CCL4L2

Summary

CCL4L2 (C-C motif chemokine ligand 4 like 2, HGNC:24066) is a protein-coding gene on chromosome 17q12, encoding C-C motif chemokine 4-like (Q8NHW4). Chemokine that induces chemotaxis of cells expressing CCR5 or CCR1.

This gene is one of several cytokine genes that are clustered on the q-arm of chromosome 17. Cytokines are a family of secreted proteins that function in inflammatory and immunoregulatory processes. The protein encoded by this family member is similar to the chemokine (C-C motif) ligand 4 product, which inhibits HIV entry by binding to the cellular receptor CCR5. The copy number of this gene varies among individuals, where most individuals have one to five copies. This gene copy contains a non-consensus splice acceptor site at the 3’ terminal exon found in other highly similar gene copies, and it thus uses other alternative splice sites for the 3’ terminal exon, resulting in multiple transcript variants.

Source: NCBI Gene 9560 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 2 total
• MANE Select transcript: NM_001291468

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24066
Approved symbol	CCL4L2
Name	C-C motif chemokine ligand 4 like 2
Location	17q12
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000276070
Ensembl biotype	protein_coding
OMIM	610757
Entrez	9560

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 10 protein_coding

ENST00000610565, ENST00000613173, ENST00000615418, ENST00000617405, ENST00000617416, ENST00000620055, ENST00000620098, ENST00000620250, ENST00000620576, ENST00000620732

RefSeq mRNA: 8 — MANE Select: NM_001291468 NM_001291468, NM_001291469, NM_001291470, NM_001291471, NM_001291472, NM_001291473, NM_001291474, NM_001291475

CCDS: CCDS32627, CCDS76999, CCDS77000, CCDS77001, CCDS77002, CCDS77003, CCDS77004, CCDS77005

Canonical transcript exons

ENST00000613828 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 130 present calls, max score 88.69.

FANTOM5 (CAGE): breadth broad, TPM avg 36.2130 / max 3677.5369, expressed in 315 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160412	36.2130	315
208156	24.6770	250
208155	0.2583	67

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bone marrow	UBERON:0002371	88.69	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.84	gold quality
gall bladder	UBERON:0002110	84.99	gold quality
bone marrow cell	CL:0002092	84.89	gold quality
vermiform appendix	UBERON:0001154	84.49	gold quality
granulocyte	CL:0000094	84.18	gold quality
spleen	UBERON:0002106	84.08	gold quality
lymph node	UBERON:0000029	83.48	gold quality
blood	UBERON:0000178	83.20	gold quality
placenta	UBERON:0001987	79.14	gold quality
duodenum	UBERON:0002114	78.29	gold quality
rectum	UBERON:0001052	76.94	gold quality
smooth muscle tissue	UBERON:0001135	76.81	gold quality
mucosa of transverse colon	UBERON:0004991	73.15	gold quality
upper lobe of left lung	UBERON:0008952	72.48	gold quality
leukocyte	CL:0000738	72.12	gold quality
liver	UBERON:0002107	71.64	gold quality
monocyte	CL:0000576	70.48	gold quality
omental fat pad	UBERON:0010414	70.29	gold quality
lung	UBERON:0002048	70.26	gold quality
prefrontal cortex	UBERON:0000451	69.32	gold quality
right lobe of liver	UBERON:0001114	68.88	gold quality
left uterine tube	UBERON:0001303	68.67	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	68.44	gold quality
mucosa of stomach	UBERON:0001199	67.90	gold quality
right coronary artery	UBERON:0001625	67.42	gold quality
superior frontal gyrus	UBERON:0002661	67.19	gold quality
fallopian tube	UBERON:0003889	67.18	gold quality
small intestine Peyer’s patch	UBERON:0003454	67.12	gold quality
small intestine	UBERON:0002108	67.07	gold quality

Single-cell (SCXA)

Detected in 18 experiment(s), a significant marker in 16.

Experiment	Marker?	Max mean expression
E-MTAB-6075	yes	1277.96
E-CURD-46	yes	772.98
E-MTAB-8322	yes	561.71
E-HCAD-8	yes	319.87
E-HCAD-1	yes	297.70
E-HCAD-4	yes	285.16
E-MTAB-8207	yes	211.55
E-MTAB-9467	yes	211.16
E-MTAB-8142	yes	197.48
E-MTAB-8530	yes	180.60
E-MTAB-8221	yes	107.18
E-MTAB-9906	yes	105.15
E-MTAB-8381	yes	89.26
E-MTAB-10885	yes	80.96
E-MTAB-8410	yes	24.29

