C5AR2

Summary

C5AR2 (complement C5a receptor 2, HGNC:4527) is a protein-coding gene on chromosome 19q13.32, encoding C5a anaphylatoxin chemotactic receptor 2 (Q9P296). Receptor for the chemotactic and inflammatory peptide anaphylatoxin C5a, stimulating chemotaxis, granule enzyme release, intracellular calcium release and superoxide anion production.

This gene encodes a G-protein coupled receptor 1 family member involved in the complement system of the innate immune response. Unlike classical G-protein coupled receptors, the encoded protein does not associate with intracellular G-proteins. It may instead modulate signal transduction through the beta-arrestin pathway, and may alternatively act as a decoy receptor. This gene may be involved in coronary artery disease and in the pathogenesis of sepsis. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 27202 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 90 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001271749

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4527
Approved symbol	C5AR2
Name	complement C5a receptor 2
Location	19q13.32
Locus type	gene with protein product
Status	Approved
Aliases	C5L2
Ensembl gene	ENSG00000134830
Ensembl biotype	protein_coding
OMIM	609949
Entrez	27202

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000595464, ENST00000600626, ENST00000874258

RefSeq mRNA: 3 — MANE Select: NM_001271749 NM_001271749, NM_001271750, NM_018485

CCDS: CCDS12699

Canonical transcript exons

ENST00000595464 — 2 exons

Exon	Start	End
ENSE00003156411	47332175	47332349
ENSE00003205211	47340785	47347329

Expression profiles

Bgee: expression breadth ubiquitous, 155 present calls, max score 86.49.

FANTOM5 (CAGE): breadth broad, TPM avg 2.7722 / max 128.7205, expressed in 577 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176674	1.9304	526
176675	0.7758	219
176673	0.0660	24

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	86.49	gold quality
mononuclear cell	CL:0000842	86.16	gold quality
leukocyte	CL:0000738	85.91	gold quality
blood	UBERON:0000178	81.85	gold quality
granulocyte	CL:0000094	81.23	gold quality
spleen	UBERON:0002106	77.82	gold quality
right lung	UBERON:0002167	74.43	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	74.17	gold quality
upper lobe of left lung	UBERON:0008952	71.73	gold quality
upper lobe of lung	UBERON:0008948	69.37	gold quality
mucosa of stomach	UBERON:0001199	68.23	gold quality
bone marrow cell	CL:0002092	67.92	gold quality
left uterine tube	UBERON:0001303	67.71	gold quality
right coronary artery	UBERON:0001625	67.64	gold quality
omental fat pad	UBERON:0010414	67.60	gold quality
peritoneum	UBERON:0002358	67.52	gold quality
adipose tissue of abdominal region	UBERON:0007808	66.12	gold quality
vermiform appendix	UBERON:0001154	65.95	gold quality
descending thoracic aorta	UBERON:0002345	65.24	gold quality
left coronary artery	UBERON:0001626	65.07	gold quality
thoracic aorta	UBERON:0001515	64.33	gold quality
ascending aorta	UBERON:0001496	64.08	gold quality
right atrium auricular region	UBERON:0006631	63.98	gold quality
coronary artery	UBERON:0001621	63.92	gold quality
subcutaneous adipose tissue	UBERON:0002190	63.68	gold quality
left adrenal gland cortex	UBERON:0035825	62.86	gold quality
cardiac atrium	UBERON:0002081	62.77	gold quality
right adrenal gland cortex	UBERON:0035827	62.29	gold quality
left adrenal gland	UBERON:0001234	62.02	gold quality
caecum	UBERON:0001153	61.93	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	196.66
E-GEOD-111727	yes	173.49
E-GEOD-86618	yes	62.12
E-ANND-3	yes	12.45

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

18 targeting C5AR2, 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-1252-5P	100.00	69.80	2774
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-6080	99.43	69.43	373
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-599	98.32	66.99	1037
HSA-MIR-1267	98.24	69.05	837
HSA-MIR-33B-3P	97.92	67.39	529
HSA-MIR-515-3P	97.92	67.98	506
HSA-MIR-519E-3P	97.92	68.25	508
HSA-MIR-4676-5P	97.54	65.29	715
HSA-MIR-575	97.54	65.18	718

Literature-anchored findings (GeneRIF, showing 39)

