CCL4

Summary

CCL4 (C-C motif chemokine ligand 4, HGNC:10630) is a protein-coding gene on chromosome 17q12, encoding C-C motif chemokine 4 (P13236). Monokine with inflammatory and chemokinetic properties.

The protein encoded by this gene is a mitogen-inducible monokine and is one of the major HIV-suppressive factors produced by CD8+ T-cells. The encoded protein is secreted and has chemokinetic and inflammatory functions.

Source: NCBI Gene 6351 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 20 total
• MANE Select transcript: NM_002984

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10630
Approved symbol	CCL4
Name	C-C motif chemokine ligand 4
Location	17q12
Locus type	gene with protein product
Status	Approved
Aliases	MIP-1-beta, Act-2, AT744.1
Ensembl gene	ENSG00000275302
Ensembl biotype	protein_coding
OMIM	182284
Entrez	6351

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 retained_intron

ENST00000613947, ENST00000615863, ENST00000621626

RefSeq mRNA: 1 — MANE Select: NM_002984 NM_002984

CCDS: CCDS11308

Canonical transcript exons

ENST00000615863 — 3 exons

Exon	Start	End
ENSE00003720228	36104528	36104642
ENSE00003721742	36105225	36105614
ENSE00003750603	36103827	36103981

Expression profiles

Bgee: expression breadth ubiquitous, 131 present calls, max score 97.94.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.7076 / max 67.2150, expressed in 143 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160412	36.2130	315
160413	0.7076	143

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	97.94	gold quality
spleen	UBERON:0002106	95.32	gold quality
bone marrow	UBERON:0002371	95.11	gold quality
gall bladder	UBERON:0002110	94.80	gold quality
bone marrow cell	CL:0002092	92.87	gold quality
lymph node	UBERON:0000029	92.51	gold quality
blood	UBERON:0000178	91.68	gold quality
vermiform appendix	UBERON:0001154	91.43	gold quality
placenta	UBERON:0001987	88.56	gold quality
smooth muscle tissue	UBERON:0001135	87.63	gold quality
upper lobe of left lung	UBERON:0008952	86.81	gold quality
omental fat pad	UBERON:0010414	85.19	gold quality
rectum	UBERON:0001052	84.86	gold quality
leukocyte	CL:0000738	83.94	gold quality
lung	UBERON:0002048	83.84	gold quality
left uterine tube	UBERON:0001303	83.60	gold quality
liver	UBERON:0002107	83.53	gold quality
monocyte	CL:0000576	82.68	gold quality
right lobe of liver	UBERON:0001114	82.62	gold quality
right lung	UBERON:0002167	82.23	gold quality
duodenum	UBERON:0002114	80.69	gold quality
fallopian tube	UBERON:0003889	80.48	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	80.10	gold quality
right coronary artery	UBERON:0001625	79.69	gold quality
small intestine Peyer’s patch	UBERON:0003454	79.56	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.88	gold quality
small intestine	UBERON:0002108	78.59	gold quality
ascending aorta	UBERON:0001496	78.56	gold quality
thoracic aorta	UBERON:0001515	78.53	gold quality
adipose tissue	UBERON:0001013	77.76	gold quality

Single-cell (SCXA)

Detected in 32 experiment(s), a significant marker in 29.

Experiment	Marker?	Max mean expression
E-HCAD-29	yes	36752.75
E-GEOD-84465	yes	22906.92
E-CURD-126	yes	10757.31
E-MTAB-6075	yes	6380.97
E-CURD-46	yes	5979.16
E-MTAB-10287	yes	3894.85
E-CURD-84	yes	2025.06
E-MTAB-7407	yes	1724.54
E-HCAD-8	yes	1534.77
E-MTAB-6308	yes	1252.01
E-ANND-5	yes	761.61
E-CURD-95	yes	558.01
E-MTAB-8207	yes	450.58
E-MTAB-8894	yes	336.99
E-HCAD-1	yes	151.67

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ATF3, BCL6, CEBPB, CREB1, CREM, EGR1, HIF1A, IRF1, IRF5, IRF6, JUN, MEIS1, NFKB1, NFKB, REL, RELA, TBX21, YY1

miRNA regulators (miRDB)

