CLEC4M

Summary

CLEC4M (C-type lectin domain family 4 member M, HGNC:13523) is a protein-coding gene on chromosome 19p13.2, encoding C-type lectin domain family 4 member M (Q9H2X3). Probable pathogen-recognition receptor involved in peripheral immune surveillance in liver.

This gene encodes a C-type lectin that functions in cell adhesion and pathogen recognition. This receptor recognizes a wide range of evolutionarily divergent pathogens with a large impact on public health, including tuberculosis mycobacteria, and viruses including Ebola, hepatitis C, HIV-1, influenza A, West Nile virus and the SARS-CoV acute respiratory syndrome coronavirus. The protein is organized into four distinct domains: a C-terminal carbohydrate recognition domain, a flexible tandem-repeat neck domain of variable length, a transmembrane region and an N-terminal cytoplasmic domain involved in internalization. This gene is closely related in terms of both sequence and function to a neighboring gene, CD209 (Gene ID: 30835), also known as DC-SIGN. The two genes differ in viral recognition and expression patterns, with this gene showing high expression in endothelial cells of the liver, lymph node and placenta. Polymorphisms in the tandem repeat neck domain are associated with resistance to SARS infection.

Source: NCBI Gene 10332 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 37 total
• Druggable target: yes
• MANE Select transcript: NM_014257

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13523
Approved symbol	CLEC4M
Name	C-type lectin domain family 4 member M
Location	19p13.2
Locus type	gene with protein product
Status	Approved
Aliases	L-SIGN, CD209L1, HP10347, DC-SIGNR, LSIGN, DCSIGNR, DC-SIGN2
Ensembl gene	ENSG00000104938
Ensembl biotype	protein_coding
OMIM	605872
Entrez	10332

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 12 protein_coding, 3 retained_intron

ENST00000327325, ENST00000359059, ENST00000394122, ENST00000596363, ENST00000598879, ENST00000601089, ENST00000602143, ENST00000861108, ENST00000861109, ENST00000861110, ENST00000861111, ENST00000861112, ENST00000861113, ENST00000861114, ENST00000861115

RefSeq mRNA: 4 — MANE Select: NM_014257 NM_001144911, NM_001416369, NM_001416370, NM_014257

CCDS: CCDS12187, CCDS59348

Canonical transcript exons

ENST00000327325 — 7 exons

Exon	Start	End
ENSE00001767528	7765638	7766207
ENSE00002691036	7766656	7766807
ENSE00002981594	7768838	7769605
ENSE00003554996	7765185	7765268
ENSE00003557413	7763393	7763476
ENSE00003673393	7767516	7767628
ENSE00003896021	7763243	7763312

Expression profiles

Bgee: expression breadth ubiquitous, 137 present calls, max score 92.99.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0525 / max 17.5144, expressed in 14 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
173600	0.0525	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	92.99	gold quality
adrenal tissue	UBERON:0018303	91.94	gold quality
germinal epithelium of ovary	UBERON:0001304	91.43	gold quality
liver	UBERON:0002107	89.28	gold quality
lymph node	UBERON:0000029	86.23	gold quality
pancreatic ductal cell	CL:0002079	73.68	silver quality
right lung	UBERON:0002167	73.03	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	70.64	gold quality
placenta	UBERON:0001987	69.70	gold quality
left ovary	UBERON:0002119	69.47	gold quality
endometrium epithelium	UBERON:0004811	69.44	gold quality
ovary	UBERON:0000992	68.58	gold quality
right adrenal gland	UBERON:0001233	67.45	gold quality
left adrenal gland cortex	UBERON:0035825	66.91	gold quality
adrenal gland	UBERON:0002369	66.53	gold quality
left adrenal gland	UBERON:0001234	66.03	gold quality
right adrenal gland cortex	UBERON:0035827	65.85	gold quality
adrenal cortex	UBERON:0001235	65.16	gold quality
olfactory bulb	UBERON:0002264	64.73	gold quality
upper lobe of left lung	UBERON:0008952	64.45	gold quality
right ovary	UBERON:0002118	63.71	gold quality
upper lobe of lung	UBERON:0008948	63.54	gold quality
left testis	UBERON:0004533	61.18	gold quality
testis	UBERON:0000473	61.01	gold quality
ileal mucosa	UBERON:0000331	60.67	gold quality
right testis	UBERON:0004534	60.63	gold quality
vermiform appendix	UBERON:0001154	58.63	gold quality
superficial temporal artery	UBERON:0001614	58.62	gold quality
tongue squamous epithelium	UBERON:0006919	57.98	gold quality
lung	UBERON:0002048	57.22	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-10553	yes	48.65
E-HCAD-9	yes	20.89
E-ANND-3	no	2.75

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

43 targeting CLEC4M, 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-6748-5P	100.00	65.81	1057
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-1255A	99.74	68.09	744
HSA-MIR-1255B-5P	99.74	68.16	741
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-3975	99.62	65.97	697
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-2392	99.43	67.50	708
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-1843	98.97	66.07	838

