CCL21

Summary

CCL21 (C-C motif chemokine ligand 21, HGNC:10620) is a protein-coding gene on chromosome 9p13.3, encoding C-C motif chemokine 21 (O00585). Inhibits hemopoiesis and stimulates chemotaxis.

This antimicrobial gene is one of several CC cytokine genes clustered on the p-arm of chromosome 9. Cytokines are a family of secreted proteins involved in immunoregulatory and inflammatory processes. The CC cytokines are proteins characterized by two adjacent cysteines. Similar to other chemokines the protein encoded by this gene inhibits hemopoiesis and stimulates chemotaxis. This protein is chemotactic in vitro for thymocytes and activated T cells, but not for B cells, macrophages, or neutrophils. The cytokine encoded by this gene may also play a role in mediating homing of lymphocytes to secondary lymphoid organs. It is a high affinity functional ligand for chemokine receptor 7 that is expressed on T and B lymphocytes and a known receptor for another member of the cytokine family (small inducible cytokine A19).

Source: NCBI Gene 6366 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 19 total
• MANE Select transcript: NM_002989

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10620
Approved symbol	CCL21
Name	C-C motif chemokine ligand 21
Location	9p13.3
Locus type	gene with protein product
Status	Approved
Aliases	SLC, exodus-2, TCA4, CKb9, 6Ckine, ECL
Ensembl gene	ENSG00000137077
Ensembl biotype	protein_coding
OMIM	602737
Entrez	6366

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000259607, ENST00000378792, ENST00000714162, ENST00000714163, ENST00000885823, ENST00000885824

RefSeq mRNA: 1 — MANE Select: NM_002989 NM_002989

CCDS: CCDS6571

Canonical transcript exons

ENST00000259607 — 4 exons

Exon	Start	End
ENSE00000928120	34709005	34709427
ENSE00004023038	34710000	34710136
ENSE00004023039	34709500	34709682
ENSE00004023041	34709777	34709897

Expression profiles

Bgee: expression breadth ubiquitous, 206 present calls, max score 99.57.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 13.5437 / max 3019.5796, expressed in 119 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
100543	13.5146	119
100542	0.0291	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lymph node	UBERON:0000029	99.57	gold quality
right lobe of thyroid gland	UBERON:0001119	99.28	gold quality
vermiform appendix	UBERON:0001154	98.67	gold quality
left lobe of thyroid gland	UBERON:0001120	98.59	gold quality
caecum	UBERON:0001153	98.15	gold quality
rectum	UBERON:0001052	97.98	gold quality
thyroid gland	UBERON:0002046	97.82	gold quality
gall bladder	UBERON:0002110	96.97	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.93	gold quality
mucosa of stomach	UBERON:0001199	96.89	gold quality
mucosa of transverse colon	UBERON:0004991	96.46	gold quality
right uterine tube	UBERON:0001302	96.45	gold quality
upper lobe of left lung	UBERON:0008952	96.36	gold quality
upper lobe of lung	UBERON:0008948	95.71	gold quality
small intestine	UBERON:0002108	95.34	gold quality
spleen	UBERON:0002106	95.32	gold quality
lower esophagus	UBERON:0013473	95.10	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.09	gold quality
omental fat pad	UBERON:0010414	94.66	gold quality
lower esophagus mucosa	UBERON:0035834	94.64	gold quality
peritoneum	UBERON:0002358	94.63	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.33	gold quality
left uterine tube	UBERON:0001303	94.20	gold quality
esophagus	UBERON:0001043	94.04	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.48	gold quality
esophagus mucosa	UBERON:0002469	93.18	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.73	gold quality
superficial temporal artery	UBERON:0001614	92.55	gold quality
ileal mucosa	UBERON:0000331	92.50	gold quality
decidua	UBERON:0002450	91.51	gold quality

Single-cell (SCXA)

Detected in 18 experiment(s), a significant marker in 17.

