CLEC12A

Summary

CLEC12A (C-type lectin domain family 12 member A, HGNC:31713) is a protein-coding gene on chromosome 12p13.31, encoding C-type lectin domain family 12 member A (Q5QGZ9). Myeloid inhibitory C-type lectin receptor that acts as a negative regulator of myeloid cell activation.

This gene encodes a member of the C-type lectin/C-type lectin-like domain (CTL/CTLD) superfamily. Members of this family share a common protein fold and have diverse functions, such as cell adhesion, cell-cell signaling, glycoprotein turnover, and roles in inflammation and immune response. The protein encoded by this gene is a negative regulator of granulocyte and monocyte function. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. This gene is closely linked to other CTL/CTLD superfamily members in the natural killer gene complex region on chromosome 12p13.

Source: NCBI Gene 160364 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 105 total
• MANE Select transcript: NM_138337

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:31713
Approved symbol	CLEC12A
Name	C-type lectin domain family 12 member A
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Aliases	CLL-1, MICL, CD371, DCAL-2
Ensembl gene	ENSG00000172322
Ensembl biotype	protein_coding
OMIM	612088
Entrez	160364

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 retained_intron

ENST00000304361, ENST00000350667, ENST00000355690, ENST00000396507, ENST00000434319, ENST00000449959, ENST00000543839

RefSeq mRNA: 4 — MANE Select: NM_138337 NM_001207010, NM_001300730, NM_138337, NM_201623

CCDS: CCDS55803, CCDS73442, CCDS8608, CCDS8609

Canonical transcript exons

ENST00000304361 — 6 exons

Exon	Start	End
ENSE00001180024	9984870	9985595
ENSE00001611301	9979336	9979524
ENSE00001703826	9978966	9979064
ENSE00002304425	9971409	9971687
ENSE00003534677	9980582	9980733
ENSE00003560082	9982020	9982129

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 99.34.

FANTOM5 (CAGE): breadth broad, TPM avg 10.8592 / max 1348.1054, expressed in 313 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
124110	9.1710	290
124107	0.7448	53
124112	0.4181	92
124111	0.2705	72
124105	0.0660	25
124108	0.0557	16
124104	0.0546	27
124109	0.0536	19
124106	0.0249	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.34	gold quality
leukocyte	CL:0000738	99.20	gold quality
granulocyte	CL:0000094	96.57	gold quality
bone marrow	UBERON:0002371	94.80	gold quality
trabecular bone tissue	UBERON:0002483	94.73	gold quality
blood	UBERON:0000178	93.65	gold quality
bone marrow cell	CL:0002092	92.85	gold quality
spleen	UBERON:0002106	87.20	gold quality
vermiform appendix	UBERON:0001154	86.95	gold quality
right lung	UBERON:0002167	86.62	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.37	gold quality
upper lobe of left lung	UBERON:0008952	81.94	gold quality
upper lobe of lung	UBERON:0008948	80.73	gold quality
mucosa of stomach	UBERON:0001199	77.94	gold quality
caecum	UBERON:0001153	76.99	gold quality
lung	UBERON:0002048	76.89	gold quality
sural nerve	UBERON:0015488	76.64	gold quality
smooth muscle tissue	UBERON:0001135	76.38	gold quality
gall bladder	UBERON:0002110	75.25	gold quality
lymph node	UBERON:0000029	73.38	gold quality
right coronary artery	UBERON:0001625	73.02	gold quality
rectum	UBERON:0001052	72.56	gold quality
visceral pleura	UBERON:0002401	69.84	gold quality
omental fat pad	UBERON:0010414	69.13	gold quality
peritoneum	UBERON:0002358	69.06	gold quality
tibial nerve	UBERON:0001323	68.94	gold quality
subcutaneous adipose tissue	UBERON:0002190	68.94	gold quality
adipose tissue of abdominal region	UBERON:0007808	68.90	gold quality
calcaneal tendon	UBERON:0003701	67.91	gold quality
lower lobe of lung	UBERON:0008949	66.97	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	33.18
E-MTAB-9221	yes	26.00
E-MTAB-6678	yes	22.84
E-ANND-3	yes	14.74

