ACKR2

Summary

ACKR2 (atypical chemokine receptor 2, HGNC:1565) is a protein-coding gene on chromosome 3p22.1, encoding Atypical chemokine receptor 2 (O00590). Atypical chemokine receptor that controls chemokine levels and localization via high-affinity chemokine binding that is uncoupled from classic ligand-driven signal transduction cascades, resulting instead in chemokine sequestration, degradation, or transcytosis.

This gene encodes a beta chemokine receptor, which is predicted to be a seven transmembrane protein similar to G protein-coupled receptors. Chemokines and their receptor-mediated signal transduction are critical for the recruitment of effector immune cells to the inflammation site. This gene is expressed in a range of tissues and hemopoietic cells. The expression of this receptor in lymphatic endothelial cells and overexpression in vascular tumors suggested its function in chemokine-driven recirculation of leukocytes and possible chemokine effects on the development and growth of vascular tumors. This receptor appears to bind the majority of beta-chemokine family members; however, its specific function remains unknown. This gene is mapped to chromosome 3p21.3, a region that includes a cluster of chemokine receptor genes.

Source: NCBI Gene 1238 — RefSeq curated summary.

At a glance

• GWAS associations: 44
• Clinical variants (ClinVar): 13 total
• Druggable target: yes
• MANE Select transcript: NM_001296

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1565
Approved symbol	ACKR2
Name	atypical chemokine receptor 2
Location	3p22.1
Locus type	gene with protein product
Status	Approved
Aliases	CCR10, D6, CCR9
Ensembl gene	ENSG00000144648
Ensembl biotype	protein_coding
OMIM	602648
Entrez	1238

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 20 protein_coding, 5 protein_coding_CDS_not_defined

ENST00000422265, ENST00000442925, ENST00000460855, ENST00000463699, ENST00000480215, ENST00000492609, ENST00000493193, ENST00000494619, ENST00000497921, ENST00000498111, ENST00000565749, ENST00000865513, ENST00000865514, ENST00000865515, ENST00000865516, ENST00000865517, ENST00000865518, ENST00000865519, ENST00000865520, ENST00000865521, ENST00000865522, ENST00000865523, ENST00000865524, ENST00000913479, ENST00000947398

RefSeq mRNA: 1 — MANE Select: NM_001296 NM_001296

CCDS: CCDS2706

Canonical transcript exons

ENST00000422265 — 3 exons

Exon	Start	End
ENSE00003705950	42819631	42819711
ENSE00003841923	42809445	42809532
ENSE00003845476	42864466	42867286

Expression profiles

Bgee: expression breadth ubiquitous, 173 present calls, max score 80.53.

FANTOM5 (CAGE): breadth broad, TPM avg 1.5616 / max 259.6155, expressed in 212 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36283	0.7772	74
36284	0.5950	42
36282	0.1566	35
36286	0.1514	69
36292	0.1423	1
36288	0.1301	42
36289	0.1203	61
36285	0.0365	18
36290	0.0294	7
36291	0.0178	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
placenta	UBERON:0001987	80.53	gold quality
right lobe of liver	UBERON:0001114	79.17	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.80	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.35	gold quality
tibial nerve	UBERON:0001323	75.58	gold quality
liver	UBERON:0002107	72.10	gold quality
sural nerve	UBERON:0015488	71.93	gold quality
subcutaneous adipose tissue	UBERON:0002190	71.58	gold quality
tibialis anterior	UBERON:0001385	71.51	silver quality
mucosa of transverse colon	UBERON:0004991	69.58	gold quality
left coronary artery	UBERON:0001626	68.84	gold quality
endothelial cell	CL:0000115	68.53	gold quality
omental fat pad	UBERON:0010414	68.46	gold quality
popliteal artery	UBERON:0002250	68.45	gold quality
tibial artery	UBERON:0007610	68.43	gold quality
peritoneum	UBERON:0002358	68.39	gold quality
right lobe of thyroid gland	UBERON:0001119	68.36	gold quality
left lobe of thyroid gland	UBERON:0001120	68.05	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	67.67	gold quality
amniotic fluid	UBERON:0000173	67.08	silver quality
coronary artery	UBERON:0001621	67.08	gold quality
lower esophagus muscularis layer	UBERON:0035833	67.07	gold quality
thyroid gland	UBERON:0002046	67.05	gold quality
rectum	UBERON:0001052	67.00	gold quality
adipose tissue of abdominal region	UBERON:0007808	66.99	gold quality
lower esophagus	UBERON:0013473	66.95	gold quality
colonic epithelium	UBERON:0000397	66.87	silver quality
C1 segment of cervical spinal cord	UBERON:0006469	66.60	gold quality
skin of leg	UBERON:0001511	66.51	gold quality
mucosa of stomach	UBERON:0001199	66.19	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	16.26
E-ANND-3	yes	7.64

