CLEC12B

Summary

CLEC12B (C-type lectin domain family 12 member B, HGNC:31966) is a protein-coding gene on chromosome 12p13.2, encoding C-type lectin domain family 12 member B (Q2HXU8). Inhibitory receptor postulated to negatively regulate immune and non-immune functions.

Enables protein phosphatase binding activity and signaling receptor inhibitor activity. Involved in several processes, including melanocyte proliferation; natural killer cell inhibitory signaling pathway; and regulation of signal transduction. Located in external side of plasma membrane. Part of protein-containing complex.

Source: NCBI Gene 387837 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 31 total
• MANE Select transcript: NM_001129998

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:31966
Approved symbol	CLEC12B
Name	C-type lectin domain family 12 member B
Location	12p13.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000256660
Ensembl biotype	protein_coding
OMIM	617573
Entrez	387837

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 2 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000338896, ENST00000396502, ENST00000535903, ENST00000539155, ENST00000544853

RefSeq mRNA: 5 — MANE Select: NM_001129998 NM_001129998, NM_001319241, NM_001319242, NM_001387138, NM_205852

CCDS: CCDS44830, CCDS8610

Canonical transcript exons

ENST00000338896 — 6 exons

Exon	Start	End
ENSE00001372501	10018331	10018796
ENSE00001377920	10015612	10015727
ENSE00001388759	10012785	10012883
ENSE00001391438	10014523	10014741
ENSE00002296691	10010627	10010850
ENSE00003661352	10015252	10015406

Expression profiles

Bgee: expression breadth ubiquitous, 136 present calls, max score 91.22.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0380 / max 32.7486, expressed in 3 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
124119	0.0192	3
124118	0.0168	3
206584	0.0020	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	91.22	gold quality
leukocyte	CL:0000738	89.80	gold quality
right testis	UBERON:0004534	88.07	gold quality
left testis	UBERON:0004533	87.24	gold quality
testis	UBERON:0000473	85.56	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.93	gold quality
granulocyte	CL:0000094	82.09	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.61	gold quality
blood	UBERON:0000178	72.00	gold quality
spleen	UBERON:0002106	71.29	gold quality
mucosa of stomach	UBERON:0001199	68.67	gold quality
vermiform appendix	UBERON:0001154	67.49	gold quality
skin of leg	UBERON:0001511	66.87	gold quality
right lung	UBERON:0002167	65.91	gold quality
skin of abdomen	UBERON:0001416	65.32	gold quality
sperm	CL:0000019	64.96	silver quality
bone marrow cell	CL:0002092	64.93	silver quality
upper lobe of left lung	UBERON:0008952	64.18	gold quality
zone of skin	UBERON:0000014	64.08	gold quality
upper lobe of lung	UBERON:0008948	63.44	gold quality
upper leg skin	UBERON:0004262	63.15	gold quality
caecum	UBERON:0001153	61.59	gold quality
bone marrow	UBERON:0002371	61.02	gold quality
rectum	UBERON:0001052	57.39	gold quality
gall bladder	UBERON:0002110	56.60	gold quality
upper arm skin	UBERON:0004263	55.57	gold quality
lung	UBERON:0002048	54.83	gold quality
right coronary artery	UBERON:0001625	54.63	gold quality
trabecular bone tissue	UBERON:0002483	54.46	silver quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.70

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

108 targeting CLEC12B, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-106B-5P	99.88	74.72	2795

Literature-anchored findings (GeneRIF, showing 6)

• CLEC12B is an inhibitory receptor on myeloid cells (PMID:17562706)
• we identified a potential deleterious, missense mutation in CLEC12B in two children affected by ganglioneuroma and neuroblastoma (PMID:30350915)
• Selective expression of a C-type lectin receptor, Clec12b, on skin mast cells. (PMID:34020140)
• CLEC12B Decreases Melanoma Proliferation by Repressing Signal Transducer and Activator of Transcription 3. (PMID:34310951)
• CLEC12B suppresses lung cancer progression by inducing SHP-1 expression and inactivating the PI3K/AKT signaling pathway. (PMID:34780782)
• CLEC12B Is a Melanocytic Gene Regulating the Color of the Skin. (PMID:34896119)