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

34 targeting CLEC12A, 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-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-3128	99.50	67.85	1258
HSA-MIR-2392	99.43	67.50	708
HSA-MIR-452-3P	99.01	66.25	1241
HSA-MIR-7851-3P	98.72	64.88	980
HSA-MIR-619-3P	98.38	65.58	693
HSA-MIR-1302	97.92	67.27	844
HSA-MIR-4799-3P	97.78	65.97	893
HSA-MIR-483-3P	97.77	64.95	731
HSA-MIR-1972	97.67	67.38	1172
HSA-MIR-4720-5P	97.46	65.67	893
HSA-MIR-5588-5P	97.46	65.70	913
HSA-MIR-3157-5P	97.41	67.61	998

Literature-anchored findings (GeneRIF, showing 39)

• MICL is a negative regulator of granulocyte and monocyte function (PMID:14739280)
• the molecular cloning, tissue distribution, and functional characterization of a novel NK cell receptor, KLRL1, from human and mouse dendritic cells [KLRL1] (PMID:15238421)
• Expression cloning identified the antigen recognized as C-type lectin-like molecule-1, a previously undescribed transmembrane glycoprotein (PMID:15548716)
• Dendritic-cell (DC)-associated C-type lectin receptors (CLRs) take up antigens to present to T cells and regulate DC functions. (PMID:16239426)
• human MICL may be involved in the control of myeloid cell activation during inflammation (PMID:16838277)
• CLL-1 expression is also present on the CD34(+)CD38(-) stem- cell compartment in acute myeloid leukemia (PMID:17609428)
• mMICL recognises an endogenous ligand in a variety of murine tissues, suggesting that the receptor plays a role in homeostasis (PMID:18350551)
• Anti-Clec12A mAb alone produced only moderate responses, but these were amplified by coinjecting only small amounts of LPS as a dendritic cell activation agent (PMID:19494282)
• For production of cytotoxic T cells, transgenic DEC-205 and Clec9A, but not Clec12A, are effective targets for antibody-mediated delivery of antigens for vaccination, although only in the presence of adjuvants. (PMID:21677141)
• There is a potential genetic association of CLEC12A with rheumatoid arthritis (RA). Since CLEC12A encodes for the myeloid inhibitory C-type lectin-like receptor that modulates cytokine synthesis, this receptor may contribute to the pathogenesis of RA. (PMID:22341585)
• We conclude the hMICL/CD123-based MFC assay is a promising MRD tool in AML. (PMID:24152218)
• Upon CLL1-selective binding of this fusion protein, granulocytes acquire additional TRAIL-mediated cytotoxic activity that, importantly, potentiates antibody-mediated cytotoxicity of clinically used therapeutic antibodies (PMID:25760768)
• We propose the hypothesis that decreased expression of CLEC12A is a common denominator in the hyperinflammatory responses observed in Behcet’s syndrome and gout. (PMID:25957656)
• Antibacterial autophagy is impaired in CLEC12A-deficient cells, and this effect is exacerbated in the presence of the ATG16L1( *)300A risk allele. (PMID:26095365)
• BMI-1, TIM-3 and CLL-1 have roles in acute myeloid leukemia prognosis and therapy (PMID:27506934)
• The CLEC12A is an effective new candidate with great potential for in vivo Ag delivery into mDCs and pDCs, thereby using the specialized functions and cross-talk capacity of these DC subsets to boost tumor-reactive T cell immunity in cancer patients. (PMID:27566820)
• Due to the absence of CLEC12A on normal haematopoietic stem cells, CLEC12A stem cell immunophenotyping may contribute to diagnosing and monitoring MDS patients and could furthermore add knowledge about disease propagating cells in MDS. (PMID:27612176)
• Awareness of minor normal CLEC12A+ subpopulations is crucial when using CLEC12A as a minimal residual disease marker in myeloid malignancies. (PMID:28718199)