• C5L2 is a high affinity binding protein for C5a and C5a des Arg74, and has a moderate affinity for C3a. Unlike the original receptors for C5a (CD88) and C3a (C3aR), C5L2 couples weakly to Gi-mediated signalling pathways. (PMID:11773063)
• These results suggest that C5L2 is an anaphylatoxin-binding protein with unique ligand binding and signaling properties. (PMID:11773063)
• C3a des Arg77 binds to C5L2 but not to the C3a receptor (LocusID: 719). C3a and C3a des Arg77 both stimulate triglyceride synthesis (acylation stimulating protein, ASP) in adipocytes and fibroblasts and so C5L2 could be the receptor for ASP. (PMID:12540846)
• A8Delta71-73 is the first antagonist of c5a that blocks C5a and C5adesArg74 binding to C5L2 making it a valuable tool for studying C5L2 functions. (PMID:14570896)
• C5L2 on neutrophils diminishes during sepsis due to systemic generation of complement 5a (C5a), which is associated with a poor prognosis. (PMID:15634936)
• first demonstration that C5L2 is a functional receptor, mediating acylation-stimulating protein triglyceride stimulation (PMID:15833747)
• C5L2 is a highly regulated scavenger receptor for C5a and C5a-des-Arg(74) (PMID:17068344)
• C5L2 appears to bind complement factor C5a and C5a des Arg by different mechanisms, and, unlike C5a receptor (C5aR), C5L2 uses critical residues in its N-terminal domain for binding only to C5a des Arg. (PMID:17158873)
• a major function of human C5L2 is to remove active complement fragments from the extracellular environment. (PMID:19100624)
• C5L2 is a functional metabolic receptor, and serine 323 is important for ASP induced functionality. (PMID:19615750)
• Recombinant C3adesArg/acylation stimulating protein (ASP) is highly bioactive: a critical evaluation of C5L2 binding and 3T3-L1 adipocyte activation. (PMID:19767107)
• Data show that C5L2 is predominantly intracellular, while C5aR is expressed on the plasma membrane, and that internalized C5aR following ligand binding is co-localized with both C5L2 and beta-arrestin. (PMID:20044484)
• negatively modulated during TLR-mediated enhancement of C5a-induced proinflammatory responses (PMID:21630250)
• 698CT genotype of C5L2 may be a genetic maker of CAD in the Han and Uygur population in western China (PMID:21698200)
• genetic association studies in the Chinese Han population: Data suggest that an SNP in C5L2 (C698T) is associated with type 2 diabetes mellitus; 698CT heterozygotes exhibited increased serum triglyceride levels. (PMID:22180093)
• The aim of this study was to investigate the genetic alterations and mRNA expression pattern of C5aR and C5L2 genes in neutrophils from attack-free familial Mediterranean fever patients. (PMID:22187344)
• Neither the familial combined hyperlipidemia subjects nor the type 2 diabetes patients were found to have the S323I variant of the C5L2 gene. (PMID:22194190)
• C5L2 was expressed in the kidney and localized to the distal convoluted tubule and connecting tubule. (PMID:22960554)
• C5L2 has been recently demonstrated to physically interact with both C5aR and beta-arrestin to negatively regulate C5aR signaling toward an anti-inflammatory manner (PMID:23239822)
• C5L2 receptors are abundant in neurofibrillary tangles in Alzheimer’s disease brain compared to controls. (PMID:23394121)
• The results suggest that insulin sensitivity may be permissive for coupling of C5L2 levels to lipid storage and utilization. (PMID:23460866)
• C5L2 may be implicated in the pro-inflammatory role in C5a-primed neutrophils for ANCA-induced activation. (PMID:23785491)
• A novel polymorphism (901G > a) of C5L2 gene is associated with coronary artery disease in Chinese Han and Uyghur population. (PMID:24073849)
• our study indicates that 698C>T polymorphism of C5L2 gene is associated with the T2DM in individuals of Saudi population which was found to be similar with other studies. (PMID:24078164)
• C5aR and C5L2 may have roles in adiposity in women (PMID:24523571)
• C5a2 can modulate ERK1/2 signaling in macrophages via heteromer formation with C5a1 and beta-arrestin recruitment. (PMID:24777312)
• prominent C5L2 expression in advanced atherosclerotic stages directly correlates with high levels of proinflammatory cytokines (PMID:24819959)
• The present study has extended the mutation spectrum of C5L2, and Thr196Asn mutations in C5L2 were associated with retinitis pigmentosa and serum lipid levels. (PMID:24885523)
• C5AR and C5L2-mediated neutrophil dysfunction is associated with a poor outcome in sepsis. (PMID:25726869)
• All the C698T genotypes and allele frequencies in C5L2 were almost similar in both the cases and controls. (PMID:25935173)
• this study reveals a novel role for C5aR2 in C5a-mediated activation of mast cells and demonstrates that C5aR2 ligation initiates a beta-arrestin-2-, PI3K-, and ERK-dependent signaling pathway in these cells. (PMID:26283482)
• negative regulator of BDNF secretion by pulp fibroblasts under carious teeth (PMID:28033061)
• Both rs2972607 and rs8112962 SNPs of C5L2 are associated with coronary artery disease in a Han population of China. (PMID:28052000)
• Studies indicate that the complement response lie the active fragments, C3a and C5a, acting through their specific receptors, C3aR, C5aR1 and C5aR2 to direct the cellular response to inflammation. (PMID:28576324)
• Expression of C5aR1 and C5aR2 in whole blood was significantly attenuated by IL-6R-inhibition in non-ST-elevation myocardial infarction patients. (PMID:30258440)
• C5aR2 Activation Broadly Modulates the Signaling and Function of Primary Human Macrophages. (PMID:32611725)
• Differential expression of C5aR1 and C5aR2 in innate and adaptive immune cells located in early skin lesions of bullous pemphigoid patients. (PMID:36466856)
• C5L2 modulates BDNF production in human dental pulp stem cells via p38alpha pathway. (PMID:36593314)
• C5aR2 Regulates STING-Mediated Interferon Beta Production in Human Macrophages. (PMID:38067135)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	c5ar1	ENSDARG00000040319
mus_musculus	C5ar2	ENSMUSG00000074361
rattus_norvegicus	C5ar2	ENSRNOG00000049028

