LAG3

Summary

LAG3 (lymphocyte activating 3, HGNC:6476) is a protein-coding gene on chromosome 12p13.31, encoding Lymphocyte activation gene 3 protein (P18627). Inhibitory receptor on antigen activated T-cells.

Lymphocyte-activation protein 3 belongs to Ig superfamily and contains 4 extracellular Ig-like domains. The LAG3 gene contains 8 exons. The sequence data, exon/intron organization, and chromosomal localization all indicate a close relationship of LAG3 to CD4.

Source: NCBI Gene 3902 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 120 total
• Druggable target: yes
• MANE Select transcript: NM_002286

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6476
Approved symbol	LAG3
Name	lymphocyte activating 3
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Aliases	CD223
Ensembl gene	ENSG00000089692
Ensembl biotype	protein_coding
OMIM	153337
Entrez	3902

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 retained_intron

ENST00000203629, ENST00000441671, ENST00000538079, ENST00000541049, ENST00000851036, ENST00000887797, ENST00000887798

RefSeq mRNA: 3 — MANE Select: NM_002286 NM_001414176, NM_001414177, NM_002286

CCDS: CCDS8561

Canonical transcript exons

ENST00000203629 — 8 exons

Exon	Start	End
ENSE00000715723	6777791	6777921
ENSE00001293817	6778244	6778455
ENSE00002235644	6772520	6772910
ENSE00003551214	6777264	6777506
ENSE00003565172	6774595	6774864
ENSE00003642201	6775273	6775548
ENSE00004283503	6773192	6773339
ENSE00004283504	6773697	6774001

Expression profiles

Bgee: expression breadth ubiquitous, 161 present calls, max score 88.62.

FANTOM5 (CAGE): breadth broad, TPM avg 2.5021 / max 210.5347, expressed in 270 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
123742	2.5021	270

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	88.62	gold quality
right ovary	UBERON:0002118	86.20	gold quality
left ovary	UBERON:0002119	85.02	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.76	gold quality
spleen	UBERON:0002106	82.88	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.11	gold quality
right lobe of liver	UBERON:0001114	78.61	gold quality
ovary	UBERON:0000992	77.86	gold quality
body of uterus	UBERON:0009853	77.60	gold quality
left uterine tube	UBERON:0001303	77.56	gold quality
lymph node	UBERON:0000029	77.48	gold quality
small intestine Peyer’s patch	UBERON:0003454	75.58	gold quality
vermiform appendix	UBERON:0001154	75.37	gold quality
muscle layer of sigmoid colon	UBERON:0035805	74.14	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	72.45	gold quality
small intestine	UBERON:0002108	72.24	gold quality
lower esophagus mucosa	UBERON:0035834	71.67	gold quality
mucosa of stomach	UBERON:0001199	71.11	gold quality
endometrium epithelium	UBERON:0004811	70.75	gold quality
lower esophagus muscularis layer	UBERON:0035833	70.64	gold quality
lower esophagus	UBERON:0013473	70.63	gold quality
mucosa of transverse colon	UBERON:0004991	69.58	gold quality
caecum	UBERON:0001153	69.45	gold quality
transverse colon	UBERON:0001157	69.34	gold quality
tendon of biceps brachii	UBERON:0008188	69.24	gold quality
omental fat pad	UBERON:0010414	69.14	gold quality
peritoneum	UBERON:0002358	69.06	gold quality
ectocervix	UBERON:0012249	68.92	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	68.69	gold quality
upper lobe of left lung	UBERON:0008952	68.66	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6505	yes	2664.31
E-CURD-95	yes	854.82
E-HCAD-8	yes	695.80
E-CURD-97	yes	582.83
E-ANND-3	yes	3.92
E-CURD-11	no	3.40

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 40)