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

18 targeting CCL4L2, 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-570-3P	99.96	72.41	4910
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-4717-3P	99.06	66.34	1072
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-3129-3P	97.85	67.63	1246
HSA-MIR-5583-5P	97.85	67.61	1243
HSA-MIR-6729-3P	96.91	66.79	703

Literature-anchored findings (GeneRIF, showing 9)

• Neither CCL3L1 nor CCL4L1 gene copy number variation showed appreciable impact on susceptibility to or control of HIV-1 infection. (PMID:17330138)
• A combined analysis of CCL4L copy number variation and the rs4796195 CCL4L single nucleotide polymorphism demonstrated that the effect of CCL4L copy number in acute rejection is mainly because of the number of copies of the CCL4L1 allelic variant. (PMID:19148142)
• higher level of expression at systemic level is associated with protection from HIV-1 infection in women from Benin (PMID:19898927)
• Studies indicate that complete phenotypic impact requires dissecting the combinatorial genomic complexity posed by various proportions of distinct CCL3L and CCL4L genes among individuals. (PMID:20659124)
• CCL4L1 allele frequency is higher in severe psoriasis, whereas CCL4L2 is more frequent in patients with a milder disease. (PMID:21614014)
• PCR results show that lower copy numbers of CCL4L2 are observed in the Caucasian population nd higher copy numbers are observed in the Black population of South Africa. (PMID:24727646)
• identified 13 ADCC-activated genes. Six gene expression assays including 8 of the 13 genes (CCL3, CCL4/CCL4L1/CCL4L2, CD160, IFNG, NR4A3 and XCL1/XCL2) were analyzed in 127 kidney biopsies (PMID:25449536)
• Neutrophil extracellular trap production and CCL4L2 expression influence corticosteroid response in asthma. (PMID:37285400)
• Association of VEGFA and CCL4L2 polymorphisms with hand-foot skin reaction and survival of regorafenib in Japanese patients with colorectal cancer. (PMID:38459188)

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), CCL4 (ENSG00000275302), CCL18 (ENSG00000275385), CCL15 (ENSG00000275718), CCL3L3 (ENSG00000276085), CCL14 (ENSG00000276409), CCL3 (ENSG00000277632)

Protein

Protein identifiers

C-C motif chemokine 4-like — Q8NHW4 (reviewed: Q8NHW4)

Alternative names: Lymphocyte activation gene 1 protein, Macrophage inflammatory protein 1-beta, Monocyte adherence-induced protein 5-alpha, Small-inducible cytokine A4-like

All UniProt accessions (1): Q8NHW4

UniProt curated annotations — full annotation on UniProt →

Function. Chemokine that induces chemotaxis of cells expressing CCR5 or CCR1. Inhibits HIV replication in peripheral blood monocytes that express CCR5.

Subunit / interactions. Interacts with CCR5.

Subcellular location. Secreted.

Tissue specificity. Detected in B-cells.

Polymorphism. The copy number of the CC4L1 gene varies among individuals; most individuals have 1 to 6 copies in the diploid genome.

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

Isoforms (10)

UniProt ID	Names	Canonical?
Q8NHW4-1	1	yes
Q8NHW4-2	2, CCL4L2
Q8NHW4-3	3, CC4L2d
Q8NHW4-4	4, CC4L2f
Q8NHW4-5	5, CC4L2b1, CC4L2b2
Q8NHW4-6	6, CC4L2e
Q8NHW4-7	7, CC4L2d2
Q8NHW4-8	8, CC4L1d2
Q8NHW4-9	9, CC4L2bd2
Q8NHW4-10	10, CC44L2c

RefSeq proteins (8): NP_001278397, NP_001278398, NP_001278399, NP_001278400, NP_001278401, NP_001278402, NP_001278403, NP_001278404 (=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 (14 total): splice variant 9, disulfide bond 2, signal peptide 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NHW4-F1	89.93	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

4 pathways

ID	Pathway
R-HSA-418594	G alpha (i) signalling events
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-388396	GPCR downstream signalling

MSigDB gene sets: 80 (showing top): GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, KEGG_CYTOSOLIC_DNA_SENSING_PATHWAY, GOBP_LEUKOCYTE_CHEMOTAXIS, GOBP_TAXIS, GOBP_LEUKOCYTE_MIGRATION, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_GRANULOCYTE_MIGRATION, GOBP_HUMORAL_IMMUNE_RESPONSE, GOMF_CHEMOKINE_ACTIVITY, GOMF_CYTOKINE_ACTIVITY, GOMF_G_PROTEIN_COUPLED_RECEPTOR_BINDING