Experiment	Marker?	Max mean expression
E-MTAB-10137	yes	45995.76
E-HCAD-15	yes	41263.43
E-HCAD-11	yes	31397.04
E-GEOD-130148	yes	31038.15
E-MTAB-6308	yes	30218.16
E-HCAD-24	yes	29918.64
E-MTAB-6653	yes	27341.62
E-MTAB-8410	yes	26921.19
E-CURD-126	yes	26469.51
E-HCAD-1	yes	26438.39
E-MTAB-6701	yes	23683.11
E-MTAB-8322	yes	16735.37
E-MTAB-8142	yes	12549.25
E-MTAB-8381	yes	8518.60
E-CURD-46	yes	8365.37

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB2, RELB, SMAD3

miRNA regulators (miRDB)

29 targeting CCL21, 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-6756-5P	99.82	67.97	2466
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-4710	98.61	65.96	1048
HSA-MIR-4722-5P	98.46	66.34	1611
HSA-MIR-624-3P	98.37	67.06	1067
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-4768-3P	98.16	66.02	2330
HSA-MIR-4483	98.09	64.12	1642
HSA-MIR-506-5P	98.02	67.41	1065
HSA-MIR-6893-3P	97.79	64.91	1238
HSA-MIR-6812-5P	97.56	65.39	1059
HSA-MIR-342-5P	97.25	64.10	817
HSA-MIR-939-5P	97.10	65.80	1579
HSA-MIR-370-3P	97.09	64.92	1221
HSA-MIR-331-5P	96.59	67.94	705
HSA-MIR-1343-5P	96.48	66.06	1506
HSA-MIR-6742-5P	96.32	64.01	869
HSA-MIR-6747-5P	96.17	64.99	743
HSA-MIR-1293	96.16	64.69	916
HSA-MIR-9900	96.06	65.48	557

Literature-anchored findings (GeneRIF, showing 40)