22 targeting CCL4, 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-5692A	100.00	74.40	6850
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-425-5P	99.59	67.67	900
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-1843	98.97	66.07	838
HSA-MIR-4802-5P	98.97	66.26	833
HSA-MIR-6894-5P	98.70	63.78	809
HSA-MIR-3129-3P	97.85	67.63	1246
HSA-MIR-5583-5P	97.85	67.61	1243
HSA-MIR-7154-3P	97.65	65.02	985
HSA-MIR-6729-3P	96.91	66.79	703
HSA-MIR-3619-3P	95.59	65.99	428
HSA-MIR-6514-5P	95.07	66.02	655

Literature-anchored findings (GeneRIF, showing 40)

• Cholesterol is essential for macrophage inflammatory protein 1 beta binding and signaling and conformational integrity of CC chemokine receptor 5. (Is MIP-1 beta the entry SCYA4 or LD78? If so, please add the term to SCYA4 or LD78.) (PMID:12036855)
• results demonstrate that NH(2)-terminally truncated MIP-1 beta functions as a chemokine agonist with expanded receptor reactivity; may represent an important mechanism for regulation of immune cell recruitment during inflammatory and antiviral responses (PMID:12070155)
• role in the development of osteolytic lesions in multiple myeloma (PMID:12200385)
• Expression of MIP-1 beta is induced by stimulation of monocytic cells through Fc gamma receptors and involves activation of CCAAT/enhancer-binding protein beta sites. (PMID:12218153)
• role of IL-12 and IFN-gamma on inducing inflammatory chemokine (MIP-1beta) secretion and down-regulating CCR5 expression in human T cells (PMID:12377943)
• After stimulation via high-affinity FcepsilonRI, the transcriptional levels of I-309 (CCL1), MIP-1alpha (CCL3) and MIP-1beta (CCL4) were found among the 10 most increased human and mouse transcripts from approximately 12 000 genes (PMID:12393595)
• Lymphotactin, (MIP)-1alpha, and MIP-1beta chemokines were all rapidly induced by engagement of CD28 and were calcineurin sensitive. (PMID:12393716)
• MIP-1alpha and MIP-1beta show diverging signaling capacities [review] (PMID:12401480)
• binding surface and affinity of monomeric and dimeric forms for various glycosaminoglycan disaccharides (PMID:12411442)
• IL-1beta-induced MIP-1alpha and -1beta expression in NT2-N cells (PMID:12603824)
• Cathepsin D specifically cleaves this protein that is expressed in human breast cancer. (PMID:12651610)
• results suggest that endometrial macrophage inflammatory protein-1beta may be involved in the recruitment of NK cells from circulating peripheral blood (PMID:12679478)
• MIP-1beta may be related to the scattering and invasion step of gastric carcinoma cells with undifferentiated phenotype (PMID:14582706)
• Monocytes and B cells utilize different mechanisms to regulate expression of the 2 CCL4 genes (ACT-2 and LAG-1) & suggest that the 2 genes may not have identical activities. (PMID:14673550)
• Results suggest that interleukin-1beta-mediated up-regulation of macrophage inflammatory protein-1beta production in hepatic cells may contribute to continuous recruitment of inflammatory cells to the liver and maintenance of inflammation. (PMID:14746807)
• Activated T cells from GRK2+/- mice, which have a 50% reduction in GRK2 protein levels, showed a significant 40% increase in chemotaxis toward the CCR5 ligand CCL4 (PMID:14761932)
• MCP-1, MIP-1beta, and IL-8 elevated in relapsing polychondritis(RP) are proinflammatory chemokines, characteristic of activation of monocytes and macrophages and, in the case of IL-8, also of neutrophils. Role for cell-mediated immune response in RP. (PMID:15529362)
• lymphocytes of HIV patients display a disrupted capacity to secrete the beta-chemokines MIP-1 alpha and MIP-1 beta, which may constitute a mechanism of immune dysfunction in progressive HIV infection (PMID:15585099)