Literature-anchored findings (GeneRIF, showing 40)

• Crystal structures of carbohydrate-recognition domains of DC-SIGNR bound to oligosaccharide, in combination with binding studies, reveal that it selectively recognizes endogenous high-mannose oligosaccharides (PMID:11739956)
• mediates cellular entry by Ebola virus in cis and in trans (PMID:12050398)
• reasons underlying the restricted distribution of DC-SIGNR; and expression in relation to HIV entry receptors (PMID:12152166)
• Review. This article reviews the interaction of DC-SIGN & DC-SIGNR with HIV and Ebola & discusses the mechanism of DC-SIGN-mediated viral transmission. (PMID:12223058)
• the influx or proliferation of DC-SIGN+ immature and mature DCs and L-SIGN+ cells is dynamically regulated (PMID:15111305)
• data demonstrate for the first time that lectins DC-SIGN and L-SIGN differ in their carbohydrate binding profiles (PMID:15184372)
• largely expressed on endothelial cells in liver sinusoids; results demonstrate that hepatitis C pseudoviruses captured by L-SIGN+ or DC-SIGN+ cells efficiently transinfect adjacent human liver cells (PMID:15371595)
• can serve as an alternative receptor for SARS coronavirus (PMID:15496474)
• crystal forms of truncated DC-SIGNR comprising two neck repeats and the carbohydrate-recognition domain reveal that the CRDs are flexibly linked to the neck, which contains alpha-helical segments interspersed with non-helical regions (PMID:15509576)
• crystal structure of DC-SIGNR with its last repeat region (PMID:15784257)
• DC-SIGNR, in addition to DC-SIGN, should be considered as a cofactor in sexual HIV-1 transmission; soluble isoforms, in particular, may modulate the efficiency of viral transmission and dissemination. (PMID:15812562)
• A change in the number of DC-SIGN-related (DC-SIGNR) repeats may influence its normal functions as well as its binding capacity to viral and nonviral pathogens. (PMID:16061998)
• genetic risk association study shows that individuals homozygous for CLEC4M tandem repeats are less susceptible to SARS infection. (PMID:16369534)
• Recognizes pathogens and contributes to innate immunity. (PMID:16386217)
• Molecular explanation for the ability of DC-SIGN-interacting pathogens to preferentially evoke Th2-type immune responses. (PMID:16434485)
• DC-SIGNR homozygous 7/7 repeat was associated with increased risk of HIV-1 infection; the heterozygous 7/5 repeat tended to be correlated with resistance to HIV-1 infection; findings suggest DC-SIGNR polymorphisms may influence susceptibility to HIV-1 (PMID:16453266)
• DC-SIGN and DC-SIGNR genotypes and alleles distribution in Chinese Han population are significantly different from Caucasian population and with Chinese own population genetic characteristics, compared with Caucasians. (PMID:16883544)
• molecular mechanism whereby L-SIGN polymorphism could influence the establishment and progression of HCV infection (PMID:16894195)
• Expression of VAP-1, Stabilin-1, L-SIGN can be used to identify sinusoidal endothelium and to permit discrimination from vascular and lymphatic endothelial cells. (PMID:17006978)
• CD209L (L-SIGN) is used by coronavirus 229E to enter cells (PMID:17037540)
• study showed that polymorphisms in DC-SIGNR were significantly associated with HIV-exposed seronegative (ESN) Thai females but not with ESN males (PMID:17530994)
• DC-SIGN- and L-SIGN-mediated severe acute respiratory syndrome coronavirus entry requires specific asparagine-linked glycosylation sites (PMID:17715238)
• A total of 13 genotypes were found in DC-SIGNR neck repeat region polymorphism. Among all the genotypes, only 5/5 homozygous showed significant reduced risk of HIV-1 infection in HIV-1-exposed seronegative individuals (PMID:17876530)
• Our results reveal important differences between Ebola virus and HIV-1 capture by DC-SIGN/R and LSECtin and hint towards different biological functions of these lectins. (PMID:18083206)
• 9/5 genotype distribution frequency of DC-SIGNR’s exon 4 in patients with hepatitis C is significantly higher and may be associated with HCV infection susceptibility. (PMID:18171520)
• when B-ALL cells enter the blood circulation and are able to interact with DC-SIGN and L-SIGN the immune response is shifted toward tolerance. (PMID:18375037)
• DC-SIGN, DC-SIGNR and SDF-1 polymorphism was detected in high risk seronegative and HIV-1 patients in Northern Asian Indians. (PMID:18775666)
• association of the polymorphism of homologue of dendritic cell-specific intercellular adhesion molecule-3 (ICAM-3) grabbing nonintegrin (DC-SIGN related, DC-SIGNR) gene with the susceptibility to HIV-1 infection (PMID:18841568)
• The present study was undertaken to identify the polymorphic variants in the DC-SIGN and DC-SIGNR repeat regions in healthy HIV-1 seronegative Northern Asian Indians. (PMID:19046307)
• differences near the C-terminal end of the neck domains lead to significantly enhanced stability of DC-SIGNR tetramers compared to DC-SIGN (PMID:19249311)
• TLR2 and DC-SIGNR1 differentially regulate SOCS1 expression during M. tb infection. (PMID:19617348)
• DC-SIGNR plays a crucial role in MTCT of HIV-1 and impaired placental DC-SIGNR expression increases risk of transmission (PMID:19809496)
• determinants in DC-SIGN necessary for HIV-1 transmission and the differences between DC-SIGN and L-SIGN that affect HIV-1 interactions (PMID:19833723)
• Based on the structure and arrangement of the repeats in the crystal, the neck region can be described as a series of fourhelix bundles connected by short, non-helical linkers. (PMID:19835887)
• Our study indicated that there was absence of association between the neck region polymorphism of DC-SIGNR and longevity in Han Chinese population (PMID:20003397)
• DC-SIGNR was mainly expressed in the membrane and plasm in placental trophoblast cells. (PMID:20108443)
• these results suggest that the variation of the tested DC-SIGNR genotypes affects the efficacy of HIV-1 trans-infection by affecting the amounts of the protein expressed on the cell surface. (PMID:20152818)
• Together, these data indicate that human C-type lectins (DC-SIGN and L-SIGN) can mediate attachment and entry of influenza viruses independently of cell surface sialic acid. (PMID:21191006)
• Upon binding to membrane-anchored ligand, DC-SIGNR undergoes a conformational change similar to that previously observed for DC-SIGN. (PMID:21650186)
• data demonstrate that the signaling events mediated by RSV G interactions with DC/L-SIGN are immunomodulatory and diminish DC activation, which may limit induction of RSV-specific immunity (PMID:22090124)