• located in high endothelial venules in an appropriate location to induce transendothelial migration of CLL cells into lymph nodes (PMID:11929789)
• the expression of CCL21 but not CCL19 or 20 was highly induced in endothelial cells of T-cell autoimmune diseases (PMID:12393410)
• CCL21 binding to CCR7 on primary lymphocytes brings about rapid Jak2 phosphorylation. (PMID:12393730)
• Cathepsin D specifically cleaves this protein that is expressed in human breast cancer. (PMID:12651610)
• Most blood vessels in tissue samples from patients with rheumatoid arthritis and ulcerative colitis express CCL21, and many perivascular CD45RA+ naive T cells are found in these tissues, but not in psoriasis, where CCL21+ vessels are rare. (PMID:12707342)
• CCL21 is an antimicrobial protein with bacteriocidal activity against E. coli and S. aureus. (PMID:12949249)
• Expression of CCL21 during chronic hepatitis C is implicated in the recruitment of T lymphocytes and the organization of inflammatory lymphoid tissue and may promote fibrogenesis in the inflamed areas via activation of CCR7 on hepatic stellate cells (PMID:14517790)
• monocyte-derived dendritic cell migration to CCL19 and CCL21 is dependent on phospholipase C and intracellular calcium flux but not on phosphatidylinositol-3 kinase (PMID:14592837)
• 6Ckine may be a potential chemoattractant for endometrial NK cells. (PMID:14667884)
• expression of CCL21, and TLRs 2 and 4 is predominantly induced in the peripheral lymphatic endothelium of the small intestinal microcirculation (PMID:14709406)
• CCL21, a constitutively expressed chemokine, is strongly upregulated in human lymphatic vessels during a Th1/Tc1 allergic inflammatory response. (PMID:14726633)
• Evidence is provided that human CCL21 is a functional ligand for endogenously expressed CXCR3 in human adult microglia. (PMID:14978072)
• CCL21 chemokine has a role in regulating chemokine receptor CCR7 in malignant melanoma (PMID:15073111)
• Activation of CCR7 on mesangial cells by SLC/CCL21 enhances the degree and firmness of cell adhesion and increases cell spreading and the formation of cell-cell contacts (PMID:15569314)
• The CCL-21 chemokine migrated poorly towards the (GFP)-transduced umbilical cord blood (UCB) CD34+ cells. (PMID:15674360)
• no CCL21 mRNA could be detected in high endothelial venules, whereas immunostaining revealed CCL21 protein (PMID:15863780)
• The acquisition of lymphoid features in periductal foci in Sjogrens syndrome is associated with the expression of CXCL13 and CCL21 within the infiltrate. (PMID:15934082)
• The CCL19,CCL21/CCR7 chemokine system is expressed in inflamed muscles of polymyositis and may be involved in the pathomechanism of polymyositis. (PMID:16887149)
• Despite sharing only 25% sequence identity with CCL19, the amino terminal hexapeptide of CCL21 is capable of performing an in vitro role similar to that of CCL19, resulting in G protein activation of the CCR7 receptor. (PMID:16904643)
• chemokine ligand 21 modulates the functional properties of idiopathic pulmonary fibrosis/usual interstitial pneumonia fibroblasts, but not normal fibroblasts (PMID:17331965)
• Results of electrophoresis of the purified SLC protein showed that the molecular weight was larger than the predicted molecular weight. (PMID:17460916)
• The abundance of CD83+ plasmacytoid dendritic cells (DCs) in perivascular areas and the overexpression of CCL19 and CCL21 in perivascular cellular foci suggest plasmacytoid DCs are central to the muscle inflammation in juvenile dermatomyositis. (PMID:17469160)
• prostate-associated lymphoid aggregates, frequently below the epithelia, arranged in B cell follicles expressed CXCL13, and parafollicular T cell areas showed CCL21 expression. (PMID:17474076)
• CXCL13 and CCL21 are expressed in ectopic lymphoid follicles in cutaneous lymphoproliferative disorders. (PMID:17495955)
• after HIV-1 infection of CCL19- or CCL21-treated CD4(+) T-cells, low-level HIV-1 production but high concentrations of integrated HIV-1 DNA, approaching that seen in mitogen-stimulated T-cell blasts, was observed (PMID:17881634)
• CCL21 significantly increased B-cell chronic lymphocytic leukemia MMP-9 production (PMID:17890452)
• knee synovial fluid CCL 21 levels were found to be increased in Rheumatoid arthritis patients as compared to Behcets disease and osteoarthritis patients (PMID:17949547)
• the pattern of CCL21 production in SLOs is maintained during inflammation and that the phenotypic and functional properties of stromal cells, found in SLO T-cell areas, are reproduced at ectopic sites. (PMID:17982129)
• in salivary gland MALT lymphoma the lymphoid chemokines CXCL13 and CCL21 are directly implicated in the organization of ectopic reactive lymphoid tissue (PMID:18354239)
• experiments performed to investigate the survival, adhesion, and metalloproteases secretion indicate that CXCL13 combined with CCL19 and CCL21 mainly affects the chemotaxis of Sezary syndrome cells (PMID:18757429)
• Independent of arrestin 2 or arrestin 3 expression, CCR7/CCL21 internalize. (PMID:18802075)
• Our study implied that lower level of CCL21 in colorectal cancer tissue supports the idea that cancer is related to immunodeficiency (PMID:19082456)
• CCL21 enhances the invasive ability of SW480 cells, induces MMP-9 expression, and promotes the survival of SW480 cells. (PMID:19624896)
• prolonged TLR4 engagement is required for the generation of polySia-expressing DCs that facilitate CCL21 capture and subsequent CCL21-directed migration (PMID:19750015)
• Dendritic cell transfected with secondary lymphoid-tissue chemokine and/or interleukin-2 gene-enhanced cytotoxicity of T-lymphocyte in human bladder tumor cell S in vitro. (PMID:19832038)
• Although CCL21 attracts both human T and B cells, it acts more strongly on naive pathogenic antibody-producing B cells. (PMID:19847900)
• In patients with inflammatory polyarthritis carriage of 1 or more risk alleles of the CCL21 gene was associated with increased cardiovascular disease mortality, whereas carriage of 2 copies was associated with increased all-cause mortality. (PMID:20461788)
• Analysis of migratory and prosurvival pathways induced by the homeostatic chemokines CCL19 and CCL21 in B-cell chronic lymphocytic leukemia. (PMID:20488224)
• Polysialyted NRP2 enhances dendritic cell migration of basic C-terminal ergion of CCL21. (PMID:20488940)
• These results imply a direct role for CCL21 in lymphatic transmigration that involves the selective use of integrin activation in inflammation. (PMID:20739459)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	cxcl32b.1	ENSDARG00000071499
mus_musculus	Ccl21f	ENSMUSG00000073878
mus_musculus	Ccl21d	ENSMUSG00000094065
mus_musculus	Ccl21a	ENSMUSG00000094686
mus_musculus	Ccl21b	ENSMUSG00000095675
mus_musculus	Ccl21e	ENSMUSG00000096596
rattus_norvegicus	Ccl21	ENSRNOG00000034290