• produced by neonatal natural killer cells and contributes to suppession of HIV replication (PMID:15588341)
• RANTES, MIP-1beta and IL-18 are expressed in LGL leukemia (PMID:15645140)
• Normal human vaginal epithelial cells constitutively secrete the chemokine macrophage inflammatory protein CCL20, known to recruit Langerhans cell precursors selectively via its cognate CC chemokine receptor CCR6. (PMID:15831560)
• upregulation of MIP-1beta and downregulation of VE-cadherin may strongly participate in human acute heart rejection. (PMID:15897346)
• Higher amounts of MIP-1alpha, MIP-1beta, and RANTES were detected in plasma of HIV-1-positive individuals, particularly those with concomitant pulmonary tuberculosis, although the increase was not found to be statistically significant. (PMID:16379602)
• variation in the CCL18-CCL3-CCL4 chemokine gene cluster influences HIV Type 1 transmission and AIDS disease progression (PMID:16773571)
• Results describe the structure of an orthopoxvirus vCCI in complex with a human CC chemokine, MIP-1beta (macrophage inflammatory protein 1beta). (PMID:16963564)
• findings show that CCL3, CCL4 and CCL5 bind on the Leishmania promastigotes (PMID:17005260)
• the CC chemokine MIP-1beta dimer is not able to bind or activate its receptor and implicates the CC chemokine monomer as the sole receptor-interacting unit (PMID:17644519)
• The strong upregulation of CCL3 and CCL4 implicates these chemokines in the etiology and pathogenesis of TLE. (PMID:18076643)
• PC-PLC activation through CCR5 is specifically induced by gp120, since triggering CCR5 through its natural ligand CCL4 (MIP-1beta) does not affect PC-PLC cellular distribution and enzymatic activity, as well as CCL2 secretion (PMID:18203956)
• Data show that MIP-1 alpha and MIP-1 beta bind to the HIV co-receptor CCR5 and blok HIV entry into CD4(+) lymphocytes. (PMID:18346864)
• Population structure in copy number variation and SNPs in the CCL4 chemokine gene are reported. (PMID:18368065)
• MCP-1, MIP-1beta, and IL-8 play important roles in the pathophysiology of Hemophagocytic lymphohistiocytosis (HLH). In addition, the serum concentrations of these chemokines may be sensitive markers for assessing disease activity in patients with HLH. (PMID:18623207)
• CysLTs induce MIP-1alpha and MIP-1beta production mediated by ERK via binding to the CysLT(1) receptor in human monocytes/macrophages. (PMID:18802359)
• CX3CL1, IL-15, and CCL4 can serve as independent predictors of biochemical recurrence. (PMID:19047106)
• Data suggest that increased MIP-1alpha/beta production enhances multiple myeloma cell binding to stromal cells by VLA-4-VCAM-1 adhesion, forming a “vicious cycle” between MM cell adhesion to stromal cells and MIP-1 production via VLA-4-VCAM-1 interaction. (PMID:19057841)
• A novel mechanism of cross talk between chronic lymphocytic leukemia cells and their microenvironment, namely, the secretion of 2 T-cell chemokines in response to nurselike cells coculture and BCR stimulation. (PMID:19074730)
• observed that CCL4, CXCL1 and CXCL8 secretion, following PROK1 induction (PMID:19103522)
• Serum MIP-1beta level might be a useful predictor for cerebro-cardiovascular events in hypertensive patients. (PMID:19328808)
• ELISpot analysis of LPS-stimulated leukocytes: human granulocytes selectively secrete IL-8, MIP-1beta and TNF-alpha. (PMID:19358850)
• There is a unique role of osteopontin in leukocyte migration, in the context of perpetuation of rheumatoid synovitis through the induction of MCP-1 and MIP-1beta. (PMID:19565503)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ccl35.2	ENSDARG00000070378
danio_rerio	ccl35.1	ENSDARG00000103466
mus_musculus	Ccl4	ENSMUSG00000018930
rattus_norvegicus	Ccl4	ENSRNOG00000011406