Paralogs (8): GPR32 (ENSG00000142511), FPR2 (ENSG00000171049), FPR1 (ENSG00000171051), C3AR1 (ENSG00000171860), CMKLR1 (ENSG00000174600), FPR3 (ENSG00000187474), C5AR1 (ENSG00000197405), GPR33 (ENSG00000214943)

Protein

Protein identifiers

C5a anaphylatoxin chemotactic receptor 2 — Q9P296 (reviewed: Q9P296)

Alternative names: Complement component 5a receptor 2, G-protein coupled receptor 77

All UniProt accessions (1): Q9P296

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for the chemotactic and inflammatory peptide anaphylatoxin C5a, stimulating chemotaxis, granule enzyme release, intracellular calcium release and superoxide anion production. Also acts as a receptor for dearginated forms of C3a, C4a and C5a anaphylatoxin peptides (ASP/C3adesArg, C4adesArg and C5adesArg, respectively). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors, such as adenylate cyclase. C5AR1 is coupled to G(i)/G(o) (GNAI1 or GNAO1) G alpha proteins and mediates inhibition of adenylate cyclase.

Subcellular location. Cell membrane.

Tissue specificity. Frontal cortex, hippocampus, hypothalamus, pons and liver.

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

RefSeq proteins (3): NP_001258678, NP_001258679, NP_060955 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR000826	Formyl_rcpt-rel	Family
IPR002234	Anphylx_rcpt_C3a/C5a1-2	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (21 total): topological domain 8, transmembrane region 7, sequence variant 2, chain 1, modified residue 1, glycosylation site 1, disulfide bond 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P296-F1	86.24	0.62

Functional residue map

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

Post-translational modifications (1): 320

Disulfide bonds (1): 107–186

Glycosylation sites (1): 3

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-977606	Regulation of Complement cascade
R-HSA-162582	Signal Transduction
R-HSA-166658	Complement cascade
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-372790	Signaling by GPCR
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)
R-HSA-500792	GPCR ligand binding

MSigDB gene sets: 137 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_LEUKOCYTE_MIGRATION, GOBP_LEUKOCYTE_CHEMOTAXIS, GOBP_NEGATIVE_REGULATION_OF_INTERLEUKIN_6_PRODUCTION, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_TAXIS, GOBP_LEUKOCYTE_MIGRATION, REACTOME_PEPTIDE_LIGAND_BINDING_RECEPTORS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_MIGRATION, GOBP_CYTOKINE_PRODUCTION

GO Biological Process (13): complement receptor mediated signaling pathway (GO:0002430), chemotaxis (GO:0006935), inflammatory response (GO:0006954), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), positive regulation of cytosolic calcium ion concentration (GO:0007204), regulation of interleukin-8 production (GO:0032677), negative regulation of interleukin-6 production (GO:0032715), negative regulation of tumor necrosis factor production (GO:0032720), negative regulation of neutrophil chemotaxis (GO:0090024), regulation of immune system process (GO:0002682), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186), complement component C5a signaling pathway (GO:0038178)