Cross-species orthologs

24 orthologs

Organism	Symbol	Gene ID
danio_rerio	asgr1c.2	ENSDARG00000046092
danio_rerio	asgrl1	ENSDARG00000046142
danio_rerio	si:dkey-61f9.1	ENSDARG00000070414
danio_rerio	asgr1a	ENSDARG00000095963
danio_rerio	si:cabz01007816.2	ENSDARG00000102537
danio_rerio	asgr1b	ENSDARG00000103480
danio_rerio	si:ch211-283g2.5	ENSDARG00000108953
danio_rerio		ENSDARG00000111755
danio_rerio		ENSDARG00000112842
mus_musculus	Cd209f	ENSMUSG00000051906
mus_musculus	Cd209g	ENSMUSG00000079168
rattus_norvegicus	Cd209fl1	ENSRNOG00000001027
rattus_norvegicus	Cd209f	ENSRNOG00000042317
drosophila_melanogaster	tfc	FBGN0035199
drosophila_melanogaster	CG14866	FBGN0038315
drosophila_melanogaster	lectin-46Cb	FBGN0040092
drosophila_melanogaster	lectin-46Ca	FBGN0040093
drosophila_melanogaster	lectin-33A	FBGN0040096
drosophila_melanogaster	CG34033	FBGN0054033
caenorhabditis_elegans	clec-87	WBGENE00007709
caenorhabditis_elegans	clec-91	WBGENE00014117
caenorhabditis_elegans		WBGENE00016088
caenorhabditis_elegans		WBGENE00018692
caenorhabditis_elegans		WBGENE00019606

Paralogs (14): CD209 (ENSG00000090659), FCER2 (ENSG00000104921), CLEC4A (ENSG00000111729), CD207 (ENSG00000116031), CLEC10A (ENSG00000132514), ASGR1 (ENSG00000141505), CLEC4F (ENSG00000152672), ASGR2 (ENSG00000161944), CLEC4E (ENSG00000166523), CLEC4D (ENSG00000166527), CLEC4G (ENSG00000182566), CLEC17A (ENSG00000187912), CLEC4C (ENSG00000198178), CLEC6A (ENSG00000205846)

Protein

Protein identifiers

C-type lectin domain family 4 member M — Q9H2X3 (reviewed: Q9H2X3)

Alternative names: CD209 antigen-like protein 1, DC-SIGN-related protein, Dendritic cell-specific ICAM-3-grabbing non-integrin 2, Liver/lymph node-specific ICAM-3-grabbing non-integrin

All UniProt accessions (3): A0A7P0MMK7, E7ENS9, Q9H2X3

UniProt curated annotations — full annotation on UniProt →

Function. Probable pathogen-recognition receptor involved in peripheral immune surveillance in liver. May mediate the endocytosis of pathogens which are subsequently degraded in lysosomal compartments. Is a receptor for ICAM3, probably by binding to mannose-like carbohydrates. (Microbial infection) Acts as an attachment receptor for Ebolavirus. (Microbial infection) Acts as an attachment receptor for Hepatitis C virus. (Microbial infection) Acts as an attachment receptor for HIV-1. (Microbial infection) Acts as an attachment receptor for Human coronavirus 229E. (Microbial infection) Acts as an attachment receptor for Human cytomegalovirus/HHV-5. (Microbial infection) Acts as an attachment receptor for Influenzavirus. (Microbial infection) Acts as an attachment receptor for SARS-CoV. (Microbial infection) Acts as an attachment receptor for West-nile virus. (Microbial infection) Acts as an attachment receptor for Japanese encephalitis virus. (Microbial infection) Acts as an attachment receptor for Marburg virus glycoprotein. (Microbial infection) Recognition of M.bovis by dendritic cells may occur partially via this molecule.