Paralogs (26): CX3CL1 (ENSG00000006210), CCL26 (ENSG00000006606), CCL22 (ENSG00000102962), CCL17 (ENSG00000102970), CCL24 (ENSG00000106178), CCL7 (ENSG00000108688), CCL2 (ENSG00000108691), CCL8 (ENSG00000108700), CCL1 (ENSG00000108702), CCL20 (ENSG00000115009), CCL25 (ENSG00000131142), CCL21 (ENSG00000137077), XCL1 (ENSG00000143184), XCL2 (ENSG00000143185), CCL11 (ENSG00000172156), CCL19 (ENSG00000172724), CCL13 (ENSG00000181374), CCL5 (ENSG00000271503), CCL23 (ENSG00000274736), CCL16 (ENSG00000275152), CCL18 (ENSG00000275385), CCL15 (ENSG00000275718), CCL4L2 (ENSG00000276070), CCL3L3 (ENSG00000276085), CCL14 (ENSG00000276409), CCL3 (ENSG00000277632)

Protein

Protein identifiers

C-C motif chemokine 4 — P13236 (reviewed: P13236)

Alternative names: G-26 T-lymphocyte-secreted protein, HC21, Lymphocyte activation gene 1 protein, MIP-1-beta(1-69), Macrophage inflammatory protein 1-beta, PAT 744, Protein H400, SIS-gamma, Small-inducible cytokine A4, T-cell activation protein 2

All UniProt accessions (2): P13236, Q7M4M2

UniProt curated annotations — full annotation on UniProt →

Function. Monokine with inflammatory and chemokinetic properties. Binds to CCR5. One of the major HIV-suppressive factors produced by CD8+ T-cells. Recombinant MIP-1-beta induces a dose-dependent inhibition of different strains of HIV-1, HIV-2, and simian immunodeficiency virus (SIV). The processed form MIP-1-beta(3-69) retains the abilities to induce down-modulation of surface expression of the chemokine receptor CCR5 and to inhibit the CCR5-mediated entry of HIV-1 in T-cells. MIP-1-beta(3-69) is also a ligand for CCR1 and CCR2 isoform B.

Subunit / interactions. Homodimer and heterodimer of MIP-1-alpha(4-69) and MIP-1-beta(3-69).

Subcellular location. Secreted.

Post-translational modifications. N-terminal processed form MIP-1-beta(3-69) is produced by proteolytic cleavage after secretion from peripheral blood lymphocytes.

Induction. By mitogens.

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

RefSeq proteins (1): NP_002975* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000827	Chemokine_CC_CS	Conserved_site
IPR001811	Chemokine_IL8-like_dom	Domain
IPR036048	Interleukin_8-like_sf	Homologous_superfamily
IPR039809	Chemokine_b/g/d	Family

Pfam: PF00048

UniProt features (22 total): strand 6, sequence conflict 5, sequence variant 3, chain 2, helix 2, disulfide bond 2, signal peptide 1, turn 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
3TN2	X-RAY DIFFRACTION	1.6
2X6L	X-RAY DIFFRACTION	2.6
4RAL	X-RAY DIFFRACTION	3.15
1HUM	SOLUTION NMR
1HUN	SOLUTION NMR
1JE4	SOLUTION NMR
2FFK	SOLUTION NMR
2FIN	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P13236-F1	88.72	0.67

Functional residue map

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

Disulfide bonds (2): 34–58, 35–74

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-380108	Chemokine receptors bind chemokines
R-HSA-418594	G alpha (i) signalling events
R-HSA-6783783	Interleukin-10 signaling
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-162582	Signal Transduction
R-HSA-168256	Immune System
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-449147	Signaling by Interleukins
R-HSA-500792	GPCR ligand binding

MSigDB gene sets: 512 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_6HR_DN, GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, MODULE_92, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_MYELOID_LEUKOCYTE_MIGRATION, MODULE_169, GOBP_CELL_CHEMOTAXIS, LU_IL4_SIGNALING, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE

GO Biological Process (17): inflammatory response (GO:0006954), immune response (GO:0006955), cell adhesion (GO:0007155), establishment or maintenance of cell polarity (GO:0007163), signal transduction (GO:0007165), cell-cell signaling (GO:0007267), response to virus (GO:0009615), response to toxic substance (GO:0009636), positive regulation of cell migration (GO:0030335), host-mediated suppression of viral transcription (GO:0043922), eosinophil chemotaxis (GO:0048245), positive regulation of calcium-mediated signaling (GO:0050850), positive regulation of calcium ion transport (GO:0051928), antimicrobial humoral immune response mediated by antimicrobial peptide (GO:0061844), chemokine-mediated signaling pathway (GO:0070098), positive regulation of natural killer cell chemotaxis (GO:2000503), chemotaxis (GO:0006935)

