CLEC2A

Summary

CLEC2A (C-type lectin domain family 2 member A, HGNC:24191) is a protein-coding gene on chromosome 12p13.31, encoding C-type lectin domain family 2 member A (Q6UVW9). Membrane-bound protein expressed mainly on keratinocytes which acts as a ligand to stimulate the activating receptor NKp65/KLRF2, expressed on the surface of natural killer (NK) cells.

Enables protein homodimerization activity. Predicted to be involved in natural killer cell mediated cytotoxicity. Predicted to act upstream of or within several processes, including T cell receptor signaling pathway; regulation of actin filament polymerization; and regulation of interleukin-2 production. Located in plasma membrane.

Source: NCBI Gene 387836 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 66 total
• MANE Select transcript: NM_001130711

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24191
Approved symbol	CLEC2A
Name	C-type lectin domain family 2 member A
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Aliases	UNQ5792, INPE5792, KACL, PILAR
Ensembl gene	ENSG00000188393
Ensembl biotype	protein_coding
OMIM	612087
Entrez	387836

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000339766, ENST00000455827

RefSeq mRNA: 2 — MANE Select: NM_001130711 NM_001130711, NM_207375

CCDS: CCDS44829, CCDS8606

Canonical transcript exons

ENST00000455827 — 5 exons

Exon	Start	End
ENSE00001365344	9922066	9922232
ENSE00001368391	9926260	9926343
ENSE00001369314	9932275	9932370
ENSE00001385230	9916700	9916803
ENSE00001627474	9913227	9913680

Expression profiles

Bgee: expression breadth broad, 57 present calls, max score 87.69.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4835 / max 317.7311, expressed in 28 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
129447	0.4703	28
129448	0.0131	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of leg	UBERON:0001511	87.69	gold quality
zone of skin	UBERON:0000014	86.93	gold quality
skin of abdomen	UBERON:0001416	85.41	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.19	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	73.30	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	55.40	gold quality
primary visual cortex	UBERON:0002436	52.61	gold quality
placenta	UBERON:0001987	44.44	gold quality
vagina	UBERON:0000996	42.08	gold quality
monocyte	CL:0000576	38.37	silver quality
right hemisphere of cerebellum	UBERON:0014890	37.66	gold quality
cerebellar hemisphere	UBERON:0002245	37.65	gold quality
cerebellar cortex	UBERON:0002129	37.60	gold quality
cerebellum	UBERON:0002037	37.50	gold quality
leukocyte	CL:0000738	37.40	silver quality
colonic epithelium	UBERON:0000397	37.20	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
substantia nigra	UBERON:0002038	36.40	gold quality
skeletal muscle tissue	UBERON:0001134	36.19	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
sural nerve	UBERON:0015488	35.81	gold quality
blood	UBERON:0000178	35.69	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
muscle tissue	UBERON:0002385	34.51	gold quality
prefrontal cortex	UBERON:0000451	33.99	gold quality
tonsil	UBERON:0002372	33.86	silver quality
frontal cortex	UBERON:0001870	33.72	gold quality
liver	UBERON:0002107	33.10	silver quality
bone marrow	UBERON:0002371	33.04	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.93

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

20 targeting CLEC2A, 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-2110	99.96	66.68	1930
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-20B-3P	99.29	67.05	784
HSA-MIR-4477B	99.23	70.49	1733
HSA-MIR-4426	99.17	66.74	1949
HSA-MIR-146A-3P	99.13	68.99	1881
HSA-MIR-4744	99.01	69.91	1581
HSA-MIR-1257	98.97	68.02	1133
HSA-MIR-3194-3P	98.83	66.22	1167
HSA-MIR-4662B	98.33	66.37	1163
HSA-MIR-4647	98.30	66.41	1139
HSA-MIR-541-5P	98.24	67.77	1181
HSA-MIR-5691	98.23	67.02	1335
HSA-MIR-6805-3P	98.23	67.02	1334
HSA-MIR-5585-5P	97.95	68.80	1024
HSA-MIR-4469	97.93	65.81	1319
HSA-MIR-450A-2-3P	97.91	67.56	1459
HSA-MIR-6893-3P	97.79	64.91	1238
HSA-MIR-219B-3P	97.31	66.96	672
HSA-MIR-370-3P	97.09	64.92	1221