• MHC class II-mediated signals induced by the natural ligand, LAG-3, lead to complete maturation of monocyte-derived dendritic cells, which acquire the capacity to trigger naive T cells and drive polarized Th1 responses. (PMID:11937541)
• LAG-3 induces rapid protein phosphorylation of phospholipase Cgamma2 and p72syk as well as activation of phosphatidyl inositol 3-kinase/Akt, p42/44 extracellular signal-regulated protein kinase, and p38 mitogen-activated protein kinase pathways. (PMID:12775570)
• LAG3 may mediate sphingolipid metabolism (PMID:12825348)
• LAG-3 activates antigen-presenting cells through MHC class II signalling, leading to increased antigen-specific T-cell responses in vivo. (PMID:14644131)
• regulatory T cells and LAG-3 have pivotal roles in the suppression of EBV-specific cell-mediated immunity in Hodgkin lymphoma (PMID:16757686)
• The result, including a total of 2640 MS patients and 2194 controls shows no significant association with CD4 and LAG3 and MS. We conclude that these genes are of minor importance in regard of genetic predisposition to the MS. (PMID:17020785)
• Soluble human recombinant fusion protein (hLAG-3Ig) used in vitro as a single maturation agent induces phenotypic maturation of monocyte-derived dendritic cells and promotes the production of chemokines and TNF-alpha inflammatory cytokine. (PMID:18322184)
• Analysis identified a gene-set (LAG3, LPL, ZAP70) whose overexpression is assigned to unmutated immunoglobulin variable heavy chain region with 90% specificity. (PMID:20228263)
• Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. (PMID:20385810)
• LAG-3 defines an active CD4(+)CD25(high)Foxp3(+) regulatory T cell subset whose frequency is enhanced in the PBMCs of patients with cancer (PMID:20421648)
• Multiple myeloma was associated with 2 SNPs in intron regions of LAG3 within 20 k base pairs 5’ upstream of the candidate CD4 gene. The variant in LAG3 gene itself may play a role in susceptibility of MM. (PMID:20568250)
• our data suggest that the LAG-3-MHC II interaction could be viewed as a bidirectional immune escape pathway in melanoma (PMID:21441454)
• Expression of LAG-3 is coincident with the impaired effector function of HBV-specific CD8(+) T cell in HCC patients. (PMID:23261718)
• These results suggest that LAG-3-mediated activation of plasmacytoid dendritic cells takes place in vivo at tumor sites, and it is in part responsible for directing an immune-suppressive environment. (PMID:24441096)
• NFKB1, CD27, LAG3 and IKZF3 are new susceptibility genes for psoriasis. (PMID:25006012)
• LAG-3 trafficking from lysosomal compartments to the cell surface is dependent on the cytoplasmic domain through protein kinase C signaling in activated T cells. (PMID:25108024)
• The elevated expression of LAG-3 at the genital tract suggests it may regulate T-cell activation, and identify cells susceptible to HIV infection. The enrichment of LAG-3 on double negative T cells suggests LAG-3 may contribute to the immunoregulatory activity of these cells. (PMID:25154740)
• the LAG-3/MHC class II pathway may synergize with PD-1/PD ligand to enhance T cell-mediated immune responses. (PMID:25780040)
• iNKT cytokine production is profoundly altered by both HIV infection and treatment, and LAG-3, but not PD-1, expression is associated with a reduction in iNKT IFNgamma production. (PMID:25810006)
• An IL-27/Lag3 axis enhances Foxp3+ regulatory T cell-suppressive function and therapeutic efficacy. (PMID:26013006)
• Data indicate that in recurrent spontaneous abortion patients, the expression levels of CD49b and LAG-3 (CD223) on CD14(+) mononuclear cells and the plasma level of transforming growth factor beta (TGF-beta) decreased obviously compared with normal females. (PMID:26927558)