GO Molecular Function (7): cytokine activity (GO:0005125), chemokine activity (GO:0008009), CCR1 chemokine receptor binding (GO:0031726), CCR5 chemokine receptor binding (GO:0031730), identical protein binding (GO:0042802), CCR chemokine receptor binding (GO:0048020), protein binding (GO:0005515)

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

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Signaling by GPCR	2
Peptide ligand-binding receptors	1
GPCR downstream signalling	1
Signaling by Interleukins	1
Immune System	1
Signal Transduction	1
GPCR ligand binding	1
Class A/1 (Rhodopsin-like receptors)	1
Cytokine Signaling in Immune system	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	3
cell communication	2
signaling	2
response to chemical	2
chemokine receptor binding	2
CCR chemokine receptor binding	2
defense response	1
immune system process	1
response to stimulus	1
regulation of cellular process	1
cellular response to stimulus	1
response to other organism	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
host-mediated perturbation of viral transcription	1
host-mediated suppression of viral proces	1
granulocyte chemotaxis	1
eosinophil migration	1
calcium-mediated signaling	1
regulation of calcium-mediated signaling	1
positive regulation of intracellular signal transduction	1
calcium ion transport	1
positive regulation of monoatomic ion transport	1
regulation of calcium ion transport	1
antimicrobial humoral response	1
G protein-coupled receptor signaling pathway	1
cytokine-mediated signaling pathway	1
cellular response to chemokine	1
natural killer cell chemotaxis	1
positive regulation of lymphocyte chemotaxis	1
regulation of natural killer cell chemotaxis	1
taxis	1
receptor ligand activity	1
cytokine activity	1
cell chemotaxis	1
protein binding	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2876 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CCL4	CCR5	P51681	999
CCL4	CCR2	P41597	997
CCL4	CCR1	P32246	996
CCL4	CCR3	P51677	996
CCL4	CCR7	P32248	987
CCL4	CXCR4	P30991	986
CCL4	CXCR3	P49682	985
CCL4	CXCL8	P10145	970
CCL4	CCR8	P51685	951
CCL4	CCL3	P10147	943
CCL4	CCL17	Q92583	942
CCL4	CXCR2	P25025	935
CCL4	CD4	P01730	929
CCL4	IFNG	P01579	916
CCL4	CCRL2	O00421	910

IntAct

72 interactions, top by confidence:

A	B	Type	Score
SLC30A2	CCL4	psi-mi:“MI:0915”(physical association)	0.780
CCL4	SLC30A2	psi-mi:“MI:0915”(physical association)	0.780
CCL4	CCL4	psi-mi:“MI:0407”(direct interaction)	0.620
CCL4	MARCHF2	psi-mi:“MI:0915”(physical association)	0.560
	CCL4	psi-mi:“MI:0915”(physical association)	0.560
CCL4	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
CCL4	TMEM86B	psi-mi:“MI:0915”(physical association)	0.560
CCL4	GPR152	psi-mi:“MI:0915”(physical association)	0.560
CCL4	SLC7A1	psi-mi:“MI:0915”(physical association)	0.560
CCL4	TAS2R5	psi-mi:“MI:0915”(physical association)	0.560
CCL4	SLC10A6	psi-mi:“MI:0915”(physical association)	0.560
CCL4	TIMMDC1	psi-mi:“MI:0915”(physical association)	0.560
CCL4	TMEM179B	psi-mi:“MI:0915”(physical association)	0.560
CCL4	GJA8	psi-mi:“MI:0915”(physical association)	0.560
CCL4	MRM1	psi-mi:“MI:0915”(physical association)	0.560
CCL4	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
CCL4	CNR2	psi-mi:“MI:0915”(physical association)	0.560
CCL4	UNC93A	psi-mi:“MI:0915”(physical association)	0.560
CCL4	SLC30A8	psi-mi:“MI:0915”(physical association)	0.560
CCL4	ARL13B	psi-mi:“MI:0915”(physical association)	0.560
CCL4	SLC18A1	psi-mi:“MI:0915”(physical association)	0.560
	CCL4	psi-mi:“MI:0407”(direct interaction)	0.440
CCL4	IDE	psi-mi:“MI:0194”(cleavage reaction)	0.440
CCL4	PEX14	psi-mi:“MI:0914”(association)	0.350