Literature-anchored findings (GeneRIF, showing 9)

• T-cell PILAR signaling through CD161 supports CD3 antibody-dependent and antigen-specific T-cell proliferation by increasing the expression of antiapoptotic Bcl-xL and induces secretion of T helper type 1 cytokines (PMID:18550855)
• CLEC-2 is the receptor for podoplanin, a sialoglycoprotein implicated in tumor-induced platelet aggregation and tumor metastasis[review] (PMID:19630798)
• Keratinocytes express KACL and are capable of stimulating NKp65-expressing cells in a KACL-dependent manner. (PMID:20194751)
• CLEC-2, unlike platelet ITAM receptors, is not regulated by proteolysis and can be used to monitor platelet-derived microparticles (PMID:25150298)
• Key residues at the membrane-distal surface of KACL, but not glycosylation, determine the functional interaction of the keratinocyte-specific C-type lectin-like receptor KACL with its high-affinity receptor NKp65 (PMID:25510854)
• PDGF upregulates the expression of CLEC-2 on dendritic cells to induce T regulatory cells. (PMID:26416420)
• Review of C-type lectin-like receptor 2 and podoplanin interactions [review] (PMID:27960039)
• A Comprehensive Tyrosine Phosphoproteomic Analysis Reveals Novel Components of the Platelet CLEC-2 Signaling Cascade. (PMID:31901221)
• NK Cell and Fibroblast-Mediated Regulation of Skin Squamous Cell Carcinoma Invasion by CLEC2A Is Compromised in Xeroderma Pigmentosum. (PMID:32061658)

Cross-species orthologs

7 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
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), CLEC12A (ENSG00000172322), OLR1 (ENSG00000173391), KLRC4 (ENSG00000183542), 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 2 member A — Q6UVW9 (reviewed: Q6UVW9)

Alternative names: Keratinocyte-associated C-type lectin, Proliferation-induced lymphocyte-associated receptor

All UniProt accessions (1): Q6UVW9

UniProt curated annotations — full annotation on UniProt →

Function. Membrane-bound protein expressed mainly on keratinocytes which acts as a ligand to stimulate the activating receptor NKp65/KLRF2, expressed on the surface of natural killer (NK) cells. Facilitates thereby dedicated immune recognition of keratinocytes leading to natural killer cell mediated cytotoxicity. Also plays a role in modulating the extent of T-cell expansion.

Subunit / interactions. Homodimer; non-disulfide-linked. Interacts with KLRB1. Interacts with KLRF2.

Subcellular location. Cell membrane.

Tissue specificity. Mainly expressed in skin. Also expressed in keratinocytes, spleen, thymus, small intestine, peripheral blood monocytes, bone marrow, ovary, testis and skin. High expression in CD8(+), B-lymphocytes and naive CD4(+) T-cells. Restricted mostly to proliferating lymphocytes. Not detected in myeloid leukocytes or natural killer (NK) cells.

Post-translational modifications. N-glycosylated.

Induction. By phytohemagglutinin (PHA) in peripheral CD8(+) T cells.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6UVW9-1	1, CLEC2A1	yes
Q6UVW9-2	2, CLEC2A2

RefSeq proteins (2): NP_001124183, NP_997258 (=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
IPR050828	C-type_lectin/matrix_domain	Family

Pfam: PF00059

UniProt features (33 total): mutagenesis site 10, strand 7, glycosylation site 3, topological domain 2, helix 2, turn 2, disulfide bond 2, chain 1, splice variant 1, sequence variant 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4IOP	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UVW9-F1	88.23	0.70

Functional residue map

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

Disulfide bonds (2): 58–69, 86–167

Glycosylation sites (3): 78, 130, 143

Mutagenesis-validated functional residues (10):