Subunit / interactions. Homotetramer. (Microbial infection) Interacts with ebola virus glycoprotein. (Microbial infection) Interacts with hepatitis C virus E1 and E2 protein. (Microbial infection) Interacts with HIV-1 gp120. (Microbial infection) Interacts with human coronavirus 229E spike glycoprotein. (Microbial infection) Interacts with human cytomegalovirus/HHV-5 gB protein. (Microbial infection) Interacts with influenzavirus hemagglutinin. (Microbial infection) Interacts with SARS-CoV spike glycoprotein. (Microbial infection) Interacts with west-nile virus envelope protein E. (Microbial infection) Interacts with Japanese encephalitis virus E protein. (Microbial infection) Interacts with Marburg virus glycoprotein. (Microbial infection) Interacts with M.bovis LprG.

Subcellular location. Cell membrane Cell membrane Cell membrane Secreted Secreted Secreted Secreted.

Tissue specificity. Predominantly highly expressed in liver sinusoidal endothelial cells and in lymph node. Found in placental endothelium but not in macrophages. Expressed in type II alveolar cells and lung endothelial cells.

Domain organisation. The tandem repeat domain, also called neck domain, mediates oligomerization.

Polymorphism. The number of repeats in the tandem repeat domain is shown to vary between 3 and 9 per allele thus contributing to a further variability in addition to alternative splicing. The shown 7 repeat-containing form has been shown to be the most frequent one (53.9%) in a study with 350 Caucasian individuals.

Miscellaneous. In vitro, is a receptor for HIV-1 and transmits HIV-1 to permissive T-cells. May be due to intron retention. May be due to intron retention. Non-canonical intron-exon splice junction. May be due to intron retention.

Isoforms (10)

UniProt ID	Names	Canonical?
Q9H2X3-1	1, mDC-SIGN2 type I	yes
Q9H2X3-2	2, mDC-SIGN2 type III, mDC-SIGN2 type IV
Q9H2X3-3	3, mDC-SIGN2 type V
Q9H2X3-4	4, mDC-SIGN2 type VI
Q9H2X3-5	5, sDC-SIGN2 type I
Q9H2X3-6	6, sDC-SIGN2 type II
Q9H2X3-7	7, sDC-SIGN2 type III
Q9H2X3-8	8
Q9H2X3-9	9
Q9H2X3-10	10

RefSeq proteins (4): NP_001138383, NP_001403298, NP_001403299, NP_055072* (*=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
IPR018378	C-type_lectin_CS	Conserved_site
IPR033989	CD209-like_CTLD	Domain
IPR050111	C-type_lectin/snaclec_domain	Family

Pfam: PF00059

UniProt features (55 total): splice variant 11, strand 8, repeat 7, binding site 6, helix 5, disulfide bond 4, sequence variant 4, topological domain 2, glycosylation site 2, chain 1, domain 1, region of interest 1, short sequence motif 1, transmembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
1XPH	X-RAY DIFFRACTION	1.41
8RCY	X-RAY DIFFRACTION	1.8
1K9J	X-RAY DIFFRACTION	1.9
9G6W	X-RAY DIFFRACTION	2
3JQH	X-RAY DIFFRACTION	2.2
1SL6	X-RAY DIFFRACTION	2.25
1XAR	X-RAY DIFFRACTION	2.25

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H2X3-F1	70.77	0.31

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 (6): 359; 361; 363; 366; 377; 378

Disulfide bonds (4): 265–395, 268–279, 296–389, 368–381

Glycosylation sites (2): 92, 361

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9833110	RSV-host interactions

MSigDB gene sets: 108 (showing top): GOCC_CELL_SURFACE, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_ANTIGEN, GOBP_CELL_CELL_ADHESION, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION, BLALOCK_ALZHEIMERS_DISEASE_UP, CAIRO_HEPATOBLASTOMA_DN, MODULE_99, GOBP_BIOLOGICAL_PROCESS_INVOLVED_IN_INTERACTION_WITH_HOST, GOBP_VIRAL_GENOME_REPLICATION, GOBP_VIRAL_LIFE_CYCLE, GOBP_ADAPTIVE_IMMUNE_RESPONSE, SCHLOSSER_SERUM_RESPONSE_DN

GO Biological Process (16): adaptive immune response (GO:0002250), immune response (GO:0006955), leukocyte cell-cell adhesion (GO:0007159), cell-cell recognition (GO:0009988), virion attachment to host cell (GO:0019062), receptor-mediated endocytosis of virus by host cell (GO:0019065), viral genome replication (GO:0019079), antigen processing and presentation (GO:0019882), intracellular signal transduction (GO:0035556), innate immune response (GO:0045087), symbiont entry into host cell (GO:0046718), receptor-mediated virion attachment to host cell (GO:0046813), peptide antigen transport (GO:0046968), intracellular transport of virus (GO:0075733), immune system process (GO:0002376), endocytosis (GO:0006897)