Paralogs (26): CX3CL1 (ENSG00000006210), CCL26 (ENSG00000006606), CCL22 (ENSG00000102962), CCL17 (ENSG00000102970), CCL24 (ENSG00000106178), CCL7 (ENSG00000108688), CCL2 (ENSG00000108691), CCL8 (ENSG00000108700), CCL1 (ENSG00000108702), CCL20 (ENSG00000115009), CCL25 (ENSG00000131142), XCL1 (ENSG00000143184), XCL2 (ENSG00000143185), CCL11 (ENSG00000172156), CCL19 (ENSG00000172724), CCL13 (ENSG00000181374), CCL5 (ENSG00000271503), CCL23 (ENSG00000274736), CCL16 (ENSG00000275152), CCL4 (ENSG00000275302), CCL18 (ENSG00000275385), CCL15 (ENSG00000275718), CCL4L2 (ENSG00000276070), CCL3L3 (ENSG00000276085), CCL14 (ENSG00000276409), CCL3 (ENSG00000277632)

Protein

Protein identifiers

C-C motif chemokine 21 — O00585 (reviewed: O00585)

Alternative names: 6Ckine, Beta-chemokine exodus-2, Secondary lymphoid-tissue chemokine, Small-inducible cytokine A21

All UniProt accessions (4): O00585, A0AAQ5BHL9, A0AAQ5BHN2, Q5VZ73

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits hemopoiesis and stimulates chemotaxis. Chemotactic in vitro for thymocytes and activated T-cells, but not for B-cells, macrophages, or neutrophils. Shows preferential activity towards naive T-cells. May play a role in mediating homing of lymphocytes to secondary lymphoid organs. Binds to atypical chemokine receptor ACKR4 and mediates the recruitment of beta-arrestin (ARRB1/2) to ACKR4.

Subunit / interactions. Monomer. Binds to CCR7. Interacts with PDPN; relocalizes PDPN to the basolateral membrane. Interacts with TNFAIP6 (via Link domain). Interacts with GPR174.

Subcellular location. Secreted.

Tissue specificity. Highly expressed in high endothelial venules of lymph nodes, spleen and appendix. Intermediate levels found in small intestine, thyroid gland and trachea. Low level expression in thymus, bone marrow, liver, and pancreas. Also found in tonsil, fetal heart and fetal spleen.

Similarity. Belongs to the intercrine beta (chemokine CC) family.

RefSeq proteins (1): NP_002980* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001811	Chemokine_IL8-like_dom	Domain
IPR034133	Chemokine_CC_DCCL	Domain
IPR036048	Interleukin_8-like_sf	Homologous_superfamily
IPR039809	Chemokine_b/g/d	Family

Pfam: PF00048

UniProt features (15 total): strand 3, disulfide bond 3, helix 2, region of interest 2, compositionally biased region 2, signal peptide 1, chain 1, turn 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
5EKI	X-RAY DIFFRACTION	1.9
9XHI	ELECTRON MICROSCOPY	3.2
9KO4	ELECTRON MICROSCOPY	3.3
9L16	ELECTRON MICROSCOPY	3.5
2L4N	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00585-F1	73.71	0.14