• CLL-1 is a novel prognostic predictor that could be exploited to supplement the current acute myeloid leukemia prognostic risk stratification system. (PMID:28810819)
• The CLL-1 chimeric antigen receptor-T cells specifically lysed CLL-1(+) cell lines as well as primary acute myeloid leukemia patient samples in vitro. (PMID:29316944)
• these data can help determine which cells will be spared during CLEC12A-targeted therapy, and we propose CLEC12A to be included in future studies of myeloid cancer stem cell biology. (PMID:29411522)
• Enumeration of circulating hMICL+ stem cells by flow cytometry can discriminate between myeloproliferative neoplasm phenotypes and holds potential for monitoring disease evolution. (PMID:29427319)
• our data suggest that an anti-CLL-1-antibody-drug conjugate (ADC) has the potential to become an effective and safer treatment for acute myeloid leukemia (AML) in humans, by reducing and allowing for faster recovery from initial cytopenias than the current generation of ADCs for AML. (PMID:29959143)
• Revisiting CLEC12A as leukaemic stem cell marker in AML: highlighting the necessity of precision diagnostics in patients eligible for targeted therapy. (PMID:30520015)
• CLEC12A and CD33 coexpression as a preferential target for pediatric AML combinatorial immunotherapy. (PMID:33094319)
• Blast cells in acute megakaryoblastic leukaemia with Down syndrome are characterized by low CLEC12A expression. (PMID:33095915)
• Exploring blast composition in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms: CD45RA and CD371 improve diagnostic value of flow cytometry through assessment of myeloblast heterogeneity and stem cell aberrancy. (PMID:33369070)
• C-Type Lectin-Like Molecule-1 as a Biomarker for Diagnosis and Prognosis in Acute Myeloid Leukemia: A Preliminary Study. (PMID:33778076)
• Bimodal expression of potential drug target CLL-1 (CLEC12A) on CD34+ blasts of AML patients. (PMID:34053123)
• The Inhibitory Receptor CLEC12A Regulates PI3K-Akt Signaling to Inhibit Neutrophil Activation and Cytokine Release. (PMID:34234773)
• Regulation of the Expression, Oligomerisation and Signaling of the Inhibitory Receptor CLEC12A by Cysteine Residues in the Stalk Region. (PMID:34638548)
• The Fusion of CLEC12A and MIR223HG Arises from a trans-Splicing Event in Normal and Transformed Human Cells. (PMID:34830054)
• CLEC12A plays an important role in immunomodulatory function and prognostic significance of patients with acute myeloid leukemia. (PMID:35481814)
• Mycobacterial mycolic acids trigger inhibitory receptor Clec12A to suppress host immune responses. (PMID:36542980)
• Identification of two early blood biomarkers ACHE and CLEC12A for improved risk stratification of critically ill COVID-19 patients. (PMID:36928077)
• Behcet syndrome: The disturbed balance between anti- (CLEC12A, CLC) and proinflammatory (IFI27) gene expressions. (PMID:37102643)
• Mechanistic insights into the C-type lectin receptor CLEC12A-mediated immune recognition of monosodium urate crystal. (PMID:38367667)
• Crystal structure of the complex of CLEC12A and an antibody that interferes with binding of diverse ligands. (PMID:38386511)
• Recognition and control of neutrophil extracellular trap formation by MICL. (PMID:39143217)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:ch211-193e13.5	ENSDARG00000052656
danio_rerio		ENSDARG00000074732
danio_rerio	si:dkey-26c10.5	ENSDARG00000088023
danio_rerio	si:ch211-170d8.8	ENSDARG00000090945
mus_musculus	Clec12a	ENSMUSG00000053063
rattus_norvegicus	Clec12a	ENSRNOG00000054860
drosophila_melanogaster	rgn	FBGN0261258
caenorhabditis_elegans		WBGENE00009156
caenorhabditis_elegans		WBGENE00013008