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	Clec12b	ENSMUSG00000030158
rattus_norvegicus	Clec12b	ENSRNOG00000053638
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), CLEC9A (ENSG00000197992), KLRC2 (ENSG00000205809), KLRC3 (ENSG00000205810), KLRK1 (ENSG00000213809), CLEC2L (ENSG00000236279), KLRF2 (ENSG00000256797), CLEC5A (ENSG00000258227)

Protein

Protein identifiers

C-type lectin domain family 12 member B — Q2HXU8 (reviewed: Q2HXU8)

Alternative names: Macrophage antigen H

All UniProt accessions (3): A0A140VK10, Q2HXU8, F5H4H7

UniProt curated annotations — full annotation on UniProt →

Function. Inhibitory receptor postulated to negatively regulate immune and non-immune functions. Upon phosphorylation, recruits SH2 domain-containing PTPN6 and PTPN11 phosphatases to its ITIM motif and antagonizes activation signals. Although it inhibits KLRK1/NKG2D-mediated signaling, it does not bind known ligands of KLRK1/NKG2D and therefore is not its inhibitory counterpart. May limit activation of myeloid cell subsets in response to infection or tissue inflammation. May protect target cells against natural killer cell-mediated lysis. May negatively regulate cell cycle and differentiation of melanocytes via inactivation of STAT3.

Subunit / interactions. Homodimer. Interacts (via ITIM motif) with PTPN6. Interacts (via ITIM motif) with PTPN11; this interaction triggers dephosphorylation and activation of PTPN11.

Subcellular location. Cell membrane.

Tissue specificity. Detected in colon, heart, kidney, liver, lung, mammary gland, ovary, spleen and testis. Expressed in melanocytes (at protein level).

Post-translational modifications. N-glycosylated.

Domain organisation. Contains 1 copy of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM). This motif is involved in modulation of cellular responses. The phosphorylated ITIM motif can bind the SH2 domain of several SH2-containing phosphatases.

Induction. Up-regulated upon differentiation of monocytes to macrophages.

Isoforms (2)

UniProt ID	Names	Canonical?
Q2HXU8-1	1	yes
Q2HXU8-2	2

RefSeq proteins (5): NP_001123470, NP_001306170, NP_001306171, NP_001374067, NP_995324 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001304	C-type_lectin-like	Domain
IPR013600	Ly49_N	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, PF08391

UniProt features (17 total): glycosylation site 3, topological domain 2, disulfide bond 2, splice variant 2, sequence variant 2, chain 1, mutagenesis site 1, transmembrane region 1, domain 1, short sequence motif 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q2HXU8-F1	87.17	0.72

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 (2): 172–263, 242–255

Glycosylation sites (3): 91, 176, 237

Mutagenesis-validated functional residues (1):

Position	Phenotype
7	abolishes tyrosine phosphorylation and inhibitory receptor activity. abolishes interaction with ptpn6 and ptpn11. abolis

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 107 (showing top): GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_MEDIATED_IMMUNITY, KORKOLA_CHORIOCARCINOMA_DN, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, GOCC_CELL_SURFACE, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, GOBP_NEGATIVE_REGULATION_OF_NATURAL_KILLER_CELL_MEDIATED_IMMUNITY, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY, KORKOLA_EMBRYONAL_CARCINOMA_DN, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_NEGATIVE_REGULATION_OF_DEFENSE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_MOLECULAR_FUNCTION

GO Biological Process (5): natural killer cell inhibitory signaling pathway (GO:0002769), negative regulation of natural killer cell mediated cytotoxicity (GO:0045953), melanocyte proliferation (GO:0097325), negative regulation of receptor signaling pathway via STAT (GO:1904893), negative regulation of signaling receptor activity (GO:2000272)

