohexatriacontane-2,5,8,11,14,17,20,23,26,29,32,35-dodecone	2094819: Binding affinity to recombinant His-tagged human TIM-3 expressed in HEK293 assessed as dissociation constant by SPR analysis	kd	4.1000	uM
(3S,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S)-21-[(2S)-butan-2-yl]-12,27-bis[(1R)-1-hydroxyethyl]-6,9,18,30-tetrakis(hydroxymethyl)-24,33-bis[(4-hydroxyphenyl)methyl]-15-(1H-imidazol-5-ylmethyl)-3-methyl-1,4,7,10,13,16,19,22,25,28,31,34-dodecazacyclohexatriacontane-2,5,8,11,14,17,20,23,26,29,32,35-dodecone	2094819: Binding affinity to recombinant His-tagged human TIM-3 expressed in HEK293 assessed as dissociation constant by SPR analysis	kd	4.8000	uM
8-chloro-2-methyl-9-(3-methyl-4-pyridinyl)-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one	1785234: Displacement of FITC-labelled 5-(((8-Chloro-9-(3-methylpyridin-4-yl)-5-oxo-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)methyl)carbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid probe from human TIM-3 IgV domain (residues 22 to 130) expressed in Escherichia coli BL21 (DE3) by FPA competition assay	ki	4.9000	uM
N-[3-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]phenyl]-2-(3-methylphenoxy)acetamide	2011217: Binding affinity to His-tagged recombinant human TIM3 expressed in HEK293 cells assessed as dissociation constant by sensor chip immobilization based SPR analysis	kd	6.0400	uM
N-[3-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]phenyl]-2-(2-methylphenoxy)acetamide	2011217: Binding affinity to His-tagged recombinant human TIM3 expressed in HEK293 cells assessed as dissociation constant by sensor chip immobilization based SPR analysis	kd	8.3200	uM
N-[3-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]phenyl]-2-(4-methylphenoxy)acetamide	2011217: Binding affinity to His-tagged recombinant human TIM3 expressed in HEK293 cells assessed as dissociation constant by sensor chip immobilization based SPR analysis	kd	9.4500	uM
(4R,7S,10S,13S,16S,19S,25S,28S,31S,34S,37S,40S,43S,46R)-46-amino-7-[(2S)-butan-2-yl]-13,37-bis[(1R)-1-hydroxyethyl]-16,25,28,31,34,43-hexakis(hydroxymethyl)-10,19,40-tris[(4-hydroxyphenyl)methyl]-6,9,12,15,18,21,24,27,30,33,36,39,42,45-tetradecaoxo-1,2-dithia-5,8,11,14,17,20,23,26,29,32,35,38,41,44-tetradecazacycloheptatetracontane-4-carboxylic acid	2094819: Binding affinity to recombinant His-tagged human TIM-3 expressed in HEK293 assessed as dissociation constant by SPR analysis	kd	9.7000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation	2
Silicon Dioxide	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
quercitrin	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
sodium arsenite	increases expression	1
butylbenzyl phthalate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
Arsenic Trioxide	increases expression	1
Glyphosate	affects methylation	1
Air Pollutants	affects methylation, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Calcitriol	decreases expression	1
Estradiol	affects binding, increases reaction, affects expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression	1
Nickel	decreases expression	1
Nitrogen Dioxide	increases abundance, affects methylation	1
Phthalic Acids	increases methylation	1
Tobacco Smoke Pollution	increases methylation	1
Tretinoin	increases expression	1
Aflatoxin B1	decreases methylation	1
Medroxyprogesterone Acetate	increases expression	1
Antirheumatic Agents	decreases expression	1
Thapsigargin	increases expression	1

ChEMBL screening assays

13 unique, capped per target: 13 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4677432	Binding	Binding affinity to human Fc-tagged TIM3 at 500 nM measured after 600 sec by biolayer interferometry	Design, Synthesis, and Biological Evaluation of Linear Aliphatic Amine-Linked Triaryl Derivatives as Potent Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction with Promising Antitumor Effects In Vivo. — J Med Chem

Cellosaurus cell lines

7 cell lines: 3 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_B8H5	Abcam HCT 116 HAVCR2 KO	Cancer cell line	Male
CVCL_B9JF	Abcam A-549 HAVCR2 KO	Cancer cell line	Male
CVCL_D2FH	Abcam MCF-7 HAVCR2 KO	Cancer cell line	Female
CVCL_D7BW	Abeomics CHO-K1 TIM-3	Spontaneously immortalized cell line	Female
CVCL_E6QP	Genomeditech CHO-K1 H_HAVCR2(TIM3)	Spontaneously immortalized cell line	Female
CVCL_KA45	CHO-K1/Tim3	Spontaneously immortalized cell line	Female
CVCL_UE51	293T human TIM3	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01746992	PHASE4	UNKNOWN	CTOP/ITE/MTX Compared With CHOP as the First-line Therapy for Newly Diagnosed Young Patients With T Cell Lymphoma
NCT02533700	PHASE2	UNKNOWN	CEOP/IVE/GDP Compared With CEOP as the First-line Therapy for Newly Diagnosed Adult Patients With PTCL
NCT04795869	PHASE2	WITHDRAWN	Brentuximab Vedotin and Pembrolizumab in Treating Patients With Recurrent Peripheral T-Cell Lymphoma
NCT01445535	PHASE1	COMPLETED	Phase 1 Trial of Siplizumab and Dose-Adjusted EPOCH-Rituximab in T- and NK-Cell Lymphomas
NCT03598998	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Pembrolizumab and Pralatrexate in Treating Patients With Relapsed or Refractory Peripheral T-Cell Lymphomas
NCT05475925	PHASE1/PHASE2	RECRUITING	A Study of DR-01 in Subjects With Large Granular Lymphocytic Leukemia or Cytotoxic Lymphomas
NCT01787409	Not specified	ACTIVE_NOT_RECRUITING	Cholecalciferol in Improving Survival in Patients With Newly Diagnosed Cancer With Vitamin D Insufficiency
NCT02652715	Not specified	COMPLETED	Salvia Hispanica Seed in Reducing Risk of Disease Recurrence in Patients With Non-Hodgkin Lymphoma
NCT05978141	Not specified	RECRUITING	A Registry for People With T-cell Lymphoma