• LAG-3 is highly expressed in peripheral blood CD8+ T cells in chronic HBV-infected patients. (PMID:27053622)
• the upregulation of others syncytial molecules, including LAG3, CTLA4, CD28 and CD3, assisting the formation of syncytia with APC cells. (PMID:27108398)
• this study shows that LAG3 expressed on myeloid leukaemia cells possess the capacity to facilitate functional exhaustion in T helper cells (PMID:27565576)
• LAG3 binds alpha-synuclein preformed fibrils (PFF) with high affinity (dissociation constant = 77 nanomolar), whereas the alpha-syn monomer exhibited minimal binding. alpha-Syn-biotin PFF binding to LAG3 initiated alpha-syn PFF endocytosis, transmission, and toxicity. (PMID:27708076)
• Squamous cell carcinomas escape immune surveillance via inducing chronic activation and exhaustion of CD8+ T Cells co-expressing PD-1 and LAG-3 inhibitory receptors. (PMID:27835902)
• our data indicate that the evaluation of stromal TILs remains the most reliable immune prognostic marker in TNBC, and support the clinical evaluation of anti-PD-1/PD-L1 and anti-LAG-3 in a subset of patients with TNBC who have concurrent expression of both checkpoint receptors. (PMID:27912781)
• epigenetic modification on LAG-3 increased LAG-3(+) T cells and its immune regulatory roles in chronic osteomyelitis progression (PMID:28028751)
• Egr2-driven cell surface proteins LAG-3 and 4-1BB can identify dysfunctional tumor antigen-specific CD8(+) TIL. (PMID:28115575)
• LAG-3 expression was correlated with expression of PD-1 on TILs and expression of PD-L1 on tumor cells. Higher expression of LAG-3 on TILs was significantly correlated with higher expression of PD-1 on TILs and higher expression of PD-L1 on tumor cells. (PMID:28132868)
• Data suggest that blocking LAG3-MHC class II interactions is a potential therapeutic target in chronic lymphocytic leukemia. (PMID:28154084)
• this review provides the translational rationale for targeting LAG3, as well as historical and current state of clinical trials utilizing LAG3 cancer immunomodulators (PMID:28258692)
• Immune checkpoint proteins are co-inhibitory factors that can diminish the antigen-specific immune responses by attenuating the regulatory role of cytotoxic T-lymphocyte-associated protein 4, programmed cell death-1, lymphocyte-activation gene 3, and T-cell immunoglobulin mucin-3. (PMID:28349816)
• Overexpression of lymphocyte activation gene-3 inhibits regulatory T cell responses in osteoarthritis (PMID:28800255)
• LAG3-expressing CD4(+)CD25(-) T cells represent another regulatory immune cell type with potential to interfere with anti-tumor immunity. (PMID:28935468)
• LAG-3+ iTILs are enriched in estrogen receptor-negative breast cancers and represent an independent favorable prognostic factor. In addition, a high proportion of PD-1/PD-L1+ tumors are co-infiltrated with LAG-3+ TILs. (PMID:29045526)
• Among the 89 patients, CD274, LAG3, and IDO1 expressions in TIICs were observed in 68.6% (61 cases), 13.5% (12), and 28.1% (25) of patients, respectively. CD274, CTLA4, and IDO1 were expressed in tumor cells of 24.7% (22 cases), 4.5% (4), and 72.0% (64) of patients, respectively. (PMID:29520442)
• These results together suggested that LAG-3 is a marker of CD4(+) T cells with regulatory function; at the same time, LAG-3 might have limited the full suppressive potential of Treg cells. (PMID:29671649)
• This study identify LAG3 genes with expression patterns that are highly significant predictors of regional brain atrophy. (PMID:29868450)
• Co-expression of LAG3 and TIM3 identifies a potent Treg population that suppresses macrophage functions in colorectal cancer patients (PMID:29905955)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	zmp:0000000936	ENSDARG00000088672
danio_rerio		ENSDARG00000090844
mus_musculus	Lag3	ENSMUSG00000030124
rattus_norvegicus	Lag3	ENSRNOG00000021334