Antibody-complex structures (SAbDab): 1 — 9KO4

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): 31–57, 32–75, 103–122

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-380108	Chemokine receptors bind chemokines
R-HSA-418594	G alpha (i) signalling events
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-388396	GPCR downstream signalling
R-HSA-500792	GPCR ligand binding

MSigDB gene sets: 355 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, MODULE_92, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_DENDRITIC_CELL_MIGRATION, GOBP_REGULATION_OF_T_CELL_CHEMOTAXIS, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_RESPONSE_TO_PROSTAGLANDIN_E, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_LIPID

GO Biological Process (47): establishment of T cell polarity (GO:0001768), immunological synapse formation (GO:0001771), positive regulation of cell-matrix adhesion (GO:0001954), dendritic cell chemotaxis (GO:0002407), positive regulation of dendritic cell antigen processing and presentation (GO:0002606), inflammatory response (GO:0006954), immune response (GO:0006955), G protein-coupled receptor signaling pathway (GO:0007186), cell-cell signaling (GO:0007267), positive regulation of glycoprotein biosynthetic process (GO:0010560), positive regulation of T cell chemotaxis (GO:0010820), positive regulation of cell migration (GO:0030335), positive regulation of actin filament polymerization (GO:0030838), positive regulation of pseudopodium assembly (GO:0031274), T cell costimulation (GO:0031295), ruffle organization (GO:0031529), positive regulation of cell adhesion mediated by integrin (GO:0033630), mesangial cell-matrix adhesion (GO:0035759), chemokine (C-C motif) ligand 21 signaling pathway (GO:0038116), CCL21-activated CCR7 signaling pathway (GO:0038120), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), positive regulation of JNK cascade (GO:0046330), eosinophil chemotaxis (GO:0048245), positive regulation of receptor-mediated endocytosis (GO:0048260), cell maturation (GO:0048469), positive regulation of chemotaxis (GO:0050921), release of sequestered calcium ion into cytosol (GO:0051209), positive regulation of filopodium assembly (GO:0051491), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), cell chemotaxis (GO:0060326), antimicrobial humoral immune response mediated by antimicrobial peptide (GO:0061844), chemokine-mediated signaling pathway (GO:0070098), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to prostaglandin E stimulus (GO:0071380), positive regulation of neutrophil chemotaxis (GO:0090023), dendritic cell dendrite assembly (GO:0097026), positive regulation of phospholipase C/protein kinase C signal transduction (GO:0141214), negative regulation of leukocyte tethering or rolling (GO:1903237), cellular response to chemokine (GO:1990869), positive regulation of cell motility (GO:2000147)

GO Molecular Function (6): chemokine activity (GO:0008009), CCR7 chemokine receptor binding (GO:0031732), chemokine receptor binding (GO:0042379), CCR chemokine receptor binding (GO:0048020), cytokine activity (GO:0005125), protein binding (GO:0005515)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Signaling by GPCR	2
Peptide ligand-binding receptors	1
GPCR downstream signalling	1
Signal Transduction	1
GPCR ligand binding	1
Class A/1 (Rhodopsin-like receptors)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell-matrix adhesion	2
chemokine receptor binding	2
establishment of lymphocyte polarity	1
T cell activation	1
cell-cell recognition	1
lymphocyte activation	1
regulation of cell-matrix adhesion	1
positive regulation of cell-substrate adhesion	1
leukocyte chemotaxis	1
dendritic cell migration	1
dendritic cell antigen processing and presentation	1
positive regulation of antigen processing and presentation	1
regulation of dendritic cell antigen processing and presentation	1
defense response	1
immune system process	1
response to stimulus	1
G protein-coupled receptor activity	1
signal transduction	1
cell communication	1
signaling	1
glycoprotein biosynthetic process	1
positive regulation of macromolecule biosynthetic process	1
regulation of glycoprotein biosynthetic process	1
positive regulation of glycoprotein metabolic process	1
T cell chemotaxis	1
regulation of T cell chemotaxis	1
positive regulation of lymphocyte chemotaxis	1
positive regulation of T cell migration	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
actin filament polymerization	1
regulation of actin filament polymerization	1
positive regulation of protein polymerization	1
positive regulation of cytoskeleton organization	1
positive regulation of supramolecular fiber organization	1
pseudopodium assembly	1
regulation of pseudopodium assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
lymphocyte costimulation	1