GO Molecular Function (5): protein phosphatase binding (GO:0019903), carbohydrate binding (GO:0030246), signaling receptor inhibitor activity (GO:0030547), protein binding (GO:0005515), signaling receptor regulator activity (GO:0030545)

GO Cellular Component (4): external side of plasma membrane (GO:0009897), protein-containing complex (GO:0032991), plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signaling receptor activity	3
binding	2
immune response-inhibiting cell surface receptor signaling pathway	1
negative regulation of leukocyte mediated cytotoxicity	1
negative regulation of natural killer cell mediated immunity	1
natural killer cell mediated cytotoxicity	1
regulation of natural killer cell mediated cytotoxicity	1
epithelial cell proliferation	1
negative regulation of signal transduction	1
cell surface receptor signaling pathway via STAT	1
regulation of receptor signaling pathway via STAT	1
regulation of signaling receptor activity	1
negative regulation of molecular function	1
phosphatase binding	1
signaling receptor regulator activity	1
molecular function inhibitor activity	1
molecular function regulator activity	1
plasma membrane	1
cell surface	1
side of membrane	1
cellular_component	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

512 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLEC12B	PTPN11	Q06124	530
CLEC12B	ASB17	Q8WXJ9	506
CLEC12B	SRFBP1	Q8NEF9	461
CLEC12B	CLEC4D	Q8WXI8	458
CLEC12B	SYK	P43405	437
CLEC12B	RNF207	Q6ZRF8	428
CLEC12B	CD164L2	Q6UWJ8	427
CLEC12B	CAV1	Q03135	418
CLEC12B	THBD	P07204	415
CLEC12B	MROH8	Q9H579	384
CLEC12B	CPSF6	Q16630	378
CLEC12B	CHID1	Q9BWS9	373
CLEC12B	ALKBH7	Q9BT30	370
CLEC12B	LY75	O60449	367
CLEC12B	NEMP2	A6NFY4	359

IntAct

3 interactions, top by confidence:

A	B	Type	Score
CLEC12B	GXYLT2	psi-mi:“MI:0914”(association)	0.350
CLEC12B	CLGN	psi-mi:“MI:0914”(association)	0.350

BioGRID (183): CLEC12B (Two-hybrid), CLEC12B (Two-hybrid), CLEC12B (Two-hybrid), CLEC12B (Two-hybrid), CLEC12B (Two-hybrid), CLEC12B (Two-hybrid), CLEC12B (Two-hybrid), CLEC12B (Two-hybrid), CLEC12B (Two-hybrid), CLEC12B (Two-hybrid), CLEC12B (Two-hybrid), FAM69A (Affinity Capture-MS), MGAT1 (Affinity Capture-MS), ST3GAL2 (Affinity Capture-MS), POMGNT2 (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: A8WUV1, Q2HXU8, Q2NL33, Q61282, Q86NG3, Q94417, Q9XVS3, B2KG20, B4XSZ4, D4AD02, O54709, O70215, P0DL30, P26718, P61252, Q149M0, Q38HS3, Q49BZ4, Q4TU93, Q5DT36, Q5DT39, Q64449, Q67EQ0, Q6QLQ4, Q6UXN8, Q80ZC8, Q8BRU4, Q8MJH1, Q9MZ37, Q9MZJ7, Q9UBG0, O35778, O54707, O70156, P21063, P24765, P26715, P26717, Q0VCS6, Q13241

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	29
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1117 predictions. Top by Δscore:

Variant	Effect	Δscore
12:10012879:GATGT:G	donor_gain	1.0000
12:10012882:GT:G	donor_gain	1.0000
12:10012884:G:GG	donor_gain	1.0000
12:10013898:T:G	donor_gain	1.0000
12:10010848:GAG:G	donor_gain	0.9900
12:10010849:AGGTA:A	donor_loss	0.9900
12:10010850:GGT:G	donor_loss	0.9900
12:10010851:GTAGG:G	donor_loss	0.9900
12:10010852:T:A	donor_loss	0.9900
12:10014690:C:T	donor_gain	0.9900
12:10014723:C:G	donor_gain	0.9900
12:10014737:TTCAG:T	donor_loss	0.9900
12:10014738:TCAG:T	donor_loss	0.9900
12:10014739:CAG:C	donor_loss	0.9900
12:10014740:AG:A	donor_loss	0.9900
12:10014741:GG:G	donor_loss	0.9900
12:10014742:G:A	donor_loss	0.9900
12:10014743:T:A	donor_loss	0.9900
12:10015699:G:T	donor_gain	0.9900
12:10012780:TCCA:T	acceptor_loss	0.9800
12:10012781:CCAG:C	acceptor_loss	0.9800
12:10012782:CA:C	acceptor_loss	0.9800
12:10012783:A:AT	acceptor_loss	0.9800
12:10012783:AG:A	acceptor_gain	0.9800
12:10012784:G:GC	acceptor_loss	0.9800
12:10012784:GG:G	acceptor_gain	0.9800
12:10012784:GGGC:G	acceptor_gain	0.9800
12:10012880:ATGTG:A	donor_loss	0.9800
12:10012881:TGT:T	donor_gain	0.9800
12:10012881:TGTGT:T	donor_loss	0.9800

AlphaMissense

1838 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:10015337:G:C	W165C	0.984
12:10015337:G:T	W165C	0.984
12:10015698:G:C	W217C	0.980
12:10015698:G:T	W217C	0.980
12:10015283:G:C	W147C	0.979
12:10015283:G:T	W147C	0.979
12:10015358:C:G	C172W	0.977
12:10015344:A:C	S168R	0.976
12:10015346:T:A	S168R	0.976
12:10015346:T:G	S168R	0.976
12:10018374:T:A	C242S	0.976
12:10018375:G:C	C242S	0.976
12:10015356:T:A	C172S	0.973
12:10015357:G:C	C172S	0.973
12:10015656:G:C	W203C	0.972
12:10015656:G:T	W203C	0.972
12:10018413:T:A	C255S	0.970
12:10018414:G:C	C255S	0.970
12:10018437:T:A	C263S	0.968
12:10018438:G:C	C263S	0.968
12:10015357:G:A	C172Y	0.967
12:10015304:C:G	C154W	0.963
12:10015260:T:A	C140S	0.962
12:10015261:G:C	C140S	0.962
12:10015303:G:A	C154Y	0.961
12:10015302:T:A	C154S	0.960
12:10015303:G:C	C154S	0.960
12:10015356:T:C	C172R	0.960
12:10015371:T:C	S177P	0.958
12:10018374:T:C	C242R	0.954

dbSNP variants (sampled 300 via entrez): RS1000533348 (12:10011658 T>C), RS1000685912 (12:10006182 G>A), RS1000722848 (12:10009573 A>C), RS1000990775 (12:10011894 G>A), RS1001158510 (12:10009349 G>T), RS1001376790 (12:10007130 G>T), RS1001474979 (12:10013457 C>T), RS1001604761 (12:10018893 G>A), RS1001655973 (12:10011960 G>A,T), RS1001990737 (12:10008666 A>G), RS1002312296 (12:10006794 G>A), RS1002426062 (12:10007988 T>C), RS1002803384 (12:10008346 T>C), RS1003011782 (12:10006377 C>G), RS1003323224 (12:10013386 C>T)

Disease associations

OMIM: gene MIM:617573 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002090_6	Sensory disturbances after bilateral sagittal split ramus osteotomy	6.000000e-06
GCST002187_10	Systolic blood pressure in sickle cell anemia	5.000000e-06
GCST010725_46	Malaria	1.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005324	post-operative sensory disturbance
EFO:0006335	systolic blood pressure

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
triphenyl phosphate	affects expression	1
sodium arsenite	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases methylation	1
Endosulfan	increases expression	1
Nickel	decreases expression	1
Oxygen	decreases expression	1
Antirheumatic Agents	decreases expression	1

Clinical trials (associated diseases)

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