Position	Phenotype
78	partial loss of glycosylation.
130	partial loss of glycosylation.
143	partial loss of glycosylation.
148	reduces affinity for klrf2 40-fold.
152	no effect on affinity for klrf2.
155	slightly reduces affinity for klrf2.
157–158	reduces affinity for klrf2 over 10'000-fold.
160–161	reduces affinity for klrf2 550-fold.
161	complete abrogation of klrf2 binding.
162	reduces affinity for klrf2 360-fold.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 46 (showing top): GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOCC_CELL_SURFACE, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY, GOBP_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_NATURAL_KILLER_CELL_MEDIATED_IMMUNITY, GOBP_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_IMMUNE_EFFECTOR_PROCESS, GOMF_SIGNALING_RECEPTOR_BINDING, GOBP_CELL_KILLING, GOCC_SIDE_OF_MEMBRANE, GOMF_PROTEIN_DIMERIZATION_ACTIVITY

GO Biological Process (1): natural killer cell mediated cytotoxicity (GO:0042267)

GO Molecular Function (4): carbohydrate binding (GO:0030246), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
leukocyte mediated cytotoxicity	1
natural killer cell mediated immunity	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

320 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLEC2A	KLRF2	D3W0D1	994
CLEC2A	KLRB1	Q12918	799
CLEC2A	KLRF1	Q9NZS2	775
CLEC2A	CLEC7A	Q9BXN2	631
CLEC2A	OLR1	P78380	547
CLEC2A	ZNF696	Q9H7X3	520
CLEC2A	LYG2	Q86SG7	490
CLEC2A	KRABD3	A5PL33	449
CLEC2A	A0A087WTH5	A0A087WTH5	446
CLEC2A	KCNJ12	Q14500	406
CLEC2A	TMPRSS5	Q9H3S3	389
CLEC2A	ADAMTSL2	Q86TH1	378
CLEC2A	DCLK3	Q9C098	372
CLEC2A	BCL2L1	Q07817	369
CLEC2A	CLEC1B	Q9P126	360

IntAct

24 interactions, top by confidence:

A	B	Type	Score
KLRF2	CLEC2A	psi-mi:“MI:0407”(direct interaction)	0.740
CLEC2A	KLRF2	psi-mi:“MI:0407”(direct interaction)	0.740
CLEC2A	KLRF2	psi-mi:“MI:0915”(physical association)	0.740
CLEC2A	CLEC2A	psi-mi:“MI:0407”(direct interaction)	0.720
CLEC2A	CLEC2D	psi-mi:“MI:0915”(physical association)	0.560
GPR37L1	CLEC2A	psi-mi:“MI:0915”(physical association)	0.560
CLEC2A	GPX8	psi-mi:“MI:0915”(physical association)	0.560
HIBADH	CLEC2A	psi-mi:“MI:0915”(physical association)	0.560
CLEC2A	TEX29	psi-mi:“MI:0915”(physical association)	0.560
GPR37L1	CLEC2A	psi-mi:“MI:0915”(physical association)	0.000
CLEC2A	CLEC2D	psi-mi:“MI:0915”(physical association)	0.000
CLEC2A	GPX8	psi-mi:“MI:0915”(physical association)	0.000
CLEC2A	HIBADH	psi-mi:“MI:0915”(physical association)	0.000
CLEC2A	TEX29	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (5): CLEC2A (Two-hybrid), CLEC2A (Two-hybrid), CLEC2A (Two-hybrid), CLEC2A (Two-hybrid), CLEC2A (Two-hybrid)

ESM2 similar proteins: A0A0E4BZH1, A4KWA1, D3W0D1, O35778, O54707, P27471, P27812, P27814, P78380, P79391, Q0VCS6, Q0ZUP0, Q0ZUP1, Q12918, Q13241, Q2HXU8, Q38HS3, Q49BZ4, Q58DF9, Q5NKN2, Q5NKN4, Q5QGZ9, Q60651, Q60652, Q60653, Q60660, Q60682, Q63378, Q64329, Q6QLQ4, Q6UVW9, Q80ZC8, Q863H3, Q8BWY2, Q8C567, Q8CJC7, Q8HZR8, Q8MHY9, Q8NC01, Q8VD98

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, A4KWA1, P02706, P0C7M8, P14371, P24721, P26715, P26717

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	59
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

693 predictions. Top by Δscore:

Variant	Effect	Δscore
12:9916699:CCAA:C	donor_gain	1.0000
12:9916801:TTC:T	acceptor_gain	1.0000
12:9916803:CC:C	acceptor_loss	1.0000
12:9916804:C:CC	acceptor_gain	1.0000
12:9916804:C:CG	acceptor_loss	1.0000
12:9916805:T:C	acceptor_gain	1.0000
12:9916805:T:G	acceptor_loss	1.0000
12:9916808:C:CT	acceptor_gain	1.0000
12:9916810:C:CT	acceptor_gain	1.0000
12:9922228:TGTGG:T	acceptor_gain	1.0000
12:9922233:C:CC	acceptor_gain	1.0000
12:9932270:CTTA:C	donor_loss	1.0000
12:9932271:TTACC:T	donor_loss	1.0000
12:9932272:TAC:T	donor_loss	1.0000
12:9932273:A:AC	donor_gain	1.0000
12:9932273:ACCTA:A	donor_loss	1.0000
12:9932274:C:CC	donor_gain	1.0000
12:9913961:T:A	donor_gain	0.9900
12:9916693:AACT:A	donor_loss	0.9900
12:9916695:CTCAC:C	donor_loss	0.9900
12:9916696:T:TC	donor_loss	0.9900
12:9916697:C:CA	donor_loss	0.9900
12:9916698:A:AC	donor_gain	0.9900
12:9916698:A:C	donor_loss	0.9900
12:9916699:C:CC	donor_gain	0.9900
12:9916799:AATTC:A	acceptor_gain	0.9900
12:9916800:ATTC:A	acceptor_gain	0.9900
12:9916803:CCT:C	acceptor_gain	0.9900
12:9916811:A:T	acceptor_gain	0.9900
12:9916815:C:CT	acceptor_gain	0.9900

AlphaMissense

1176 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:9922135:C:A	W79C	0.996
12:9922135:C:G	W79C	0.996
12:9916726:C:A	W128C	0.993
12:9916726:C:G	W128C	0.993
12:9922126:A:C	S82R	0.993
12:9922126:A:T	S82R	0.993
12:9922128:T:G	S82R	0.993
12:9916732:C:A	W126C	0.992
12:9916732:C:G	W126C	0.992
12:9922115:C:G	C86S	0.992
12:9922116:A:T	C86S	0.992
12:9916765:C:A	W115C	0.991
12:9916765:C:G	W115C	0.991
12:9922114:A:C	C86W	0.991
12:9913647:G:C	F148L	0.990
12:9913647:G:T	F148L	0.990
12:9913649:A:G	F148L	0.990
12:9916728:A:G	W128R	0.989
12:9916728:A:T	W128R	0.989
12:9922127:C:A	S82I	0.989
12:9922115:C:T	C86Y	0.988
12:9913623:A:C	S156R	0.986
12:9913623:A:T	S156R	0.986
12:9913625:T:G	S156R	0.986
12:9916734:A:G	W126R	0.986
12:9916734:A:T	W126R	0.986
12:9916767:A:G	W115R	0.986
12:9916767:A:T	W115R	0.986
12:9922116:A:G	C86R	0.985
12:9913598:A:G	W165R	0.984

dbSNP variants (sampled 300 via entrez): RS1000057303 (12:9912845 C>T), RS1000074056 (12:9907621 G>C), RS1000074847 (12:9900239 A>T), RS1000115796 (12:9894491 C>T), RS1000218250 (12:9908098 C>T), RS1000252515 (12:9917341 G>A), RS1000375068 (12:9928431 C>T), RS1000427346 (12:9928712 A>G), RS1000453609 (12:9886165 T>G), RS1000483496 (12:9922879 T>C), RS1000486619 (12:9896164 C>A), RS1000507038 (12:9898042 C>T), RS1000513543 (12:9913064 G>A), RS1000535739 (12:9898210 A>G), RS1000594892 (12:9928956 A>G)

Disease associations

OMIM: gene MIM:612087 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010725_46	Malaria	1.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

4 total (human), top 4 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation, increases mutagenesis	2
2-palmitoylglycerol	increases expression	1
Copper Sulfate	increases expression	1
Lactic Acid	affects expression	1

Clinical trials (associated diseases)

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