GO Molecular Function (11): virus receptor activity (GO:0001618), D-mannose binding (GO:0005537), carbohydrate binding (GO:0030246), ICAM-3 receptor activity (GO:0030369), signaling receptor activity (GO:0038023), pattern recognition receptor activity (GO:0038187), peptide antigen binding (GO:0042605), virion binding (GO:0046790), metal ion binding (GO:0046872), calcium-dependent protein binding (GO:0048306), protein binding (GO:0005515)

GO Cellular Component (6): extracellular region (GO:0005576), cytoplasm (GO:0005737), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), membrane (GO:0016020), host cell (GO:0043657)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Respiratory Syncytial Virus Infection Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
viral life cycle	4
cellular anatomical structure	3
immune response	2
immune system process	2
symbiont entry into host cell	2
intracellular anatomical structure	2
binding	2
protein binding	2
response to stimulus	1
cell-cell adhesion	1
cell recognition	1
adhesion of symbiont to host cell	1
virion binding	1
host cell surface binding	1
receptor-mediated endocytosis	1
endocytosis involved in viral entry into host cell	1
viral process	1
signal transduction	1
defense response to symbiont	1
symbiont entry into host	1
signaling receptor binding	1
virion attachment to host cell	1
peptide transport	1
antigen processing and presentation of peptide antigen	1
host cell	1
biological process involved in symbiotic interaction	1
transport of virus	1
biological_process	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
exogenous protein binding	1
monosaccharide binding	1
transmembrane signaling receptor activity	1
molecular transducer activity	1
signaling receptor activity	1
antigen binding	1
peptide binding	1
cation binding	1

Protein interactions and networks

STRING

766 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLEC4M	ICAM3	P32942	992
CLEC4M	ACE2	Q9BYF1	977
CLEC4M	ITIH4	Q14624	968
CLEC4M	CD209	Q9NNX6	920
CLEC4M	GTPBP1	O00178	814
CLEC4M	ERVW-1	Q9UQF0	803
CLEC4M	ANPEP	P15144	763
CLEC4M	STAB2	Q8WWQ8	710
CLEC4M	DPP4	P27487	693
CLEC4M	ALB	P02768	688
CLEC4M	ACE	P12821	685
CLEC4M	GHITM	Q9H3K2	676
CLEC4M	BSG	P35613	644
CLEC4M	FURIN	P09958	607
CLEC4M	TMPRSS2	O15393	584

IntAct

37 interactions, top by confidence:

A	B	Type	Score
S	CLEC4M	psi-mi:“MI:0915”(physical association)	0.860
S	CLEC4M	psi-mi:“MI:0407”(direct interaction)	0.860
CLEC4M	ACE2	psi-mi:“MI:0915”(physical association)	0.590
CLEC4M	IFT20	psi-mi:“MI:0915”(physical association)	0.560
IFT20	CLEC4M	psi-mi:“MI:0915”(physical association)	0.560
PLPP6	CLEC4M	psi-mi:“MI:0915”(physical association)	0.560
CLEC4M	GRN	psi-mi:“MI:0915”(physical association)	0.500
CLEC4M	GRN	psi-mi:“MI:0914”(association)	0.500
	CLEC4M	psi-mi:“MI:0407”(direct interaction)	0.440
CLEC4M	ICAM3	psi-mi:“MI:0407”(direct interaction)	0.440
S	CLEC4M	psi-mi:“MI:0915”(physical association)	0.400
CLEC4M	CEACAM1	psi-mi:“MI:0915”(physical association)	0.400
ITGAM	CLEC4M	psi-mi:“MI:0915”(physical association)	0.400
CLEC4M	ITGAM	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (36): CLEC4M (Affinity Capture-MS), GRN (Affinity Capture-MS), CLEC4M (Affinity Capture-MS), GRN (Affinity Capture-MS), GFAP (Affinity Capture-MS), CLEC4M (Affinity Capture-Western), IFT20 (Two-hybrid), PPAPDC2 (Two-hybrid), CLEC4M (Reconstituted Complex), CLEC4M (Reconstituted Complex), S (Reconstituted Complex), S (Reconstituted Complex), S (Reconstituted Complex), S (Reconstituted Complex), CLEC4M (Reconstituted Complex)

ESM2 similar proteins: A0A087WUL8, A0A0J9YX57, A0A1B0GV03, A2A6M5, A2A9R3, A5A3E0, A6NEF3, A6NI86, A8MZA4, B4DH59, B5DUH6, D3ZVV1, E9Q0N2, H0YKK7, H0YM25, O04492, O18737, P0C6Y7, P0CG38, P0CG39, P0DPF3, P0DX00, P0DX01, P0DX02, Q3BBV2, Q4R914, Q5TAG4, Q5TI25, Q5W0A0, Q6P3W6, Q6RI63, Q6S8J3, Q86T75, Q86X53, Q8HXZ7, Q8HXZ8, Q8HY00, Q8HY01, Q8HY03, Q8HY11

