CLEC9A

Summary

CLEC9A (C-type lectin domain containing 9A, HGNC:26705) is a protein-coding gene on chromosome 12p13.2, encoding C-type lectin domain family 9 member A (Q6UXN8). Functions as an endocytic receptor on a small subset of myeloid cells specialized for the uptake and processing of material from dead cells.

CLEC9A is a group V C-type lectin-like receptor (CTLR) that functions as an activation receptor and is expressed on myeloid lineage cells (Huysamen et al., 2008 [PubMed 18408006]).

Source: NCBI Gene 283420 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 38 total
• MANE Select transcript: NM_207345

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26705
Approved symbol	CLEC9A
Name	C-type lectin domain containing 9A
Location	12p13.2
Locus type	gene with protein product
Status	Approved
Aliases	DNGR1, UNQ9341, HEEE9341, CD370, DNGR-1
Ensembl gene	ENSG00000197992
Ensembl biotype	protein_coding
OMIM	612252
Entrez	283420

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000355819, ENST00000538482, ENST00000544751, ENST00000906255

RefSeq mRNA: 1 — MANE Select: NM_207345 NM_207345

CCDS: CCDS8611

Canonical transcript exons

ENST00000355819 — 9 exons

Exon	Start	End
ENSE00001404371	10065500	10066031
ENSE00001412728	10030682	10030972
ENSE00001422394	10054271	10054351
ENSE00001423423	10051991	10052094
ENSE00001425642	10052630	10052778
ENSE00001426652	10061127	10061273
ENSE00001432375	10063055	10063206
ENSE00001432968	10064732	10064853
ENSE00003672648	10041466	10041620

Expression profiles

Bgee: expression breadth ubiquitous, 129 present calls, max score 82.43.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.7269 / max 85.0180, expressed in 151 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
124125	0.2391	95
124127	0.1958	54
124123	0.1248	46
124126	0.0836	39
124120	0.0387	9
124124	0.0316	15
124121	0.0068	3
124122	0.0066	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.43	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	77.78	gold quality
lymph node	UBERON:0000029	76.49	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	73.30	gold quality
spinal cord	UBERON:0002240	73.27	gold quality
substantia nigra	UBERON:0002038	70.42	gold quality
monocyte	CL:0000576	67.33	gold quality
leukocyte	CL:0000738	67.31	gold quality
smooth muscle tissue	UBERON:0001135	67.13	gold quality
vermiform appendix	UBERON:0001154	65.26	gold quality
thymus	UBERON:0002370	63.98	silver quality
testis	UBERON:0000473	63.91	gold quality
gall bladder	UBERON:0002110	63.72	gold quality
hypothalamus	UBERON:0001898	63.58	gold quality
left testis	UBERON:0004533	63.57	gold quality
duodenum	UBERON:0002114	63.25	gold quality
right testis	UBERON:0004534	62.94	gold quality
prefrontal cortex	UBERON:0000451	62.65	gold quality
Ammon’s horn	UBERON:0001954	62.43	gold quality
temporal lobe	UBERON:0001871	62.16	gold quality
spleen	UBERON:0002106	62.14	gold quality
amygdala	UBERON:0001876	62.10	gold quality
right lung	UBERON:0002167	62.10	gold quality
caudate nucleus	UBERON:0001873	62.03	gold quality
placenta	UBERON:0001987	61.67	gold quality
mucosa of transverse colon	UBERON:0004991	61.67	gold quality
quadriceps femoris	UBERON:0001377	61.63	gold quality
blood	UBERON:0000178	60.93	gold quality
upper lobe of left lung	UBERON:0008952	60.16	gold quality
granulocyte	CL:0000094	59.95	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-GEOD-89232	yes	1042.01
E-MTAB-10553	yes	694.01
E-MTAB-9906	yes	556.91
E-HCAD-32	yes	533.55
E-MTAB-9801	yes	519.81
E-HCAD-1	yes	29.16
E-MTAB-6701	yes	24.35
E-CURD-88	yes	10.39
E-MTAB-6678	yes	8.75
E-MTAB-10042	yes	8.66
E-ANND-3	yes	4.02