Paralogs (10): IL1R2 (ENSG00000115590), IL1R1 (ENSG00000115594), IL1RL2 (ENSG00000115598), IL1RL1 (ENSG00000115602), IL18R1 (ENSG00000115604), IL18RAP (ENSG00000115607), IL1RAPL1 (ENSG00000169306), SIGIRR (ENSG00000185187), IL1RAPL2 (ENSG00000189108), IL1RAP (ENSG00000196083)

Protein

Protein identifiers

Lymphocyte activation gene 3 protein — P18627 (reviewed: P18627)

All UniProt accessions (1): P18627

UniProt curated annotations — full annotation on UniProt →

Function. Inhibitory receptor on antigen activated T-cells. Delivers inhibitory signals upon binding to ligands, such as MHC class II, its main ligand present at the surface of antigen-presenting cells (APCs), and FGL1, which is secreted by hepatocytes and certain types of tumor cells. Ligand-binding initiates a signaling that inhibits the T-cell receptor (TCR) in the immunological synapse, preventing T-cell activation. Mechanistically, ligand-binding promotes (1) ubiquitination of the KIEELE motif, unleashing the RRFSALE motif from the membrane and (2) leading to the formation of condensates with the TCR component CD3E, thereby disrupting the association between CD3E and LCK and preventing TCR activation. May inhibit antigen-specific T-cell activation in synergy with PDCD1/PD-1. Negatively regulates the proliferation, activation, effector function and homeostasis of both CD8(+) and CD4(+) T-cells. Also mediates immune tolerance: constitutively expressed on a subset of regulatory T-cells (Tregs) and contributes to their suppressive function. Also acts as a negative regulator of plasmacytoid dendritic cell (pDCs) activation. The LAG3-mediated inhibitory pathway is exploited by tumors to attenuate anti-tumor immunity and escape destruction by the immune system, thereby facilitating tumor survival. The blockage of the LAG3- and PDCD1-mediated pathways results in the reversal of the exhausted T-cell phenotype and the normalization of the anti-tumor response, providing a rationale for cancer immunotherapy. May function as a ligand for MHC class II (MHC-II) on antigen-presenting cells (APC), promoting APC activation/maturation and driving Th1 immune response.

Subunit / interactions. Homodimer; laterally engages two MHC class II molecules. Interacts with CD3E; disrupting the association between CD3E and LCK, thereby preventing TCR activation.

Subcellular location. Cell membrane Secreted.

Tissue specificity. Primarily expressed in activated T-cells and a subset of natural killer (NK) cells.

Post-translational modifications. Ubiquitinated by CBL and CBLB in response to ligand-binding, initiating a signaling that prevents TCR activation: ubiquitination at Lys-498 via ‘Lys-63’-linked ubiquitin chains unleashes the RRFSALE motif from the membrane. MHC class II and membrane-bound FGL1 promote ubiquitination by CBL and CBLB; in contrast secreted FGL1 is not able to trigger LAG3 ubiquitination. Proteolytically cleaved by ADAM10 and ADAM17 within the connecting peptide region, leading to release of Secreted lymphocyte activation gene 3 protein (sLAG-3). ADAM10 mediates constitutive cleavage, but cleavage increases following T-cell activation, whereas shedding by ADAM17 is induced by TCR signaling in a PRKCQ-dependent manner.

Activity regulation. Inhibited by relatlimab, a monoclonal antibody, which shows clinical efficacy in the treatment of cancers. Relatlimab prevents ubiquitination by CBL or CBLB and activation. Inhibited by favezelimab, a therapeutic antibody.

Domain organisation. The KIEELE motif is essential for TCR inhibition. Its ubiquitination by CBL and CBLB unleashes the RRFSALE motif from the membrane, initiating a signaling that prevents TCR activation. The RRFSALE motif is essential for TCR inhibition. In absence of ligand, the RRFSALE motif associates with the membrane; ligand-binding and subsequent ubiquitination unleashes the motif, initiating a signaling that prevents TCR activation.

Induction. Expression is induced by interleukin-2 (IL2), interleukin-7 (IL7) and interleukin-12 (IL12A and IL12B) on activated T-cells.

Similarity. Belongs to the LAG3 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P18627-1	1	yes
P18627-2	2

RefSeq proteins (3): NP_001401105, NP_001401106, NP_002277* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015621	IL-1_rcpt_fam	Family
IPR036179	Ig-like_dom_sf	Homologous_superfamily

UniProt features (77 total): mutagenesis site 31, strand 12, region of interest 5, glycosylation site 4, disulfide bond 4, domain 4, chain 2, short sequence motif 2, compositionally biased region 2, splice variant 2, topological domain 2, helix 2, signal peptide 1, cross-link 1, sequence variant 1, transmembrane region 1, turn 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
7UM3	X-RAY DIFFRACTION	2.4
7TZH	X-RAY DIFFRACTION	2.43
9BF9	X-RAY DIFFRACTION	3.4
8SR0	ELECTRON MICROSCOPY	3.53
8SO3	ELECTRON MICROSCOPY	3.61
7TZG	X-RAY DIFFRACTION	3.71