Paralogs (23): CLEC2D (ENSG00000069493), CD69 (ENSG00000110848), CLEC2B (ENSG00000110852), KLRB1 (ENSG00000111796), KLRD1 (ENSG00000134539), KLRC1 (ENSG00000134545), KLRG1 (ENSG00000139187), KLRF1 (ENSG00000150045), CLEC1A (ENSG00000150048), CLEC1B (ENSG00000165682), CLEC7A (ENSG00000172243), OLR1 (ENSG00000173391), KLRC4 (ENSG00000183542), CLEC2A (ENSG00000188393), KLRG2 (ENSG00000188883), CLEC9A (ENSG00000197992), KLRC2 (ENSG00000205809), KLRC3 (ENSG00000205810), KLRK1 (ENSG00000213809), CLEC2L (ENSG00000236279), CLEC12B (ENSG00000256660), KLRF2 (ENSG00000256797), CLEC5A (ENSG00000258227)

Protein

Protein identifiers

C-type lectin domain family 12 member A — Q5QGZ9 (reviewed: Q5QGZ9)

Alternative names: C-type lectin-like molecule 1, Dendritic cell-associated lectin 2, Killer cell C-type lectin-like receptor L1, Myeloid inhibitory C-type lectin-like receptor

All UniProt accessions (2): Q5QGZ9, A8MVL9

UniProt curated annotations — full annotation on UniProt →

Function. Myeloid inhibitory C-type lectin receptor that acts as a negative regulator of myeloid cell activation. Myeloid cell inhibition is required to limit proinflammatory pathways and protect against excessive inflammation. Specifically recognizes and binds various structures, such as neutrophil extracellular traps (NETs) or monosodium urate crystals. Also acts as a pattern-recognition receptor for pathogen-associated molecules, such as plasmodium hemozoin or mycobacterial micolic acid. Ligand-binding induces phosphorylation of its ITIM motif, followed by recruitment of tyrosine-protein phosphatases PTPN6 and PTPN11, which counteract tyrosine-protein kinase SYK, thereby preventing myeloid cell activation. Acts as a pattern-recognition receptor for NETs in neutrophils: specifically recognizes DNA in NETs, leading to inhibit neutrophil activation and limit further NET formation. This regulation is essential for controlling key neutrophil responses and limit NET-mediated inflammatory conditions. Also recognizes dead cells by acting as a receptor for monosodium urate crystals, leading to down-regulate neutrophil activation. Binding to monosodium urate crystals also promotes the type I interferon response. Acts as an inhibitor of natural killer (NK) cell cytotoxicity. Also acts as an inhibitor of dendritic cell maturation in an IL10-dependent manner.

Subunit / interactions. Homodimer; disulfide-linked. Interacts (when the ITIM motif is phosphorylated) with PTPN6 and PTPN11.

Subcellular location. Cell membrane.

Tissue specificity. Preferentially expressed in lymphoid tissues and immune cells, including natural killer (NK) cells, T-cells, dendritic cells and monocytes or macrophages. Detected in spleen macrophage-rich red pulp and in lymph node (at protein level). Detected in peripheral blood leukocytes, dendritic cells, bone marrow, monocytes, mononuclear leukocytes and macrophages.

Post-translational modifications. Phosphorylated at Tyr-7 by SRC in the ITIM motif following ligand-binding, promoting recruitment of tyrosine-protein phosphatases PTPN6 and PTPN11. Highly N-glycosylated; glycosylation varies between cell types.

Domain organisation. The immunoreceptor tyrosine-based inhibitor motif (ITIM) is involved in modulation of cellular responses. The phosphorylated ITIM motif can bind the SH2 domain of several SH2-containing protein phosphatases, such as PTPN6 and PTPN11.