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

21 targeting CLEC9A, 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-548AN	99.97	70.91	2817
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-4753-5P	99.54	68.51	1356
HSA-MIR-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055
HSA-MIR-6740-3P	99.48	68.49	1392
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-2116-5P	99.32	69.34	1273
HSA-MIR-223-5P	99.24	68.82	1206
HSA-MIR-6739-3P	99.22	68.84	1843
HSA-MIR-6768-3P	99.14	67.38	1319
HSA-MIR-3926	98.95	69.26	1438
HSA-MIR-502-5P	98.77	66.51	906
HSA-MIR-3190-3P	97.61	66.95	1406
HSA-MIR-6818-5P	97.50	67.10	1167
HSA-MIR-3137	97.26	66.78	761
HSA-MIR-4484	96.35	64.08	382
HSA-MIR-6823-5P	96.26	65.69	919

Literature-anchored findings (GeneRIF, showing 19)

• CLEC9A functions as an activation receptor (PMID:18408006)
• DC, NK lectin group receptor-1 (DNGR-1) is a C-type lectin of the NK cell receptor group (PMID:18497879)
• The paper cited (J Clin Invest. 2008 Jun;118(6):2098-110) is the first characterization of human and mouse CLEC9A (a.k.a DNGR-1) (PMID:18497879)
• analysis of differences between mouse and human Clec9A (PMID:18669894)
• CLEC9A functions as a SYK-coupled C-type lectin receptor to mediate sensing of necrosis by the principal dendritic-cell subset involved in regulating cross-priming to cell-associated antigens (PMID:19219027)
• A population of human dendritic cells (DC) that expresses DNGR-1 (CLEC9A) and high levels of BDCA3 and resembles mouse CD8alpha+ DCs in phenotype and function, is characterized. (PMID:20479117)
• 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)
• Data show that CLEC9A is only expressed on immature BDCA3(+) myeloid dendritic cells (mDCs). (PMID:22234694)
• High expression of DNGR-1 specifically and universally identifies a unique dendritic cells subset in mouse and humans. (PMID:22442345)
• study showsn that the DNGR-1 ligand is preserved from yeast to man and corresponds to the F-actin component of the cellular cytoskeleton; identification of F-actin as a DNGR-1 ligand suggests that cytoskeletal exposure is a universal sign of cell damage that can be targeted by the innate immune system to initiate immunity (PMID:22483800)
• propose that Clec9A provides targeted recruitment of the adaptive immune system during infection and can also be utilized to enhance immune responses generated by vaccines. (PMID:22483802)
• Activated dendritic cell subsets expressing CD141/CLEA9A/CD1c, likely recruited into the tubulointerstitium, are positioned to play a role in the development of fibrosis and, thus, progression to chronic kidney disease. (PMID:24049150)
• Data indicate that blood dendritic cell antigen 3 BDCA3(+) and C-type lectin domain family 9, member A CLEC9A(+) dendritic cells (DC) are of major importance in the induction of anti-viral and anti-tumor immunity. (PMID:24910448)
• Clec9a is responsible for the antigen cross-presentation of dendritic cell subsets and may be a target of immunotherapy (PMID:27250027)
• findings demonstrate that CLEC9A is a specialized receptor that modulates the innate immune response when there is a mycobacterial infection (PMID:29065139)
• The receptor DNGR-1 signals for phagosomal rupture to promote cross-presentation of dead-cell-associated antigens. (PMID:33349708)
• Secreted gelsolin inhibits DNGR-1-dependent cross-presentation and cancer immunity. (PMID:34081922)
• Expression of clec9a in the oral cancer microenvironment. A preliminary immunohistochemical pilot study. (PMID:34415004)
• Increased expression of Clec9A on cDC1s associated with cytotoxic CD8(+) T cell response in COPD. (PMID:35901921)

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	Clec9a	ENSMUSG00000046080
rattus_norvegicus	Clec9a	ENSRNOG00000051690
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), CLEC2A (ENSG00000188393), KLRG2 (ENSG00000188883), KLRC2 (ENSG00000205809), KLRC3 (ENSG00000205810), KLRK1 (ENSG00000213809), CLEC2L (ENSG00000236279), CLEC12B (ENSG00000256660), KLRF2 (ENSG00000256797), CLEC5A (ENSG00000258227)