Diamond homologs: A4KWA1, A4KWA6, P20693, P20937, P21063, P24765, P27471, P27811, P27812, P27814, P79391, Q0ZUP0, Q0ZUP1, Q12918, Q49BZ4, Q5NKN2, Q5NKN4, Q60651, Q60654, Q61830, Q63378, Q67EQ1, Q8HY06, Q8HY10, Q8HY11, Q8HY12, Q8HYC0, Q8VD98, Q8WTT0, Q90WJ8, Q91ZW8, Q925N7, Q95LG1, Q99JB4, Q9GLF3, Q9GME8, Q9H2X3, Q9JKF4, Q9NY25, Q9QZ15

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
S	“up-regulates activity”	CLEC4M	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	29
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

963 predictions. Top by Δscore:

Variant	Effect	Δscore
19:7765630:T:A	acceptor_gain	1.0000
19:7765636:A:AG	acceptor_gain	1.0000
19:7765637:G:GA	acceptor_gain	1.0000
19:7765637:GT:G	acceptor_gain	1.0000
19:7763311:GG:G	donor_gain	0.9900
19:7763312:GG:G	donor_gain	0.9900
19:7765631:G:A	acceptor_gain	0.9900
19:7765633:CCCA:C	acceptor_loss	0.9900
19:7765633:CCCAG:C	acceptor_gain	0.9900
19:7765634:CCAG:C	acceptor_gain	0.9900
19:7765634:CCAGT:C	acceptor_loss	0.9900
19:7765635:CAG:C	acceptor_gain	0.9900
19:7765636:AGT:A	acceptor_gain	0.9900
19:7765636:AGTG:A	acceptor_gain	0.9900
19:7765637:GTG:G	acceptor_gain	0.9900
19:7765637:GTGT:G	acceptor_gain	0.9900
19:7765637:GTGTC:G	acceptor_gain	0.9900
19:7766654:A:AG	acceptor_gain	0.9900
19:7766655:G:GG	acceptor_gain	0.9900
19:7766655:GAAC:G	acceptor_gain	0.9900
19:7766763:G:GT	donor_gain	0.9900
19:7766807:GG:G	donor_loss	0.9900
19:7766808:G:A	donor_loss	0.9900
19:7766809:T:C	donor_loss	0.9900
19:7767585:G:GT	donor_gain	0.9900
19:7767586:A:T	donor_gain	0.9900
19:7768836:A:AG	acceptor_gain	0.9900
19:7768837:G:GG	acceptor_gain	0.9900
19:7763310:TGGG:T	donor_loss	0.9800
19:7763313:G:GA	donor_loss	0.9800

AlphaMissense

2607 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:7768916:G:C	W376C	0.999
19:7768916:G:T	W376C	0.999
19:7768853:G:C	W355C	0.998
19:7768853:G:T	W355C	0.998
19:7768914:T:A	W376R	0.998
19:7768914:T:C	W376R	0.998
19:7766687:G:C	W272C	0.997
19:7766687:G:T	W272C	0.997
19:7767560:G:C	W327C	0.997
19:7767560:G:T	W327C	0.997
19:7767602:G:C	W341C	0.997
19:7767602:G:T	W341C	0.997
19:7766738:G:C	W289C	0.996
19:7766738:G:T	W289C	0.996
19:7767596:G:C	W339C	0.996
19:7767596:G:T	W339C	0.996
19:7768890:T:A	C368S	0.996
19:7768891:G:C	C368S	0.996
19:7766757:T:A	C296S	0.995
19:7766758:G:A	C296Y	0.995
19:7766758:G:C	C296S	0.995
19:7766759:C:G	C296W	0.995
19:7768953:T:A	C389S	0.995
19:7768954:G:C	C389S	0.995
19:7767600:T:A	W341R	0.994
19:7767600:T:C	W341R	0.994
19:7768929:T:A	C381S	0.994
19:7768930:G:C	C381S	0.994
19:7768915:G:C	W376S	0.993
19:7768954:G:A	C389Y	0.993

dbSNP variants (sampled 300 via entrez): RS1000220929 (19:7761604 C>G), RS1000295277 (19:7766954 G>A), RS1000532585 (19:7769760 G>A), RS1001226639 (19:7762818 A>C,G,T), RS1001414400 (19:7767917 G>T), RS1001755787 (19:7766989 CAT>C), RS1002242078 (19:7764048 C>G), RS1002357244 (19:7765699 C>T), RS1002745706 (19:7768987 A>G), RS1003127936 (19:7763071 C>T), RS1003129408 (19:7765441 G>A,T), RS1003341579 (19:7769960 C>T), RS1003411280 (19:7767983 C>T), RS1004883292 (19:7764308 T>C), RS1005146414 (19:7767843 C>A,T)