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

87 targeting ACKR2, 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-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-7978	99.86	66.90	856
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-1321	99.84	65.30	1811

Literature-anchored findings (GeneRIF, showing 36)

• CCR10 is unlikely to be necessary for cutaneous homing of TH cells in the models studied here. CCR10 may instead play a role in the movement of specialized “effector” cutaneous TH cells to and/or within epidermal microenvironments. (PMID:12406880)
• In lymphatic vessels D6 acts as a nonsignaling decoy receptor and scavenger for inflammatory CC chemokines, by clearing them and preventing excessive diffusion via afferent lymphatics to lymph nodes. (PMID:12594248)
• CCR10 and its mucosal epithelial ligand CCL28 have roles in the migration of circulating IgA plasmablasts (PMID:12671049)
• D6 is constitutively internalized via a ligand-independent, phosphorylation-independent association with beta-arrestin. (PMID:15084596)
• We also propose that lymphatic endothelial cell-expressed D6 might have a distinct but complementary role in restricting inflammatory leukocyte access to the lymphatic vasculature. (PMID:16814608)
• demonstrate the importance of proinflammatory CC chemokines in de novo tumorigenesis and reveal chemokine sequestration by D6 to be a novel and effective method of tumor suppression (PMID:17607362)
• the heptahelical body of D6 on its own can engage the endocytotic machinery of HEK293 cells but that the C terminus is indispensable for scavenging because it prevents initial chemokine engagement of D6 from inhibiting subsequent chemokine uptake. (PMID:18201974)
• Emphasis on two new players involved in regulating inflammation at the maternal-fetal interface: the long pentraxin PTX3 and the decoy receptor for inflammatory chemokines D6. (PMID:18676013)
• D6 plays a negative role in the growth and metastasis of breast cancer. (PMID:18708360)
• D6 expression is GATA1 dependent (PMID:18714007)
• Genetic variations are associated with liver inflammation in chronic hepatitis C (PMID:18822328)
• Immunohistochemistry on lung lymph nodes from patients with pulmonary tuberculosis showed that D6 expression was prominent in lymphatic endothelial cells, while CD68-positive macrophages did not stain for D6. (PMID:19446728)
• D6 cooperates with CD26 in the negative regulation of CCL14 by the selective degradation of its biologically active isoform. (PMID:19632987)
• D6 protein is found predominantly inside human choriocarcinoma-derived cells with only a small fraction available on the cell surface at any one time, yet it can progressively remove extracellular chemokines, without apparent desensitization. (PMID:20147628)
• Chemokne D6 expression is higher in biopsies taken from more severe cardiac allograft rejection. (PMID:20404785)
• DARC and D6, the most studied members of this group of molecules, are reviewed. (PMID:21151196)
• CCL2 binding to primary adult human astrocytes is CCR2-independent and is likely to be mediated via the D6 decoy. (PMID:22226505)
• Chemokine decoy receptor D6 limits CC-chemokine-dependent pathogenic inflammation and is required for adequate cardiac remodeling after myocardial infarction. (PMID:22796582)