BioGRID (55): SLC30A2 (Two-hybrid), ATP5S (Affinity Capture-MS), AMZ2 (Affinity Capture-MS), PEX14 (Affinity Capture-MS), CCL4 (Two-hybrid), CCL4 (Two-hybrid), CCL4 (Two-hybrid), CCL4 (Two-hybrid), CCL4 (Two-hybrid), CCL4 (Two-hybrid), CCL4 (Two-hybrid), CCL4 (Two-hybrid), CCL4 (Two-hybrid), CCL4 (Two-hybrid), CCL4 (Two-hybrid)

ESM2 similar proteins: A9QWQ1, O14625, O46675, O46676, O46677, O46678, O89098, O97919, P08317, P09340, P09341, P10147, P10855, P10889, P12850, P13236, P13501, P14095, P14097, P16619, P19875, P19876, P30782, P30882, P42831, P46632, P47854, P50229, P50230, P50231, P97272, Q17QA1, Q5EBF6, Q5I1Z0, Q5RA36, Q68A92, Q68AZ0, Q711P4, Q8HYQ1, Q8HYQ2

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

1 interactions.

A	Effect	B	Mechanism
CCL4	“up-regulates activity”	CCR5	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	15
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

194 predictions. Top by Δscore:

Variant	Effect	Δscore
17:36104526:A:AG	acceptor_gain	1.0000
17:36104526:AGT:A	acceptor_gain	1.0000
17:36104526:AGTG:A	acceptor_gain	1.0000
17:36104527:G:GG	acceptor_gain	1.0000
17:36104527:GT:G	acceptor_gain	1.0000
17:36104527:GTG:G	acceptor_gain	1.0000
17:36104527:GTGG:G	acceptor_gain	1.0000
17:36104638:GTGGT:G	donor_gain	1.0000
17:36104641:GT:G	donor_gain	1.0000
17:36104643:G:GG	donor_gain	1.0000
17:36103979:CAA:C	donor_gain	0.9900
17:36103982:G:GG	donor_gain	0.9900
17:36104526:AGTGG:A	acceptor_gain	0.9900
17:36104527:G:GC	acceptor_loss	0.9900
17:36104527:GTGGG:G	acceptor_gain	0.9900
17:36104639:TGGT:T	donor_gain	0.9900
17:36104640:GGTG:G	donor_gain	0.9900
17:36104643:G:A	donor_loss	0.9900
17:36104644:TGAG:T	donor_loss	0.9900
17:36104646:AGTAT:A	donor_loss	0.9900
17:36105215:T:TA	acceptor_gain	0.9900
17:36105220:TACA:T	acceptor_loss	0.9900
17:36105222:C:G	acceptor_gain	0.9900
17:36105222:CA:C	acceptor_loss	0.9900
17:36105223:A:AG	acceptor_gain	0.9900
17:36105223:A:T	acceptor_loss	0.9900
17:36105224:G:GG	acceptor_gain	0.9900
17:36105224:G:GT	acceptor_loss	0.9900
17:36103978:CCAA:C	donor_gain	0.9800
17:36103980:AA:A	donor_gain	0.9800

AlphaMissense

592 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:36105276:G:C	W81C	0.998
17:36105276:G:T	W81C	0.998
17:36105227:T:C	F65S	0.996
17:36105227:T:G	F65C	0.993
17:36105274:T:A	W81R	0.992
17:36105274:T:C	W81R	0.992
17:36104623:T:A	C58S	0.986
17:36104624:G:C	C58S	0.986
17:36105253:T:A	C74S	0.986
17:36105254:G:C	C74S	0.986
17:36104623:T:C	C58R	0.981
17:36104636:C:A	A62D	0.981
17:36105253:T:C	C74R	0.981
17:36105278:T:A	V82D	0.978
17:36105257:C:A	A75D	0.977
17:36105254:G:A	C74Y	0.976
17:36105256:G:C	A75P	0.976
17:36104557:T:C	F36L	0.974
17:36104559:T:A	F36L	0.974
17:36104559:T:G	F36L	0.974
17:36104594:T:A	V48E	0.974
17:36104624:G:A	C58Y	0.974
17:36104554:T:C	C35R	0.973
17:36104635:G:C	A62P	0.973
17:36104554:T:A	C35S	0.972
17:36104555:G:C	C35S	0.972
17:36104558:T:G	F36C	0.972
17:36104602:T:G	Y51D	0.969
17:36104625:C:G	C58W	0.968
17:36104624:G:T	C58F	0.964