Disease associations

OMIM: gene MIM:605872 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST004625_207	Monocyte count	2.000000e-10
GCST007446_24	vWF levels	7.000000e-16
GCST007446_31	vWF levels	2.000000e-15
GCST012232_32	Lipoprotein (a) levels	4.000000e-08
GCST90002389_261	Lymphocyte percentage of white cells	3.000000e-15
GCST90002393_639	Monocyte count	5.000000e-19
GCST90002398_79	Neutrophil count	2.000000e-24
GCST90002398_80	Neutrophil count	1.000000e-16
GCST90002399_218	Neutrophil percentage of white cells	6.000000e-12
GCST90002407_356	White blood cell count	8.000000e-25
GCST90002407_357	White blood cell count	6.000000e-13
GCST90011898_88	Alanine aminotransferase levels	5.000000e-08
GCST90011899_194	Aspartate aminotransferase levels	2.000000e-21

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0005091	monocyte count
EFO:0006925	lipoprotein A measurement
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0004833	neutrophil count
EFO:0007990	neutrophil percentage of leukocytes
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2176858 (SINGLE PROTEIN)

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

ChEMBL bioactivities

25 potent at pChembl≥5 of 36 total, top 21 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.81	IC50	156	nM	CHEMBL4554703
6.73	IC50	188	nM	CHEMBL4515649
6.66	IC50	218	nM	CHEMBL5079779
6.54	IC50	289.3	nM	CHEMBL4515649
6.52	IC50	300	nM	CHEMBL4289617
6.51	IC50	310	nM	CHEMBL4289617
6.22	IC50	601.5	nM	CHEMBL5077032
6.20	IC50	634	nM	CHEMBL4554703
6.11	IC50	777	nM	CHEMBL5079779
6.00	IC50	1000	nM	CHEMBL5077032
5.80	IC50	1600	nM	CHEMBL1503347
5.80	IC50	1600	nM	CHEMBL5268319
5.80	IC50	1600	nM	CHEMBL4072223
5.70	IC50	2000	nM	CHEMBL1503347
5.58	IC50	2600	nM	CHEMBL5194701
5.58	IC50	2600	nM	CHEMBL5275742
5.36	IC50	4400	nM	CHEMBL5270980
5.21	IC50	6200	nM	CHEMBL5268319
5.21	IC50	6100	nM	CHEMBL5276990
5.14	IC50	7300	nM	CHEMBL5288093
5.00	IC50	1e+04	nM	CHEMBL5268209