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P18627-F1	78.64	0.48

Antibody-complex structures (SAbDab): 5 — 7TZG, 7TZH, 7UM3, 8SO3, 8SR0

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): 498

Disulfide bonds (4): 44–160, 189–241, 282–333, 369–412

Glycosylation sites (4): 188, 250, 256, 343

Mutagenesis-validated functional residues (31):

Position	Phenotype
35	does not affect binding to mhc class ii (mhc-ii).
52	reduced binding to mhc class ii (mhc-ii).
78	reduced binding to mhc class ii (mhc-ii).
78	does not significantly affect binding to mhc class ii (mhc-ii).
85	does not affect binding to mhc class ii (mhc-ii).
95	increased binding to mhc class ii (mhc-ii).
97	increased binding to mhc class ii (mhc-ii).
98	increased binding to mhc class ii (mhc-ii).
99	abolishes binding to mhc class ii (mhc-ii) without affecting interaction with fgl1.
104	decreased binding to fgl1.
110	reduced binding to mhc class ii (mhc-ii).
113	decreased binding to fgl1.
117	decreased binding to fgl1.
120	decreased binding to fgl1.
125	reduced binding to mhc class ii (mhc-ii).
129	does not affect binding to mhc class ii (mhc-ii).
131	reduced binding to mhc class ii (mhc-ii).
137	reduced binding to mhc class ii (mhc-ii).
155–156	slightly affects binding to mhc class ii (mhc-ii).
219–220	decreased binding to fgl1.
225–226	decreased binding to fgl1.
228–229	decreased binding to fgl1.
244–245	decreased binding to fgl1.
247	does not affect binding to mhc class ii (mhc-ii).
250–252	decreased binding to fgl1.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2132295	MHC class II antigen presentation
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 301 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, LFA1_Q6, MODULE_522, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_MEDIATED_IMMUNITY, MODULE_64, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOCC_CELL_SURFACE, MODULE_128

GO Biological Process (14): adaptive immune response (GO:0002250), plasmacytoid dendritic cell activation (GO:0002270), negative regulation of T cell mediated immune response to tumor cell (GO:0002841), cell surface receptor signaling pathway (GO:0007166), negative regulation of interleukin-2 production (GO:0032703), T cell activation (GO:0042110), natural killer cell mediated cytotoxicity (GO:0042267), innate immune response (GO:0045087), negative regulation of regulatory T cell differentiation (GO:0045590), positive regulation of natural killer cell mediated cytotoxicity (GO:0045954), regulation of immune response (GO:0050776), negative regulation of T cell receptor signaling pathway (GO:0050860), negative regulation of T cell activation (GO:0050868), immune system process (GO:0002376)

GO Molecular Function (4): antigen binding (GO:0003823), transmembrane signaling receptor activity (GO:0004888), MHC class II protein binding (GO:0042289), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), 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
immune response	3
cellular anatomical structure	3
binding	2
leukocyte activation	1
T cell mediated immune response to tumor cell	1
negative regulation of T cell mediated immunity	1
negative regulation of immune response to tumor cell	1
regulation of T cell mediated immune response to tumor cell	1
signal transduction	1
negative regulation of cytokine production	1
interleukin-2 production	1
regulation of interleukin-2 production	1
lymphocyte activation	1
leukocyte mediated cytotoxicity	1
natural killer cell mediated immunity	1
defense response to symbiont	1
regulatory T cell differentiation	1
negative regulation of T cell differentiation	1
regulation of regulatory T cell differentiation	1
positive regulation of leukocyte mediated cytotoxicity	1
positive regulation of natural killer cell mediated immunity	1
natural killer cell mediated cytotoxicity	1
regulation of natural killer cell mediated cytotoxicity	1
regulation of immune system process	1
regulation of response to stimulus	1
T cell receptor signaling pathway	1
regulation of T cell receptor signaling pathway	1
negative regulation of antigen receptor-mediated signaling pathway	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
biological_process	1
signaling receptor activity	1
MHC protein binding	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1