Induction. Down-regulated in activated leukocytes recruited to a site of inflammation.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoforms (5)

UniProt ID	Names	Canonical?
Q5QGZ9-2	2, Alpha	yes
Q5QGZ9-1	1
Q5QGZ9-3	3, Gamma
Q5QGZ9-4	4, Beta
Q5QGZ9-5	5

RefSeq proteins (4): NP_001193939, NP_001287659, NP_612210, NP_963917 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001304	C-type_lectin-like	Domain
IPR016186	C-type_lectin-like/link_sf	Homologous_superfamily
IPR016187	CTDL_fold	Homologous_superfamily
IPR033992	NKR-like_CTLD	Domain
IPR042916	CLEC12A/B	Family

Pfam: PF00059

UniProt features (37 total): strand 7, helix 6, splice variant 5, disulfide bond 4, mutagenesis site 4, glycosylation site 3, topological domain 2, chain 1, sequence variant 1, transmembrane region 1, domain 1, short sequence motif 1, modified residue 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8W8T	X-RAY DIFFRACTION	2.3
8JAH	X-RAY DIFFRACTION	2.58
8W9J	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5QGZ9-F1	83.35	0.62

Antibody-complex structures (SAbDab): 1 — 8W9J

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): 7

Disulfide bonds (4): 118–130, 133–144, 161–248, 227–240

Glycosylation sites (3): 88, 98, 165

Mutagenesis-validated functional residues (4):

Position	Phenotype
7	abolished phosphorylation.
185	strongly decreased ligand-binding.
232	decreased ligand-binding.
234	decreased ligand-binding.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 125 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_DENDRITIC_CELL_DIFFERENTIATION, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_DENDRITIC_CELL_DIFFERENTIATION, GOCC_SECRETORY_GRANULE, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_REGULATION_OF_LEUKOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_REGULATION_OF_HEMOPOIESIS, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS

GO Biological Process (8): signal transduction (GO:0007165), positive regulation of type I interferon production (GO:0032481), negative regulation of natural killer cell activation (GO:0032815), negative regulation of inflammatory response (GO:0050728), negative regulation of immune response (GO:0050777), negative regulation of neutrophil activation (GO:1902564), negative regulation of dendritic cell differentiation (GO:2001199), neutrophil activation involved in immune response (GO:0002283)

GO Molecular Function (5): transmembrane signaling receptor activity (GO:0004888), carbohydrate binding (GO:0030246), signaling receptor regulator activity (GO:0030545), pattern recognition receptor activity (GO:0038187), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), specific granule membrane (GO:0035579), tertiary granule membrane (GO:0070821), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signaling receptor activity	3
immune response	2
neutrophil activation	2
binding	2
secretory granule membrane	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
positive regulation of cytokine production	1
regulation of type I interferon production	1
type I interferon production	1
natural killer cell activation	1
regulation of natural killer cell activation	1
negative regulation of lymphocyte activation	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
negative regulation of immune system process	1
negative regulation of response to stimulus	1
regulation of immune response	1
negative regulation of leukocyte activation	1
regulation of neutrophil activation	1
dendritic cell differentiation	1
negative regulation of leukocyte differentiation	1
regulation of dendritic cell differentiation	1
myeloid cell activation involved in immune response	1
molecular function regulator activity	1
membrane	1
cell periphery	1
specific granule	1
tertiary granule	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1474 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLEC12A	PTPN11	Q06124	973
CLEC12A	COLEC11	Q9BWP8	860
CLEC12A	CD33	P20138	783
CLEC12A	IL3RA	P26951	716
CLEC12A	NR0B2	Q15466	697
CLEC12A	HAVCR2	Q8TDQ0	663
CLEC12A	MASP2	O00187	662
CLEC12A	COLEC10	Q9Y6Z7	623
CLEC12A	SIRPA	P78324	594
CLEC12A	CD38	P28907	592
CLEC12A	INPP5D	Q92835	588
CLEC12A	CLEC6A	Q6EIG7	584
CLEC12A	CD96	P40200	581
CLEC12A	CD93	Q9NPY3	576
CLEC12A	CCR1	P32246	548