PubChem BioAssay actives

25 with measured affinity, of 115 total; 14 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-hydroxy-N-[[1-[3-[[5,11,17,23-tetratert-butyl-26,27,28-tris[3-[4-[[hydroxy-[6-[4-[[(2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]triazol-1-yl]hexanoyl]amino]methyl]triazol-1-yl]propoxy]-25-pentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(24),3,5,7(28),9,11,13(27),15(26),16,18,21(25),22-dodecaenyl]oxy]propyl]triazol-4-yl]methyl]-6-[4-[[(2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]triazol-1-yl]hexanamide	1811209: Inhibition of full-length DC-SIGN (unknown origin) expressed in human monocyte derived dendritic cells assessed as inhibition of binding to recombinant HCMV gB using flow cytometry	ic50	0.1560	uM
N-hydroxy-N-[[1-[3-[[5,11,17,23-tetratert-butyl-26,27,28-tris[3-[4-[[hydroxy-[6-[4-[[(2R,3S,4R,5S,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]triazol-1-yl]hexanoyl]amino]methyl]triazol-1-yl]propoxy]-25-pentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(24),3,5,7(28),9,11,13(27),15(26),16,18,21(25),22-dodecaenyl]oxy]propyl]triazol-4-yl]methyl]-6-[4-[[(2R,3S,4R,5S,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]triazol-1-yl]hexanamide	1811209: Inhibition of full-length DC-SIGN (unknown origin) expressed in human monocyte derived dendritic cells assessed as inhibition of binding to recombinant HCMV gB using flow cytometry	ic50	0.1880	uM
methyl 2-[[2-[[1-[3-[[5,11,17,23-tetratert-butyl-26,27,28-tris[3-[4-[[[2-[(2-methoxy-2-oxoethyl)amino]-2-oxoethyl]-[6-[4-[[(2R,3S,4R,5S,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]triazol-1-yl]hexanoyl]amino]methyl]triazol-1-yl]propoxy]-25-pentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(24),3,5,7(28),9,11,13(27),15(26),16,18,21(25),22-dodecaenyl]oxy]propyl]triazol-4-yl]methyl-[6-[4-[[(2R,3S,4R,5S,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]triazol-1-yl]hexanoyl]amino]acetyl]amino]acetate	1811212: Inhibition of DC-SIGN (unknown origin) expressed in human Jurkat cells assessed as inhibition of EBOV-pseudotyped virus infection measured after 48 hrs by luciferase assay	ic50	0.2180	uM
4-[3-[3-oxo-6-(4-pyridin-4-ylpiperazine-1-carbonyl)-2,4-dihydro-1H-quinoxalin-2-yl]propyl]benzenesulfonamide	1930115: Inhibition of DC-SIGN (unknown origin) by high-throughput ELLA-type assay	ic50	0.3000	uM
methyl 2-[[2-[[1-[3-[[5,11,17,23-tetratert-butyl-26,27,28-tris[3-[4-[[[2-[(2-methoxy-2-oxoethyl)amino]-2-oxoethyl]-[6-[4-[[(2R,3S,4R,5S,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]triazol-1-yl]hexanoyl]amino]methyl]triazol-1-yl]propoxy]-2,8,14,20-tetrathiapentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(24),3,5,7(28),9,11,13(27),15(26),16,18,21(25),22-dodecaen-25-yl]oxy]propyl]triazol-4-yl]methyl-[6-[4-[[(2R,3S,4R,5S,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]triazol-1-yl]hexanoyl]amino]acetyl]amino]acetate	1811212: Inhibition of DC-SIGN (unknown origin) expressed in human Jurkat cells assessed as inhibition of EBOV-pseudotyped virus infection measured after 48 hrs by luciferase assay	ic50	0.6015	uM
N-[5-[2-[4-(dimethylamino)anilino]-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]propanamide	1938517: Inhibition of DC-SIGN extracellular domain (unknown origin) expressed in Escherichia coli DE3(BL21) incubated for 1 hrs in presence of Man-Fl-BSA by high-throughput fluorescence-based assay	ic50	1.6000	uM
7-[4-(2-methoxyphenyl)piperazine-1-carbonyl]-3-[(2-methylphenyl)methylsulfanylmethyl]-3,4-dihydro-1H-quinoxalin-2-one	1930116: Inhibition of fluorescent labeled mannosylated BSA probe to DC-SIGN (unknown origin)	ic50	1.6000	uM
propan-2-yl 4-[5-[(Z)-[5-oxo-1-(4-sulfamoylphenyl)-3-(trifluoromethyl)pyrazol-4-ylidene]methyl]furan-2-yl]benzoate	1930116: Inhibition of fluorescent labeled mannosylated BSA probe to DC-SIGN (unknown origin)	ic50	1.6000	uM
amino 4-[3-[3-oxo-6-(4-pyrimidin-2-ylpiperazine-1-carbonyl)-2,4-dihydro-1H-quinoxalin-2-yl]propyl]benzoate	1938517: Inhibition of DC-SIGN extracellular domain (unknown origin) expressed in Escherichia coli DE3(BL21) incubated for 1 hrs in presence of Man-Fl-BSA by high-throughput fluorescence-based assay	ic50	2.6000	uM
4-[3-[3-oxo-6-(4-pyrimidin-2-ylpiperazine-1-carbonyl)-2,4-dihydro-1H-quinoxalin-2-yl]propyl]benzamide	1859219: Inhibition of DC-SIGN (unknown origin)	ic50	2.6000	uM
7-[4-(2-methoxyphenyl)piperazine-1-carbonyl]-3-[3-(2-methylphenyl)propyl]-3,4-dihydro-1H-quinoxalin-2-one	1938517: Inhibition of DC-SIGN extracellular domain (unknown origin) expressed in Escherichia coli DE3(BL21) incubated for 1 hrs in presence of Man-Fl-BSA by high-throughput fluorescence-based assay	ic50	4.4000	uM
N-(3,4-dimethylphenyl)-N-methyl-4-oxo-3-(4-phenylpiperazine-1-carbonyl)-1H-quinoline-6-sulfonamide	1938517: Inhibition of DC-SIGN extracellular domain (unknown origin) expressed in Escherichia coli DE3(BL21) incubated for 1 hrs in presence of Man-Fl-BSA by high-throughput fluorescence-based assay	ic50	6.1000	uM
3-[(2-chloro-6-fluorophenyl)methylsulfanylmethyl]-7-(4-phenylpiperazine-1-carbonyl)-3,4-dihydro-1H-quinoxalin-2-one	1938517: Inhibition of DC-SIGN extracellular domain (unknown origin) expressed in Escherichia coli DE3(BL21) incubated for 1 hrs in presence of Man-Fl-BSA by high-throughput fluorescence-based assay	ic50	7.3000	uM
(2Z)-2-[[4-(4-methylpiperazin-1-yl)-3-nitrophenyl]methylidene]-1-benzothiophen-3-one	1938517: Inhibition of DC-SIGN extracellular domain (unknown origin) expressed in Escherichia coli DE3(BL21) incubated for 1 hrs in presence of Man-Fl-BSA by high-throughput fluorescence-based assay	ic50	10.0000	uM

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects expression, increases reaction	2
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Folic Acid	decreases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Aflatoxin B1	increases methylation	1
Okadaic Acid	increases expression	1
Lactic Acid	increases expression	1

ChEMBL screening assays

23 unique, capped per target: 23 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2185435	Binding	Displacement of biotinylated-TM PAA from human DC-SIGNR at 50 mM after 3 hrs by colorimetry	Target Selectivity of FimH Antagonists. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0R24	NIH 3T3/L-SIGN	Spontaneously immortalized cell line	Male

Clinical trials (associated diseases)

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