Protein interactions and networks

STRING

2142 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CCL21	CCR7	P32248	999
CCL21	ACKR4	Q9NPB9	997
CCL21	CXCR4	P30991	997
CCL21	CXCR5	P32302	993
CCL21	ACKR2	O00590	992
CCL21	CXCR3	P49682	992
CCL21	CXCL13	O43927	980
CCL21	CXCL12	P48061	971
CCL21	CCR9	P51686	957
CCL21	CX3CR1	P49238	950
CCL21	CCR5	P51681	946
CCL21	SELL	P14151	924
CCL21	CCL19	Q99731	908
CCL21	CCR10	P46092	903
CCL21	CCL27	Q9Y4X3	898

IntAct

54 interactions, top by confidence:

A	B	Type	Score
CCL21	CCL5	psi-mi:“MI:0407”(direct interaction)	0.560
CCL21	PF4	psi-mi:“MI:0407”(direct interaction)	0.560
CCL21	CXCL12	psi-mi:“MI:0407”(direct interaction)	0.560
CCL21	CCL17	psi-mi:“MI:0407”(direct interaction)	0.560
CCL17	CCL21	psi-mi:“MI:0407”(direct interaction)	0.560
PF4	CCL21	psi-mi:“MI:0407”(direct interaction)	0.560
CCL21	OTP	psi-mi:“MI:0915”(physical association)	0.560
CCL21	TMEM107	psi-mi:“MI:0915”(physical association)	0.560
CCL21	TTMP	psi-mi:“MI:0915”(physical association)	0.560
CCL21	JPH3	psi-mi:“MI:0915”(physical association)	0.560
CCL13	CCL21	psi-mi:“MI:0407”(direct interaction)	0.440
CCL23	CCL21	psi-mi:“MI:0407”(direct interaction)	0.440
CCL26	CCL21	psi-mi:“MI:0407”(direct interaction)	0.440
CCL28	CCL21	psi-mi:“MI:0407”(direct interaction)	0.440
XCL1	CCL21	psi-mi:“MI:0407”(direct interaction)	0.440
PF4V1	CCL21	psi-mi:“MI:0407”(direct interaction)	0.440
PPBP	CCL21	psi-mi:“MI:0407”(direct interaction)	0.440
CXCL9	CCL21	psi-mi:“MI:0407”(direct interaction)	0.440
CXCL10	CCL21	psi-mi:“MI:0407”(direct interaction)	0.440
CXCL14	CCL21	psi-mi:“MI:0407”(direct interaction)	0.440
CCL21	CCL24	psi-mi:“MI:0407”(direct interaction)	0.440
CCL21	CCL26	psi-mi:“MI:0407”(direct interaction)	0.440
CCL21	CCL28	psi-mi:“MI:0407”(direct interaction)	0.440
CCL21	XCL2	psi-mi:“MI:0407”(direct interaction)	0.440
CCL21	CXCL2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (46): CCL21 (Reconstituted Complex), CLTCL1 (Affinity Capture-MS), TRIP6 (Affinity Capture-MS), KLHL26 (Affinity Capture-MS), KLHL22 (Affinity Capture-MS), CCL21 (Reconstituted Complex), CCL21 (Reconstituted Complex), CCL21 (Two-hybrid), OTP (Two-hybrid), TMEM107 (Two-hybrid), HNRNPA2B1 (Proximity Label-MS), SMARCB1 (Proximity Label-MS), CCL21 (Reconstituted Complex), CCL21 (Reconstituted Complex), CCL13 (Reconstituted Complex)