• D6 is expressed in AMs from patients with COPD, and its expression correlates with the degree of functional impairment and markers of immune activation. (PMID:22797410)
• These data demonstrate a novel role for D6 as a regulator of the transition from uninvolved to lesional skin in psoriasis. (PMID:22867710)
• We here summarize the knowledge available today on D6 structural and signaling properties and its essential role for the control of inflammatory cells traffic and proper development of the adaptive immune response. (PMID:22939232)
• co-expression of DARC, D6, and CCX-CKR significantly associated with higher survival in gastric cancer (PMID:23462454)
• D6, which is upregulated in both inflammatory and tumor contexts, is an essential regulator of inflammatory leukocyte interactions with lymphatic endothelial cells(LECs) and is required for immature/mature DC discrimination by LECs. (PMID:23479571)
• engagement of the ACR D6 by its ligands activates a beta-arrestin1-dependent, G protein-independent signaling pathway that results in the phosphorylation of the actin-binding protein cofilin through the Rac1-PAK1-LIMK1 cascade. (PMID:23633677)
• Data show that low decoy receptor D6 expression correlated to more invasive tumors and that tumor location influences D6 expression, which is lower in the more distal parts of the colon. (PMID:24013383)
• Data show the structural motifs in the atypical chemokine receptor 2 (ACKR2) are responsible for ligand binding, and suggest ACKR2-derived N-terminal peptides as being of potential therapeutic significance. (PMID:24644289)
• ACKR2 mediates chemokine scavenging by primary human trophoblasts. (PMID:25297873)
• Data indicates that D6 is concentrated on trophoblast cell membranes in pre-eclampsia, in line with higher circulating levels of D6-ligand chemokines, but its scavenging activity is affected by trophoblast cytoskeleton disarrangement. (PMID:27780270)
• ACKR2 is a molecular regulator play a role in inflammatory changes in patients with psoriasis. (PMID:28010760)
• ACKR2 is induced after traumatic brain injuries and has a significant impact on mortality and lesion development acutely following closed head injury. (PMID:29176798)
• Data suggest that MIRN146b and MIR10b directly bind 3’-untranslated region of ACKR2 and down-regulate expression of ACKR2 in keratinocytes and in lymphatic endothelial cells, respectively. (ACKR2 = atypical chemokine receptor 2) (PMID:29279330)
• Abnormal uterine inflammation in obstetric syndromes: molecular insights into the role of chemokine decoy receptor D6 and inflammasome NLRP3. (PMID:32030415)
• Expression of ACKR2 in placentas from different types of preeclampsia. (PMID:32056543)
• Biphasic Expression of Atypical Chemokine Receptor (ACKR) 2 and ACKR4 in Colorectal Neoplasms in Association with Histopathological Findings. (PMID:33374792)
• The Role of Atypical Chemokine Receptor D6 (ACKR2) in Physiological and Pathological Conditions; Friend, Foe, or Both? (PMID:35677043)
• Pan-cancer analysis of the prognostic significance of ACKR2 expression and the related genetic/epigenetic dysregulations. (PMID:37882761)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ACKR2	ENSDARG00000086314
mus_musculus	Ackr2	ENSMUSG00000044534
rattus_norvegicus	Ackr2	ENSRNOG00000019472