dbSNP variants (sampled 300 via entrez): RS1001482599 (17:36103753 A>C,T), RS1002080845 (17:36102907 G>T), RS1002543266 (17:36106030 T>C), RS1004106531 (17:36102934 A>G), RS1006028669 (17:36105111 C>T), RS1006614954 (17:36104032 CT>C), RS1006952412 (17:36104332 C>T), RS1007501549 (17:36103349 A>G), RS1008033238 (17:36103215 T>C), RS1008500719 (17:36102496 C>T), RS1008571135 (17:36101941 G>A,C), RS1010582667 (17:36102738 A>T), RS1010734658 (17:36102555 T>C), RS1011813787 (17:36105874 G>C), RS1013816356 (17:36103805 G>A,C)

Disease associations

OMIM: gene MIM:182284 | 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
GCST005951_15	Body mass index	3.000000e-13
GCST006291_70	Spherical equivalent or myopia (age of diagnosis)	4.000000e-10
GCST009731_60	Blood protein levels in cardiovascular risk	2.000000e-47

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004847	age at onset

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

Binding affinities (BindingDB)

5 measured of 7 human assays (7 total across all organisms); most potent 5 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
CC-220 (Compound 6)	IC50	28 nM	US-9694015: Methods for the treatment of locally advanced breast cancer
3-(4-((4-(morpholinomethyl)benzyl)-oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione	IC50	190 nM	US-9694015: Methods for the treatment of locally advanced breast cancer
19171-19-8	IC50	230 nM	US-9694015: Methods for the treatment of locally advanced breast cancer
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione	IC50	300 nM	US-9694015: Methods for the treatment of locally advanced breast cancer
(R)-3-(4-((4-(morpholinomethyl)benzyl)-oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione	IC50	450 nM	US-9694015: Methods for the treatment of locally advanced breast cancer

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	decreases reaction, increases secretion, affects cotreatment, increases expression, increases reaction (+2 more)	18
nickel sulfate	increases expression, increases secretion	6
Dinitrochlorobenzene	increases expression, increases secretion	4
Tetradecanoylphorbol Acetate	affects cotreatment, decreases expression, increases secretion, increases expression, decreases reaction	4
Troglitazone	affects cotreatment, decreases secretion, decreases expression, increases expression	3
Vehicle Emissions	decreases secretion, decreases reaction, increases expression, decreases expression	3
Eugenol	increases expression, increases secretion	3
Methotrexate	decreases expression, affects reaction, decreases response to substance, affects cotreatment	3
ferric oxide	increases expression, increases secretion	2
deoxynivalenol	increases expression	2
titanium dioxide	increases expression, increases secretion	2
hydroxyhydroquinone	affects expression, decreases reaction, increases expression	2
cobalt sulfate	increases expression, increases secretion	2
hydroquinone	increases expression	2
Benzalkonium Compounds	decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
Nickel	increases expression	2
Poly I-C	increases secretion, decreases reaction, increases expression, affects cotreatment	2
Tretinoin	affects cotreatment, increases expression	2
Valproic Acid	increases expression, decreases expression, affects cotreatment	2
Dinoprostone	decreases reaction, increases secretion, increases reaction, decreases expression	2
Ionomycin	affects cotreatment, increases secretion, decreases reaction, increases expression	2
Cyclosporine	decreases expression, increases expression	2
Antirheumatic Agents	affects cotreatment, decreases response to substance, decreases expression	2
Particulate Matter	decreases reaction, increases expression, decreases expression	2
coagulin-L	decreases reaction, increases expression	1
coralyne	decreases expression	1
TL8-506	increases secretion, affects cotreatment, increases expression	1
alexidine	decreases expression	1
7-ketocholesterol	increases expression, decreases reaction	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B9WY	Abcam THP-1 CCL4 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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