Protein

Protein identifiers

C-type lectin domain family 9 member A — Q6UXN8 (reviewed: Q6UXN8)

All UniProt accessions (1): Q6UXN8

UniProt curated annotations — full annotation on UniProt →

Function. Functions as an endocytic receptor on a small subset of myeloid cells specialized for the uptake and processing of material from dead cells. Recognizes filamentous form of actin in association with particular actin-binding domains of cytoskeletal proteins, including spectrin, exposed when cell membranes are damaged, and mediate the cross-presentation of dead-cell associated antigens in a Syk-dependent manner.

Subunit / interactions. Homodimer.

Subcellular location. Membrane.

Tissue specificity. In peripheral blood highly restricted on the surface of BDCA31(+) dendritic cells and on a small subset of CD14(+) and CD16(-) monocytes.

Post-translational modifications. N-glycosylated.

RefSeq proteins (1): NP_997228* (*=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
IPR033992	NKR-like_CTLD	Domain
IPR043315	CLEC9A	Family

Pfam: PF00059

UniProt features (25 total): strand 8, disulfide bond 3, topological domain 2, mutagenesis site 2, helix 2, glycosylation site 2, chain 1, sequence variant 1, transmembrane region 1, turn 1, domain 1, short sequence motif 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3VPP	X-RAY DIFFRACTION	1.64

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UXN8-F1	84.34	0.64

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 (3): 211–224, 113–124, 141–232

Glycosylation sites (2): 81, 223

Mutagenesis-validated functional residues (2):

Position	Phenotype
131	abolishes binding to damaged cells; when associated with a-227.
227	abolishes binding to damaged cells; when associated with a-131.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 44 (showing top): GOCC_CELL_SURFACE, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_CYTOKINE_PRODUCTION, GOBP_IMPORT_INTO_CELL, GOBP_ENDOCYTOSIS, GOBP_POSITIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_RECEPTOR_MEDIATED_ENDOCYTOSIS, YOSHIMURA_MAPK8_TARGETS_UP, DELACROIX_RARG_BOUND_MEF, GSE13522_CTRL_VS_T_CRUZI_G_STRAIN_INF_SKIN_DN, PAX3_TARGET_GENES, MIR6768_3P, MIR3137, HAY_BONE_MARROW_CD34_POS_HSC

GO Biological Process (3): positive regulation of cytokine production (GO:0001819), receptor-mediated endocytosis (GO:0006898), endocytosis (GO:0006897)

GO Molecular Function (1): carbohydrate binding (GO:0030246)

GO Cellular Component (2): cell surface (GO:0009986), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cytokine production	1
regulation of cytokine production	1
positive regulation of gene expression	1
positive regulation of multicellular organismal process	1
endocytosis	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
binding	1

Protein interactions and networks

STRING

1058 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLEC9A	THBD	P07204	888
CLEC9A	MPPE1	Q53F39	852
CLEC9A	SYK	P43405	807
CLEC9A	XCR1	P46094	801
CLEC9A	LY75	O60449	787
CLEC9A	BATF3	Q9NR55	733
CLEC9A	CD1C	P29017	718
CLEC9A	IRF8	Q02556	704
CLEC9A	ITGAE	P38570	699
CLEC9A	CLEC4D	Q8WXI8	698
CLEC9A	ITGAX	P20702	662
CLEC9A	CD8A	P01732	622
CLEC9A	SIRPA	P78324	610
CLEC9A	ITGAM	P11215	584
CLEC9A	ZBTB46	Q86UZ6	582

IntAct

0 interactions, top by confidence:

BioGRID (1): CLEC9A (Reconstituted Complex)

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

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1372 predictions. Top by Δscore:

Variant	Effect	Δscore
12:10041461:TCCA:T	acceptor_loss	1.0000
12:10041462:CCAG:C	acceptor_loss	1.0000
12:10041463:CAGGT:C	acceptor_loss	1.0000
12:10041464:A:AG	acceptor_gain	1.0000
12:10041464:A:AT	acceptor_loss	1.0000
12:10041464:AG:A	acceptor_gain	1.0000
12:10041464:AGGT:A	acceptor_gain	1.0000
12:10041465:G:GC	acceptor_gain	1.0000
12:10041465:GG:G	acceptor_gain	1.0000
12:10041465:GGT:G	acceptor_gain	1.0000
12:10041465:GGTG:G	acceptor_gain	1.0000
12:10041465:GGTGA:G	acceptor_gain	1.0000
12:10041616:TTCTG:T	donor_gain	1.0000
12:10041621:G:A	donor_loss	1.0000
12:10041621:G:GG	donor_gain	1.0000
12:10041622:T:G	donor_loss	1.0000
12:10052095:G:GG	donor_gain	1.0000
12:10064849:GGCCT:G	donor_gain	1.0000
12:10064850:GCCT:G	donor_gain	1.0000
12:10064850:GCCTG:G	donor_gain	1.0000
12:10064854:G:GG	donor_gain	1.0000
12:10041454:T:A	acceptor_gain	0.9900
12:10041455:G:A	acceptor_gain	0.9900
12:10047180:AAT:A	donor_gain	0.9900
12:10051989:A:AG	acceptor_gain	0.9900
12:10051990:G:GG	acceptor_gain	0.9900
12:10052090:ATTAT:A	donor_gain	0.9900
12:10041617:TCTG:T	donor_gain	0.9800
12:10051989:AGT:A	acceptor_gain	0.9800
12:10051989:AGTG:A	acceptor_gain	0.9800

AlphaMissense

1596 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:10064782:G:C	W174C	0.970
12:10064782:G:T	W174C	0.970
12:10064824:G:C	W188C	0.964
12:10064824:G:T	W188C	0.964
12:10063144:A:C	S137R	0.954
12:10063146:T:A	S137R	0.954
12:10063146:T:G	S137R	0.954
12:10063137:G:C	W134C	0.953
12:10063137:G:T	W134C	0.953
12:10065594:T:C	F230L	0.951
12:10065596:T:A	F230L	0.951
12:10065596:T:G	F230L	0.951
12:10065600:T:A	C232S	0.951
12:10065601:G:C	C232S	0.951
12:10063086:G:C	W117C	0.947
12:10063086:G:T	W117C	0.947
12:10063156:T:A	C141S	0.944
12:10063157:G:C	C141S	0.944
12:10064818:G:C	W186C	0.936
12:10064818:G:T	W186C	0.936
12:10064735:T:C	F159L	0.935
12:10064737:T:A	F159L	0.935
12:10064737:T:G	F159L	0.935
12:10065537:T:A	C211S	0.932
12:10065538:G:C	C211S	0.932
12:10063158:T:G	C141W	0.931
12:10063171:T:C	S146P	0.921
12:10065605:G:C	E233D	0.920
12:10065605:G:T	E233D	0.920
12:10064780:T:A	W174R	0.915

dbSNP variants (sampled 300 via entrez): RS1000005569 (12:10063685 T>A,C), RS1000160675 (12:10030568 C>A,T), RS1000406193 (12:10037905 G>A,T), RS1000437511 (12:10037646 G>A,C), RS1000649856 (12:10062514 G>T), RS1000678144 (12:10049223 A>G), RS1000715095 (12:10029401 A>C), RS1000734816 (12:10051162 G>A), RS1000747001 (12:10040520 G>A,C,T), RS1000788541 (12:10050893 A>G), RS1000791470 (12:10055924 T>G), RS1000947723 (12:10065873 A>G), RS1000956834 (12:10034865 T>C), RS1000993232 (12:10062044 C>T), RS1001038011 (12:10045126 C>T)

Disease associations

OMIM: gene MIM:612252 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
triphenyl phosphate	affects expression	1
arsenite	decreases methylation	1
sodium arsenite	increases expression	1
di-n-butylphosphoric acid	affects expression	1
Resveratrol	affects cotreatment, decreases expression	1
Copper	decreases expression, affects cotreatment	1

Clinical trials (associated diseases)

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