IntAct

8 interactions, top by confidence:

A	B	Type	Score
CLEC12A	CLEC1A	psi-mi:“MI:0915”(physical association)	0.560
CLEC12A	CFTR	psi-mi:“MI:0915”(physical association)	0.370
CLEC12A	GOSR2	psi-mi:“MI:0914”(association)	0.350
CLEC12A	GAPDHS	psi-mi:“MI:0914”(association)	0.350
CLEC12A	SNAP23	psi-mi:“MI:0914”(association)	0.350
CLEC1A	CLEC12A	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (78): BNIP1 (Affinity Capture-MS), STX6 (Affinity Capture-MS), XPO5 (Affinity Capture-MS), COLEC12 (Affinity Capture-MS), STX18 (Affinity Capture-MS), GOSR1 (Affinity Capture-MS), SOX13 (Affinity Capture-MS), STX5 (Affinity Capture-MS), MESDC2 (Affinity Capture-MS), STX10 (Affinity Capture-MS), PBXIP1 (Affinity Capture-MS), TMEM57 (Affinity Capture-MS), ADAMTS2 (Affinity Capture-MS), SNAP47 (Affinity Capture-MS), VAMP4 (Affinity Capture-MS)

ESM2 similar proteins: A4KWA1, D3W0D1, D4AD02, O54709, O70215, O88713, P20937, P26715, P27471, P27811, P27812, P27814, Q07108, Q0ZUP0, Q0ZUP1, Q12918, Q149M0, Q2HXU8, Q2NL33, Q5NKN2, Q5NKN4, Q5QGZ9, Q60652, Q60654, Q63378, Q64335, Q67EQ0, Q6QLQ4, Q6UXN8, Q80XD9, Q80ZC8, Q8BRU4, Q8BWY2, Q8C1T8, Q8CJC7, Q8MI05, Q8NC01, Q8VD98, Q8VI21, Q95MI5

Diamond homologs: A4KWA5, A4KWA6, A4KWA8, O70156, O89335, P06734, P08290, P0C7M9, P14370, P37217, P49259, P79391, Q07108, Q0H8B9, Q5M9I1, Q5QGZ9, Q60660, Q6QLQ4, Q6UVW9, Q6UXN8, Q80XD9, Q8BWY2, Q8C1T8, Q8N1N0, Q8VI21, Q91V08, Q92478, Q925N7, Q9D676, Q9UBG0, Q9UHP7, Q9WVF9, Q9XTA8, A3FM55, B4XSY4, B4XSZ2, B4XSZ3, B4XSZ4, B4XSZ5, B4XSZ6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	85
Likely benign	11
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1519 predictions. Top by Δscore:

Variant	Effect	Δscore
12:9971564:A:AG	acceptor_gain	1.0000
12:9971565:C:G	acceptor_gain	1.0000
12:9971566:A:AG	acceptor_gain	1.0000
12:9971566:ACTTT:A	acceptor_gain	1.0000
12:9971567:C:G	acceptor_gain	1.0000
12:9971570:T:TA	acceptor_gain	1.0000
12:9979327:A:AG	acceptor_gain	1.0000
12:9979327:AATGT:A	acceptor_gain	1.0000
12:9979328:ATGT:A	acceptor_gain	1.0000
12:9979331:T:TA	acceptor_gain	1.0000
12:9982126:CCTGG:C	donor_loss	1.0000
12:9982128:TGGT:T	donor_loss	1.0000
12:9982130:G:GG	donor_gain	1.0000
12:9982130:GT:G	donor_loss	1.0000
12:9982131:T:A	donor_loss	1.0000
12:9995138:A:AC	donor_gain	1.0000
12:9995139:C:CC	donor_gain	1.0000
12:9971557:T:TA	acceptor_gain	0.9900
12:9971574:A:AG	acceptor_gain	0.9900
12:9971574:AAGAT:A	acceptor_loss	0.9900
12:9971575:A:G	acceptor_gain	0.9900
12:9971575:AGATT:A	acceptor_loss	0.9900
12:9971576:GATTT:G	acceptor_gain	0.9900
12:9971685:AAGG:A	donor_loss	0.9900
12:9971687:GGTA:G	donor_loss	0.9900
12:9971689:TAAGA:T	donor_loss	0.9900
12:9979094:G:GT	donor_gain	0.9900
12:9979328:A:AG	acceptor_gain	0.9900
12:9979328:ATGTG:A	acceptor_gain	0.9900
12:9979329:T:G	acceptor_gain	0.9900

AlphaMissense

1780 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:9980664:G:C	W154C	0.993
12:9980664:G:T	W154C	0.993
12:9980613:G:C	W137C	0.988
12:9980613:G:T	W137C	0.988
12:9982058:G:C	W190C	0.988
12:9982058:G:T	W190C	0.988
12:9984907:T:A	C227S	0.986
12:9984908:G:C	C227S	0.986
12:9980632:T:A	C144S	0.985
12:9980633:G:C	C144S	0.985
12:9980683:T:A	C161S	0.984
12:9980684:G:C	C161S	0.984
12:9980698:G:C	A166P	0.984
12:9980611:T:A	W137R	0.983
12:9980611:T:C	W137R	0.983
12:9984946:T:A	C240S	0.983
12:9984947:G:C	C240S	0.983
12:9980634:T:G	C144W	0.979
12:9980685:T:G	C161W	0.979
12:9984970:T:A	C248S	0.979
12:9984971:G:C	C248S	0.979
12:9984908:G:A	C227Y	0.977
12:9984948:C:G	C240W	0.977
12:9980671:A:C	S157R	0.976
12:9980673:T:A	S157R	0.976
12:9980673:T:G	S157R	0.976
12:9984909:T:G	C227W	0.976
12:9980633:G:A	C144Y	0.975
12:9980684:G:A	C161Y	0.975
12:9980632:T:C	C144R	0.972

dbSNP variants (sampled 300 via entrez): RS1000069162 (12:9950981 C>A,T), RS1000112368 (12:9990957 C>T), RS1000156853 (12:9975043 G>A,C), RS1000245632 (12:9984195 C>T), RS1000271409 (12:9958153 A>G), RS1000305193 (12:9955378 T>C), RS1000359079 (12:9977272 T>C), RS1000407439 (12:9960926 T>A), RS1000443074 (12:9990712 A>G), RS1000685912 (12:10006182 G>A), RS1000715048 (12:9970137 A>G,T), RS1000764152 (12:9969724 G>T), RS1000849729 (12:9949880 A>T), RS1000874809 (12:9957015 T>G), RS1000961036 (12:9995984 A>G)

Disease associations

OMIM: gene MIM:612088 | 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_492	Blood protein levels	0.000000e+00
GCST010725_46	Malaria	1.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — C-type lectin-like receptors (CLRs)

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

Ligand	Action	Affinity	Parameter
tepoditamab	Binding	8.52	pKd

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
GSK-J4	decreases expression	1
alpha phellandrene	decreases expression	1
triphenyl phosphate	affects expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
entinostat	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Catechin	affects cotreatment, decreases expression	1
Cisplatin	increases expression	1
Formaldehyde	decreases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Tretinoin	increases expression	1
Aflatoxin B1	decreases methylation	1
beta-Naphthoflavone	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E6Q1	Genomeditech CHO-K1 H_CLEC12A	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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