Paralogs (23): CCR6 (ENSG00000112486), CCRL2 (ENSG00000121797), CCR2 (ENSG00000121807), CXCR4 (ENSG00000121966), CCR7 (ENSG00000126353), ACKR4 (ENSG00000129048), ACKR3 (ENSG00000144476), RGR (ENSG00000148604), CXCR5 (ENSG00000160683), CCR5 (ENSG00000160791), CXCR1 (ENSG00000163464), CCR1 (ENSG00000163823), CX3CR1 (ENSG00000168329), CXCR6 (ENSG00000172215), XCR1 (ENSG00000173578), CCR9 (ENSG00000173585), CCR8 (ENSG00000179934), CXCR2 (ENSG00000180871), GALR2 (ENSG00000182687), CCR3 (ENSG00000183625), CCR4 (ENSG00000183813), CCR10 (ENSG00000184451), CXCR3 (ENSG00000186810)

Protein

Protein identifiers

Atypical chemokine receptor 2 — O00590 (reviewed: O00590)

Alternative names: C-C chemokine receptor D6, Chemokine receptor CCR-10, Chemokine receptor CCR-9, Chemokine-binding protein 2, Chemokine-binding protein D6

All UniProt accessions (5): O00590, V9GYB7, V9GYM0, V9GYX0, V9GZ70

UniProt curated annotations — full annotation on UniProt →

Function. Atypical chemokine receptor that controls chemokine levels and localization via high-affinity chemokine binding that is uncoupled from classic ligand-driven signal transduction cascades, resulting instead in chemokine sequestration, degradation, or transcytosis. Also known as interceptor (internalizing receptor) or chemokine-scavenging receptor or chemokine decoy receptor. Acts as a receptor for chemokines including CCL2, CCL3, CCL3L1, CCL4, CCL5, CCL7, CCL8, CCL11, CCL13, CCL17, CCL22, CCL23, CCL24, SCYA2/MCP-1, SCY3/MIP-1-alpha, SCYA5/RANTES and SCYA7/MCP-3. Upon active ligand stimulation, activates a beta-arrestin 1 (ARRB1)-dependent, G protein-independent signaling pathway that results in the phosphorylation of the actin-binding protein cofilin (CFL1) through a RAC1-PAK1-LIMK1 signaling pathway. Activation of this pathway results in up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. By scavenging chemokines in tissues, on the surfaces of lymphatic vessels, and in placenta, plays an essential role in the resolution (termination) of the inflammatory response and in the regulation of adaptive immune responses. Plays a major role in the immune silencing of macrophages during the resolution of inflammation. Acts as a regulator of inflammatory leukocyte interactions with lymphatic endothelial cells (LECs) and is required for immature/mature dendritic cells discrimination by LECs.

Subcellular location. Early endosome. Recycling endosome. Cell membrane.

Tissue specificity. Found in endothelial cells lining afferent lymphatics in dermis and lymph nodes. Also found in lymph nodes subcapsular and medullary sinuses, tonsillar lymphatic sinuses and lymphatics in mucosa and submucosa of small and large intestine and appendix. Also found in some malignant vascular tumors. Expressed at high levels in Kaposi sarcoma-related pathologies. Expressed on apoptotic neutrophils (at protein level). Expressed primarily in placenta and fetal liver, and found at very low levels in the lung and lymph node.

Post-translational modifications. Phosphorylated on serine residues in the C-terminal cytoplasmic tail.

Domain organisation. The C-terminal cytoplasmic tail controls its phosphorylation, stability, intracellular trafficking itinerary, and chemokine scavenging properties.

Induction. By interleukin-6 and interferon-gamma.

Similarity. Belongs to the G-protein coupled receptor 1 family. Atypical chemokine receptor subfamily.

RefSeq proteins (1): NP_001287* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR000355	Chemokine_rcpt	Family
IPR001277	CXCR4/ACKR2	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain
IPR050119	CCR1-9-like	Family

Pfam: PF00001

UniProt features (38 total): topological domain 8, modified residue 8, transmembrane region 7, sequence variant 4, sequence conflict 3, region of interest 2, chain 1, short sequence motif 1, compositionally biased region 1, glycosylation site 1, disulfide bond 1, strand 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8J8V	ELECTRON MICROSCOPY	3.22
8GO9	ELECTRON MICROSCOPY	3.35
8J8Z	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00590-F1	80.89	0.51

Antibody-complex structures (SAbDab): 3 — 8GO9, 8J8V, 8J8Z

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 (8): 339, 343, 345, 346, 348, 350, 351, 354

Disulfide bonds (1): 117–195

Glycosylation sites (1): 19

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-380108	Chemokine receptors bind chemokines
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-500792	GPCR ligand binding

MSigDB gene sets: 479 (showing top): AHRARNT_01, MORF_RAGE, GOBP_CELL_CHEMOTAXIS, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, MODULE_45, MODULE_64, GOCC_CELL_SURFACE, HSIAO_HOUSEKEEPING_GENES, GAURNIER_PSMD4_TARGETS, MODULE_16, GGGTGGRR_PAX4_03, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GCM_PRKCG, GOBP_TAXIS

GO Biological Process (10): inflammatory response (GO:0006954), immune response (GO:0006955), positive regulation of cytosolic calcium ion concentration (GO:0007204), calcium-mediated signaling (GO:0019722), intracellular signal transduction (GO:0035556), cell chemotaxis (GO:0060326), chemotaxis (GO:0006935), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186), chemokine-mediated signaling pathway (GO:0070098)

GO Molecular Function (6): chemokine receptor activity (GO:0004950), C-C chemokine receptor activity (GO:0016493), C-C chemokine binding (GO:0019957), receptor decoy activity (GO:0140319), G protein-coupled receptor activity (GO:0004930), protein binding (GO:0005515)