ESM2 similar proteins: A9QWP9, B1AWI6, D7PDD4, O00175, O00585, O15467, O35903, O55038, O70460, P02775, P02777, P10148, P14844, P18340, P27784, P28292, P30034, P35572, P43030, P47992, P47993, P50228, P51670, P51672, P55773, P80162, P84444, P86792, P86793, P97885, Q07325, Q08782, Q1L6U9, Q4PR21, Q62401, Q68A93, Q68FP3, Q68Y86, Q6MG59, Q8HYP4

Diamond homologs: F5HET8, O00175, O00585, O00626, O55145, O88430, O97919, P10147, P10148, P10855, P13236, P13500, P13501, P14097, P14844, P16619, P27784, P28291, P28292, P30882, P42831, P46632, P47993, P49873, P50229, P50230, P50231, P51670, P51671, P52203, P55773, P55774, P61274, P61275, P78423, P80075, P80098, P80343, P82943, P97272

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CCL21	up-regulates	CCR7	binding
CCL21	“up-regulates activity”	ACKR4	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 33 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Chemokine receptors bind chemokines	14	124.8×	3e-26
G alpha (i) signalling events	12	22.3×	6e-13
Class A/1 (Rhodopsin-like receptors)	6	21.2×	5e-06
Peptide ligand-binding receptors	6	21.2×	5e-06
GPCR ligand binding	6	18.3×	9e-06
Signaling by GPCR	6	11.4×	1e-04
GPCR downstream signalling	5	10.3×	9e-04

GO biological processes:

GO term	Partners	Fold	FDR
chemokine-mediated signaling pathway	12	125.5×	1e-20
monocyte chemotaxis	5	93.7×	8e-08
neutrophil chemotaxis	8	73.7×	7e-12
antimicrobial humoral immune response mediated by antimicrobial peptide	12	62.7×	2e-17
chemotaxis	13	57.0×	3e-18
cell chemotaxis	9	53.8×	4e-12
cell-cell signaling	11	24.7×	2e-11
inflammatory response	17	20.7×	2e-17

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	14
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

369 predictions. Top by Δscore:

Variant	Effect	Δscore
9:34709523:T:A	donor_gain	1.0000
9:34709558:T:TA	donor_gain	1.0000
9:34709757:ACC:A	donor_gain	1.0000
9:34709758:CCC:C	donor_gain	1.0000
9:34709775:A:AC	donor_gain	1.0000
9:34709776:C:CC	donor_gain	1.0000
9:34709776:CA:C	donor_gain	1.0000
9:34709532:G:A	donor_gain	0.9900
9:34709680:AACC:A	acceptor_loss	0.9900
9:34709683:C:CA	acceptor_loss	0.9900
9:34709684:T:C	acceptor_loss	0.9900
9:34709772:CT:C	donor_loss	0.9900
9:34709775:ACAGG:A	donor_loss	0.9900
9:34709776:C:CA	donor_loss	0.9900
9:34709776:CAG:C	donor_gain	0.9900
9:34709776:CAGG:C	donor_gain	0.9900
9:34709776:CAGGA:C	donor_gain	0.9900
9:34709783:G:C	donor_gain	0.9900
9:34709810:T:TA	donor_gain	0.9900
9:34709994:TGGTA:T	donor_loss	0.9900
9:34709995:GGTAC:G	donor_loss	0.9900
9:34709996:GTA:G	donor_loss	0.9900
9:34709997:TACCT:T	donor_loss	0.9900
9:34709998:A:T	donor_loss	0.9900
9:34709999:C:A	donor_loss	0.9900
9:34709315:T:TA	donor_gain	0.9800
9:34709499:CCT:C	donor_gain	0.9800
9:34709683:C:CC	acceptor_gain	0.9800
9:34709817:T:TA	donor_gain	0.9800
9:34709424:AGTCC:A	acceptor_loss	0.9700