Protein interactions and networks

STRING

2448 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LAG3	LGALS9	O00182	993
LAG3	CLEC4G	Q6UXB4	992
LAG3	FGL1	Q08830	991
LAG3	LGALS9B	Q3B8N2	991
LAG3	LGALS9C	Q6DKI2	991
LAG3	LGALS3	P17931	990
LAG3	CD80	P33681	989
LAG3	CD86	P42081	979
LAG3	CD274	Q9NZQ7	975
LAG3	CTLA4	P16410	956
LAG3	PDCD1	Q15116	930
LAG3	TIGIT	Q495A1	924
LAG3	HAVCR2	Q8TDQ0	915
LAG3	CD8A	P01732	907
LAG3	SNCA	P37840	906

IntAct

11 interactions, top by confidence:

A	B	Type	Score
LAG3	FGL1	psi-mi:“MI:0915”(physical association)	0.540
LAG3	FGL1	psi-mi:“MI:0407”(direct interaction)	0.540
LAG3	Fgl1	psi-mi:“MI:0915”(physical association)	0.400
M		psi-mi:“MI:0914”(association)	0.350
LAG3	PCDH7	psi-mi:“MI:0914”(association)	0.350
	LAG3	psi-mi:“MI:0915”(physical association)	0.000
LAG3	groEL	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (15): C1QL1 (Affinity Capture-MS), PCDH20 (Affinity Capture-MS), ITIH2 (Affinity Capture-MS), FBXO2 (Affinity Capture-MS), FREM2 (Affinity Capture-MS), SNX18 (Affinity Capture-MS), HLA-DPA1 (Affinity Capture-MS), FBXO11 (Affinity Capture-MS), FAT1 (Affinity Capture-MS), CELSR1 (Affinity Capture-MS), GPR98 (Affinity Capture-MS), CELSR2 (Affinity Capture-MS), PCDH7 (Affinity Capture-MS), LAG3 (Affinity Capture-MS), SNCA (Affinity Capture-Western)

ESM2 similar proteins: A0A140LHF2, A0EQL2, D3YZF7, D7PDD4, O15533, O55237, O70394, O70540, O95866, P04278, P05111, P07994, P08689, P0C6B3, P0DP72, P15196, P17490, P18627, P40238, P55101, P60882, P97497, Q00657, Q08351, Q14393, Q14773, Q16671, Q3SWY4, Q5BK54, Q5NKT8, Q5TJE4, Q61790, Q61826, Q62588, Q6PZD2, Q6UVK1, Q6UWB1, Q7Z7M0, Q7Z7M1, Q86VR7

Diamond homologs: P18627, Q5BK54, Q61790, P27930, P43303, Q29612

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
LAG3	“down-regulates activity”	“Class II MHC:Antigen”	binding
LAG3	up-regulates	“T cell exhaustion”

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	102
Likely benign	11
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

918 predictions. Top by Δscore:

Variant	Effect	Δscore
12:6775506:G:GT	donor_gain	1.0000
12:6777410:G:GT	donor_gain	1.0000
12:6773953:G:T	donor_gain	0.9900
12:6774002:G:GG	donor_gain	0.9900
12:6774591:ACAGT:A	acceptor_gain	0.9900
12:6774592:C:G	acceptor_gain	0.9900
12:6774593:A:AG	acceptor_gain	0.9900
12:6774594:G:GG	acceptor_gain	0.9900
12:6774751:A:T	donor_gain	0.9900
12:6775269:TCA:T	acceptor_loss	0.9900
12:6775270:CAG:C	acceptor_loss	0.9900
12:6775271:A:AG	acceptor_gain	0.9900
12:6775271:A:C	acceptor_loss	0.9900
12:6775272:G:GC	acceptor_gain	0.9900
12:6775272:GGT:G	acceptor_gain	0.9900
12:6775272:GGTCT:G	acceptor_gain	0.9900
12:6775455:G:GT	donor_gain	0.9900
12:6775507:A:T	donor_gain	0.9900
12:6775545:ACAG:A	donor_loss	0.9900
12:6775546:CAGG:C	donor_loss	0.9900
12:6775549:G:C	donor_loss	0.9900
12:6775550:T:C	donor_loss	0.9900
12:6777785:CCATA:C	acceptor_loss	0.9900
12:6777786:CATAG:C	acceptor_loss	0.9900
12:6777788:TAGGT:T	acceptor_loss	0.9900
12:6777789:A:AG	acceptor_gain	0.9900
12:6777789:AGG:A	acceptor_loss	0.9900
12:6777790:G:GG	acceptor_gain	0.9900
12:6777790:GGT:G	acceptor_gain	0.9900
12:6777881:T:TA	acceptor_gain	0.9900