GO Cellular Component (10): nucleoplasm (GO:0005654), early endosome (GO:0005769), cytosol (GO:0005829), actin filament (GO:0005884), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), nuclear membrane (GO:0031965), recycling endosome (GO:0055037), endosome (GO:0005768), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
signal transduction	2
G protein-coupled receptor signaling pathway	2
chemokine binding	2
endosome	2
defense response	1
immune system process	1
response to stimulus	1
regulation of biological quality	1
intracellular signaling cassette	1
intracellular anatomical structure	1
chemotaxis	1
cell migration	1
cellular response to chemical stimulus	1
response to chemical	1
taxis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor activity	1
cytokine-mediated signaling pathway	1
cellular response to chemokine	1
G protein-coupled chemoattractant receptor activity	1
cytokine receptor activity	1
chemokine-mediated signaling pathway	1
chemokine receptor activity	1
C-C chemokine binding	1
molecular sequestering activity	1
transmembrane signaling receptor activity	1
binding	1
nuclear lumen	1
cytoplasm	1
actin cytoskeleton	1
polymeric cytoskeletal fiber	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1

Protein interactions and networks

STRING

1522 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACKR2	CCL25	O15444	999
ACKR2	CCL27	Q9Y4X3	998
ACKR2	MADCAM1	Q13477	996
ACKR2	CCL21	O00585	992
ACKR2	CCL17	Q92583	981
ACKR2	CCL2	P13500	972
ACKR2	CCL3	P10147	967
ACKR2	CCL19	Q99731	965
ACKR2	CCL5	P13501	961
ACKR2	CCL22	O00626	956
ACKR2	CXCL12	P48061	900
ACKR2	CCL8	P78388	894
ACKR2	CCL7	P80098	869
ACKR2	CCL4	P13236	867
ACKR2	CCL28	Q9NRJ3	863

IntAct

26 interactions, top by confidence:

A	B	Type	Score
MS4A1	ACKR2	psi-mi:“MI:0915”(physical association)	0.560
ACKR2	SLC13A4	psi-mi:“MI:0915”(physical association)	0.560
ACKR2	SACM1L	psi-mi:“MI:0915”(physical association)	0.560
ACKR2	TMEM167B	psi-mi:“MI:0915”(physical association)	0.560
ACKR2	NIPAL4	psi-mi:“MI:0915”(physical association)	0.560
ACKR2	EFNA5	psi-mi:“MI:0915”(physical association)	0.560
ACKR2	MS4A1	psi-mi:“MI:0915”(physical association)	0.560
ACKR2	GJA8	psi-mi:“MI:0915”(physical association)	0.560
ACKR2	CDK18	psi-mi:“MI:0915”(physical association)	0.400
CREB3	ACKR2	psi-mi:“MI:0915”(physical association)	0.370
ACKR2	TMEM223	psi-mi:“MI:0914”(association)	0.350
ACKR2	SLC13A4	psi-mi:“MI:0915”(physical association)	0.000
SACM1L	ACKR2	psi-mi:“MI:0915”(physical association)	0.000
ACKR2	TMEM167B	psi-mi:“MI:0915”(physical association)	0.000
NIPAL4	ACKR2	psi-mi:“MI:0915”(physical association)	0.000
EFNA5	ACKR2	psi-mi:“MI:0915”(physical association)	0.000
ACKR2	GJA8	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (83): CDK18 (Affinity Capture-MS), CREB3 (Two-hybrid), ACKR2 (Two-hybrid), MS4A1 (Two-hybrid), SLC13A4 (Two-hybrid), NIPAL4 (Two-hybrid), EFNA5 (Two-hybrid), SACM1L (Two-hybrid), TMEM167B (Two-hybrid), Ccl3 (Reconstituted Complex), Ccl2 (Reconstituted Complex), CCL8 (Reconstituted Complex), CCL5 (Reconstituted Complex), CCL7 (Reconstituted Complex), CCL13 (Reconstituted Complex)

ESM2 similar proteins: A7YY44, B0UXR0, B2GV46, E7FEL0, F8VQN3, O00398, O00590, O08707, O09027, O14843, O15529, O15552, O46685, P21556, P25105, P46002, P46093, P46094, P50132, P56484, Q00991, Q09QM4, Q13304, Q15743, Q1JQB3, Q3U507, Q3UFD7, Q3UJF0, Q4KLH9, Q6NS65, Q76EI6, Q86VZ1, Q8BFQ3, Q8BFU7, Q8BUD0, Q8BYC4, Q8C131, Q8TDS4, Q8TDS5, Q8VCK6

Diamond homologs: A0T2N3, F1MV99, O00155, O00590, O08707, O08858, O09027, O35210, O77590, O88410, O89039, O97666, P0C5I1, P0C7U4, P11613, P21109, P25024, P25025, P25095, P25104, P25106, P29089, P29754, P29755, P30555, P30556, P30680, P30874, P30875, P30935, P30936, P30937, P30938, P31391, P32303, P32745, P33396, P33535, P34976, P34993