GO Biological Process (7): inflammatory response (GO:0006954), positive regulation of cell migration (GO:0030335), eosinophil chemotaxis (GO:0048245), antimicrobial humoral immune response mediated by antimicrobial peptide (GO:0061844), chemokine-mediated signaling pathway (GO:0070098), chemotaxis (GO:0006935), immune response (GO:0006955)

GO Molecular Function (4): chemokine activity (GO:0008009), CCR chemokine receptor binding (GO:0048020), cytokine activity (GO:0005125), protein binding (GO:0005515)

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

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
GPCR downstream signalling	1
Signal Transduction	1
Signaling by GPCR	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
chemokine receptor binding	2
defense response	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
granulocyte chemotaxis	1
eosinophil migration	1
antimicrobial humoral response	1
G protein-coupled receptor signaling pathway	1
cytokine-mediated signaling pathway	1
cellular response to chemokine	1
response to chemical	1
taxis	1
immune system process	1
response to stimulus	1
cytokine activity	1
cell chemotaxis	1
receptor ligand activity	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

104 interactions, top by confidence:

A	B	Type	Score
SLC30A2	CCL4L1	psi-mi:“MI:0915”(physical association)	0.560
CCL4L1	SLC30A2	psi-mi:“MI:0915”(physical association)	0.560
CCL4L1	ERVFRD-1	psi-mi:“MI:0915”(physical association)	0.560
CCL4L1	COMT	psi-mi:“MI:0915”(physical association)	0.560
CCL4L1	SLC7A1	psi-mi:“MI:0915”(physical association)	0.560
CCL4L1	ELOVL4	psi-mi:“MI:0915”(physical association)	0.560
CCL4L1	SSMEM1	psi-mi:“MI:0915”(physical association)	0.560
CCL4L1	AQP6	psi-mi:“MI:0915”(physical association)	0.560
CCL4L1	SGPL1	psi-mi:“MI:0915”(physical association)	0.560
CCL4L1	GPR42	psi-mi:“MI:0915”(physical association)	0.560
CCL4L1	CATSPER4	psi-mi:“MI:0915”(physical association)	0.560
CCL4L1	TMEM51	psi-mi:“MI:0915”(physical association)	0.560
CCL4L1	ARL13B	psi-mi:“MI:0915”(physical association)	0.560
CCL4L1	MFSD14B	psi-mi:“MI:0915”(physical association)	0.560
CCL4L1	ITM2C	psi-mi:“MI:0915”(physical association)	0.560
CCL4L1	CREB3L1	psi-mi:“MI:0915”(physical association)	0.560
EBP	CCL4L1	psi-mi:“MI:0915”(physical association)	0.560
COQ9	CCL4L1	psi-mi:“MI:0915”(physical association)	0.560
CATSPER4	CCL4L1	psi-mi:“MI:0915”(physical association)	0.560
CPLX4	CCL4L1	psi-mi:“MI:0915”(physical association)	0.560
JAGN1	CCL4L1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (57): CCL4L2 (Two-hybrid), CCL4L2 (Two-hybrid), CCL4L2 (Two-hybrid), CCL4L2 (Two-hybrid), CCL4L2 (Two-hybrid), CCL4L2 (Two-hybrid), CCL4L2 (Two-hybrid), CCL4L2 (Two-hybrid), CCL4L2 (Two-hybrid), CCL4L2 (Two-hybrid), CCL4L2 (Two-hybrid), CCL4L2 (Two-hybrid), CCL4L2 (Two-hybrid), CCL4L2 (Two-hybrid), CCL4L2 (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
maraviroc	down-regulates	CCL4L1	“chemical inhibition”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1014227854 (17:36209991 CTGTTT>C), RS1024303240 (17:36213214 G>A,C), RS1027808767 (17:36211739 TGG>T), RS1043549665 (17:36209119 A>G), RS1049745 (17:36210966 A>G), RS1056373835 (17:36209469 C>A), RS1157000414 (17:36209379 G>A,C), RS1157019323 (17:36210049 G>A), RS1157226668 (17:36210740 A>G), RS1157297598 (17:36211549 T>C), RS1157350166 (17:36212341 C>T), RS1157432403 (17:36211650 GATACAAGGGACC>G), RS1157704442 (17:36212420 A>G), RS1157823168 (17:36210441 G>C), RS1157891188 (17:36212247 G>A,C)

Disease associations

OMIM: gene MIM:610757 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000189_21	Protein quantitative trait loci	4.000000e-21
GCST005951_15	Body mass index	3.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
TL8-506	affects cotreatment, increases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects cotreatment, affects response to substance	1
tebuconazole	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Benzo(a)pyrene	decreases expression	1
Doxorubicin	decreases expression	1
Lipopolysaccharides	increases expression, affects response to substance, affects cotreatment	1
Malathion	increases expression	1
Poly I-C	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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