AlphaMissense

859 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:34709625:C:A	W82C	0.998
9:34709625:C:G	W82C	0.998
9:34709680:A:G	F64S	0.996
9:34709647:C:G	C75S	0.994
9:34709648:A:T	C75S	0.994
9:34709680:A:C	F64C	0.994
9:34709795:C:G	C57S	0.994
9:34709796:A:T	C57S	0.994
9:34709831:A:T	V45D	0.989
9:34709796:A:G	C57R	0.988
9:34709846:A:G	I40T	0.986
9:34709870:C:G	C32S	0.986
9:34709871:A:T	C32S	0.986
9:34709647:C:T	C75Y	0.984
9:34709648:A:G	C75R	0.983
9:34709812:C:A	Q51H	0.983
9:34709812:C:G	Q51H	0.983
9:34709823:A:C	Y48D	0.982
9:34709783:G:T	A61D	0.981
9:34709873:C:G	C31S	0.981
9:34709874:A:T	C31S	0.981
9:34709614:A:G	L86P	0.980
9:34709819:C:G	R49P	0.980
9:34709646:A:C	C75W	0.977
9:34709795:C:T	C57Y	0.977
9:34709784:C:G	A61P	0.976
9:34709796:A:C	C57G	0.976
9:34709647:C:A	C75F	0.975
9:34709871:A:G	C32R	0.975
9:34709627:A:G	W82R	0.972

dbSNP variants (sampled 300 via entrez): RS1001446520 (9:34711975 C>T), RS1003452910 (9:34709330 G>A,C), RS1003737207 (9:34711305 GGC>G), RS1004077102 (9:34712014 A>G), RS1004112650 (9:34710921 C>T), RS1005746465 (9:34710603 G>T), RS1006903537 (9:34711249 C>G,T), RS1007018113 (9:34710860 G>A), RS1007358262 (9:34709402 C>T), RS1008881102 (9:34708516 T>C), RS1009653911 (9:34711625 C>G), RS1012043120 (9:34708663 A>G), RS1015031491 (9:34708705 G>A), RS1015219604 (9:34709337 G>A), RS1016790254 (9:34712015 C>T)

Disease associations

OMIM: gene MIM:602737 | 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
GCST000232_8	Rheumatoid arthritis	3.000000e-08
GCST002318_18	Rheumatoid arthritis	3.000000e-15
GCST002318_61	Rheumatoid arthritis	2.000000e-15
GCST005537_172	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	6.000000e-09
GCST005568_38	Rheumatoid arthritis (ACPA-positive)	1.000000e-09
GCST005569_12	Rheumatoid arthritis	9.000000e-09
GCST006048_7	Rheumatoid arthritis (ACPA-positive)	5.000000e-11
GCST006585_1714	Blood protein levels	2.000000e-10
GCST006959_148	Rheumatoid arthritis	2.000000e-13
GCST006959_53	Rheumatoid arthritis	1.000000e-13
GCST009873_20	Autoimmune traits (pleiotropy)	1.000000e-09
GCST009874_35	Celiac disease	5.000000e-06
GCST009877_7	Rheumatoid arthritis	4.000000e-11

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2812378	CCL21		0.00	0

CTD chemical–gene interactions

30 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
usnic acid	affects cotreatment, increases expression	2
Arsenic	decreases expression, affects expression, affects cotreatment	2
Nickel	increases expression	2
propionaldehyde	decreases expression	1
bromoacetate	decreases expression	1
ferrous sulfate	decreases expression	1
1-nitropyrene	decreases expression	1
Capecitabine	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	increases methylation	1
Dihydroxyacetone	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression	1
Ferric Compounds	increases expression	1
Fluorides	affects cotreatment, decreases expression	1
Hydrogen Peroxide	increases secretion	1
Latex	increases expression	1
Lipopolysaccharides	affects cotreatment, increases expression	1
Methotrexate	decreases expression	1
Mustard Gas	increases secretion	1
Perfume	increases expression	1
Silicon Dioxide	decreases expression	1
Valproic Acid	decreases methylation	1
Zearalenone	increases expression	1
Aflatoxin B1	increases methylation	1
Asbestos, Amphibole	affects expression	1
Zinc Compounds	increases expression	1
Sodium Selenite	increases expression	1
Particulate Matter	increases expression, increases abundance	1
Soot	decreases expression	1

Clinical trials (associated diseases)

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