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	8
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1672 predictions. Top by Δscore:

Variant	Effect	Δscore
17:42680615:AACCT:A	acceptor_loss	1.0000
17:42680616:ACCTG:A	acceptor_loss	1.0000
17:42683814:A:AG	acceptor_gain	1.0000
17:42683815:CCCTA:C	acceptor_loss	1.0000
17:42683816:CCTA:C	acceptor_loss	1.0000
17:42683817:CTA:C	acceptor_loss	1.0000
17:42683818:TA:T	acceptor_loss	1.0000
17:42683819:A:AG	acceptor_gain	1.0000
17:42683819:AGAC:A	acceptor_gain	1.0000
17:42683819:AGACG:A	acceptor_gain	1.0000
17:42683820:G:GG	acceptor_gain	1.0000
17:42683820:GA:G	acceptor_gain	1.0000
17:42683820:GAC:G	acceptor_gain	1.0000
17:42683820:GACG:G	acceptor_gain	1.0000
17:42683820:GACGG:G	acceptor_gain	1.0000
3:45900804:TTGCA:T	acceptor_loss	1.0000
3:45900807:CAGAG:C	acceptor_loss	1.0000
3:45900808:A:AG	acceptor_gain	1.0000
3:45900808:AGAGC:A	acceptor_loss	1.0000
3:45900809:G:GG	acceptor_gain	1.0000
3:45900809:GA:G	acceptor_gain	1.0000
3:45900809:GAGC:G	acceptor_gain	1.0000
3:45900809:GAGCC:G	acceptor_gain	1.0000
17:42680613:GAAAC:G	acceptor_gain	0.9900
17:42680616:AC:A	acceptor_gain	0.9900
17:42680617:CC:C	acceptor_gain	0.9900
17:42680618:C:CC	acceptor_gain	0.9900
17:42680628:C:CT	acceptor_gain	0.9900
17:42682895:CT:C	donor_gain	0.9900
17:42682897:G:GG	donor_gain	0.9900

AlphaMissense

2535 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:42864917:A:C	S139R	0.986
3:42864919:C:A	S139R	0.986
3:42864919:C:G	S139R	0.986
3:42864890:A:C	S130R	0.976
3:42864892:T:A	S130R	0.976
3:42864892:T:G	S130R	0.976
3:42864908:A:C	S136R	0.972
3:42864910:C:A	S136R	0.972
3:42864910:C:G	S136R	0.972
3:42865397:A:C	S299R	0.970
3:42865399:C:A	S299R	0.970
3:42865399:C:G	S299R	0.970
3:42865007:T:A	W169R	0.969
3:42865007:T:C	W169R	0.969
3:42864832:G:C	W110C	0.968
3:42864832:G:T	W110C	0.968
3:42864608:T:A	C36S	0.960
3:42864609:G:C	C36S	0.960
3:42864851:T:A	C117S	0.952
3:42864852:G:C	C117S	0.952
3:42865277:T:C	F259L	0.951
3:42865279:C:A	F259L	0.951
3:42865279:C:G	F259L	0.951
3:42864662:A:C	S54R	0.950
3:42864664:C:A	S54R	0.950
3:42864664:C:G	S54R	0.950
3:42865404:C:A	A301D	0.950
3:42865167:C:G	P222R	0.946
3:42865085:T:A	C195S	0.943
3:42865086:G:C	C195S	0.943

dbSNP variants (sampled 300 via entrez): RS1000040851 (3:42854503 T>C), RS1000098697 (3:42860813 A>G), RS1000107540 (3:42856119 A>G), RS1000129818 (3:42861090 G>C), RS1000145138 (3:42844082 G>A,T), RS1000188097 (3:42808111 G>T), RS1000240544 (3:42808442 G>T), RS1000368550 (3:42822376 C>G), RS1000419517 (3:42822016 C>A), RS1000426360 (3:42867598 C>T), RS1000490331 (3:42809843 C>A,T), RS1000518311 (3:42854315 C>T), RS1000518733 (3:42840446 T>C), RS1000527010 (3:42827473 A>T), RS1000601933 (3:42828784 C>A)

Disease associations

OMIM: gene MIM:602648 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

44 associations (top):