AlphaMissense

3327 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:6773322:G:C	W63C	0.997
12:6773322:G:T	W63C	0.997
12:6773930:A:G	Y147C	0.997
12:6773929:T:C	Y147H	0.995
12:6773232:G:C	W33C	0.994
12:6773232:G:T	W33C	0.994
12:6775385:G:C	W298C	0.994
12:6775385:G:T	W298C	0.994
12:6774800:G:C	W239C	0.993
12:6774800:G:T	W239C	0.993
12:6773930:A:C	Y147S	0.992
12:6775383:T:A	W298R	0.992
12:6775383:T:C	W298R	0.992
12:6773929:T:G	Y147D	0.991
12:6774689:G:C	W202C	0.991
12:6774689:G:T	W202C	0.991
12:6773320:T:A	W63R	0.988
12:6773320:T:C	W63R	0.988
12:6774643:T:C	L187S	0.988
12:6774654:T:C	F191L	0.988
12:6774656:C:A	F191L	0.988
12:6774656:C:G	F191L	0.988
12:6774687:T:A	W202R	0.988
12:6774687:T:C	W202R	0.988
12:6774804:T:A	C241S	0.988
12:6774805:G:C	C241S	0.988
12:6773923:G:T	G145C	0.987
12:6774650:C:G	C189W	0.987
12:6774649:G:A	C189Y	0.986
12:6774648:T:C	C189R	0.985

dbSNP variants (sampled 300 via entrez): RS1000009184 (12:6772489 G>A), RS1000012718 (12:6777672 T>C), RS1003580236 (12:6771452 T>C), RS1003858223 (12:6777167 C>T), RS1003991491 (12:6773777 C>G,T), RS1004186096 (12:6771123 G>C), RS1004292186 (12:6776829 G>T), RS1005044518 (12:6771769 A>T), RS1005549944 (12:6774247 C>T), RS1005675990 (12:6774279 G>A,T), RS1005883967 (12:6773136 T>TA), RS1007534973 (12:6773813 G>A), RS1007982032 (12:6770617 C>T), RS1008173716 (12:6773513 G>A,C), RS1008903011 (12:6774163 T>C,G)

Disease associations

OMIM: gene MIM:153337 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006585_1705	Blood protein levels	4.000000e-10
GCST006585_2231	Blood protein levels	3.000000e-09

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630881 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — CD molecules

ChEMBL bioactivities

7 potent at pChembl≥5 of 7 total, top 7 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.91	Kd	1230	nM	CHEMBL6168500
5.74	Kd	1810	nM	CHEMBL6142103
5.58	Kd	2660	nM	CHEMBL6133623
5.53	Kd	2940	nM	CHEMBL6172828
5.23	Kd	5830	nM	CHEMBL6172828
5.07	Kd	8570	nM	CHEMBL6168500
5.00	Kd	9940	nM	CHEMBL6091788

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cisplatin	affects expression, decreases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
arsenite	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	decreases expression	1
licochalcone B	increases expression	1
gardiquimod	increases expression, decreases reaction	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Decitabine	affects expression	1
Arsenic	affects expression	1
Benzo(a)pyrene	increases methylation	1
Diethylhexyl Phthalate	decreases expression	1
Formaldehyde	increases expression	1
Nickel	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Antirheumatic Agents	decreases expression	1
Copper Sulfate	increases expression	1
Acrylamide	increases expression	1
Protein Kinase Inhibitors	decreases reaction, increases expression	1

ChEMBL screening assays

15 unique, capped per target: 15 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4677430	Binding	Binding affinity to human Fc-tagged LAG3 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

4 cell lines: 2 spontaneously immortalized cell line, 1 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A8AA	Raji-hLAG3	Cancer cell line	Male
CVCL_E6QX	Genomeditech CHO-K1 H_LAG3	Spontaneously immortalized cell line	Female
CVCL_KA40	CHO-K1/Lag3	Spontaneously immortalized cell line	Female
CVCL_UE42	293T human LAG3	Transformed cell line	Female

Clinical trials (associated diseases)

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