Study	Trait	p-value
GCST001762_774	Obesity-related traits	2.000000e-07
GCST001762_789	Obesity-related traits	2.000000e-07
GCST001887_2	Monocyte count	5.000000e-07
GCST001887_6	Monocyte count	2.000000e-07
GCST002595_14	Clozapine-induced agranulocytosis	3.000000e-06
GCST002665_5	Cerebrospinal fluid levels of Alzheimer’s disease-related proteins	4.000000e-18
GCST004438_29	Monocyte chemoattractant protein-1 levels	9.000000e-20
GCST004460_31	Eotaxin levels	2.000000e-46
GCST004600_187	Eosinophil percentage of white cells	9.000000e-14
GCST004606_110	Eosinophil count	5.000000e-21
GCST004608_69	Granulocyte percentage of myeloid white cells	5.000000e-19
GCST004608_70	Granulocyte percentage of myeloid white cells	1.000000e-65
GCST004609_107	Monocyte percentage of white cells	8.000000e-38
GCST004609_108	Monocyte percentage of white cells	1.000000e-97
GCST004610_57	White blood cell count	2.000000e-14
GCST004613_100	Sum neutrophil eosinophil counts	2.000000e-11
GCST004614_138	Granulocyte count	4.000000e-12
GCST004617_81	Eosinophil percentage of granulocytes	9.000000e-14
GCST004620_138	Sum basophil neutrophil counts	4.000000e-11
GCST004623_138	Neutrophil percentage of granulocytes	3.000000e-11
GCST004624_43	Sum eosinophil basophil counts	2.000000e-19
GCST004625_65	Monocyte count	4.000000e-65
GCST004625_66	Monocyte count	7.000000e-121
GCST004626_26	Myeloid white cell count	6.000000e-18
GCST004626_27	Myeloid white cell count	6.000000e-13
GCST004629_31	Neutrophil count	1.000000e-10
GCST004632_141	Lymphocyte percentage of white cells	2.000000e-09
GCST005977_29	Monocyte count	2.000000e-14
GCST006622_18	Neonatal cytokine/chemokine levels (fetal genetic effect)	3.000000e-08
GCST006622_19	Neonatal cytokine/chemokine levels (fetal genetic effect)	4.000000e-09

EFO canonical traits (17, from GWAS)

EFO ID	Trait name
EFO:0005188	CCL11 measurement
EFO:0005091	monocyte count
EFO:0006514	Alzheimer’s disease biomarker measurement
EFO:0008122	eotaxin measurement
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007989	monocyte percentage of leukocytes
EFO:0004833	neutrophil count
EFO:0007987	granulocyte count
EFO:0007996	eosinophil percentage of granulocytes
EFO:0005090	basophil count
EFO:0007994	neutrophil percentage of granulocytes
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0004747	protein measurement
EFO:0007959	fetal genotype effect measurement
EFO:0008236	monokine induced by gamma interferon measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105988 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Chemokine receptors

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation	2
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
GSK-J4	decreases expression	1
dicrotophos	increases expression	1
cobalt oxide	increases expression	1
CGP 52608	affects binding, increases reaction	1
Acetaminophen	decreases expression	1
Allergens	increases expression, affects cotreatment	1
Arsenic	affects methylation	1
Vehicle Emissions	affects cotreatment, increases expression	1
Cadmium	decreases expression, increases abundance	1
Diethylhexyl Phthalate	increases expression	1
Diethylstilbestrol	decreases expression	1
Lead	increases expression	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Zearalenone	decreases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Okadaic Acid	decreases expression	1
Lactic Acid	decreases expression	1
Genistein	decreases expression	1
S-Nitrosoglutathione	increases expression	1

ChEMBL screening assays

3 unique, capped per target: 2 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4037559	Binding	Agonist activity at CCR10 (unknown origin)	Discovery of Novel 1-Cyclopentenyl-3-phenylureas as Selective, Brain Penetrant, and Orally Bioavailable CXCR2 Antagonists. — J Med Chem
CHEMBL5579101	Functional	Agonist activity at human ACKR2 transfected in HEK293T cells co-expressing LgBiT-fused SmBiT-beta-arrestin assessed as beta-arrestin recruitment by bioluminescence based NanoBiT assay	Novel Small-Molecule Atypical Chemokine Receptor 3 Agonists: Design, Synthesis, and Pharmacological Evaluation for Antiplatelet Therapy. — J Med Chem

Clinical trials (associated diseases)

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