GO Molecular Function (4): complement component C5a receptor activity (GO:0004878), G protein-coupled receptor activity (GO:0004930), complement receptor activity (GO:0004875), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), basal plasma membrane (GO:0009925), apical part of cell (GO:0045177), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Class A/1 (Rhodopsin-like receptors)	1
Complement cascade	1
Innate Immune System	1
Immune System	1
Signal Transduction	1
GPCR ligand binding	1
Signaling by GPCR	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor signaling pathway	3
complement receptor mediated signaling pathway	2
transmembrane signaling receptor activity	2
cellular anatomical structure	2
immune response-activating cell surface receptor signaling pathway	1
response to chemical	1
taxis	1
defense response	1
phospholipase C activator activity	1
regulation of biological quality	1
regulation of cytokine production	1
interleukin-8 production	1
negative regulation of cytokine production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
negative regulation of tumor necrosis factor superfamily cytokine production	1
neutrophil chemotaxis	1
negative regulation of granulocyte chemotaxis	1
regulation of neutrophil chemotaxis	1
negative regulation of neutrophil migration	1
immune system process	1
regulation of biological process	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
signal transduction	1
opsonin receptor activity	1
complement component C5a binding	1
complement receptor activity	1
complement component C5a signaling pathway	1
complement binding	1
immune receptor activity	1
binding	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

906 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
C5AR2	C3	P01024	996
C5AR2	C5	P01031	968
C5AR2	C4A	P01028	918
C5AR2	C5AR1	P21730	775
C5AR2	ARRB2	P32121	598
C5AR2	ARRB1	P49407	593
C5AR2	GNAI1	P04898	568
C5AR2	MAPK6	Q16659	549
C5AR2	CD46	P15529	549
C5AR2	CFP	P27918	540
C5AR2	ITGAM	P11215	538
C5AR2	C3AR1	Q16581	528
C5AR2	C1S	P09871	523
C5AR2	RPS19	P39019	521
C5AR2	MME	P08473	507

IntAct

24 interactions, top by confidence:

A	B	Type	Score
C5AR2	DCDC2	psi-mi:“MI:0915”(physical association)	0.560
C5AR2	RAMP1	psi-mi:“MI:0915”(physical association)	0.400
RAMP2	C5AR2	psi-mi:“MI:0915”(physical association)	0.400
C5AR2	RAMP2	psi-mi:“MI:0915”(physical association)	0.400
ACO2	C5AR2	psi-mi:“MI:0915”(physical association)	0.370
ABCA7	C5AR2	psi-mi:“MI:0915”(physical association)	0.370
TMEM234	C5AR2	psi-mi:“MI:0915”(physical association)	0.370
ARLN	C5AR2	psi-mi:“MI:0915”(physical association)	0.370
HERC2	C5AR2	psi-mi:“MI:0915”(physical association)	0.370
HERPUD1	C5AR2	psi-mi:“MI:0915”(physical association)	0.370
HAGHL	C5AR2	psi-mi:“MI:0915”(physical association)	0.370
PLXDC1	C5AR2	psi-mi:“MI:0915”(physical association)	0.370
SCRIB	C5AR2	psi-mi:“MI:0915”(physical association)	0.370
SCN1B	C5AR2	psi-mi:“MI:0915”(physical association)	0.370
SLC25A11	C5AR2	psi-mi:“MI:0915”(physical association)	0.370
SLC26A11	C5AR2	psi-mi:“MI:0915”(physical association)	0.370
SYNGR2	C5AR2	psi-mi:“MI:0915”(physical association)	0.370
C5AR2	ILVBL	psi-mi:“MI:0914”(association)	0.350
C5AR2	UBXN8	psi-mi:“MI:0914”(association)	0.350
cutA	C5AR2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (121): PTPN2 (Affinity Capture-MS), GSTCD (Affinity Capture-MS), ABHD17A (Affinity Capture-MS), ABHD6 (Affinity Capture-MS), PTPN1 (Affinity Capture-MS), DHRS3 (Affinity Capture-MS), TTK (Affinity Capture-MS), ABHD17B (Affinity Capture-MS), EVI5L (Affinity Capture-MS), ATP13A3 (Affinity Capture-MS), GOLPH3 (Affinity Capture-MS), EDA (Affinity Capture-MS), ARL6IP5 (Affinity Capture-MS), ADCK1 (Affinity Capture-MS), PTPN9 (Affinity Capture-MS)

ESM2 similar proteins: A0A6I8PUB9, O00155, O00270, O14842, O14843, O15529, O43603, O46685, O60755, O88626, O88634, O88853, O88854, O88855, P0C5I1, P46092, P46093, P50132, Q149R9, Q15722, Q15743, Q1JQB3, Q3T181, Q3UFD7, Q3ZC80, Q4KLH9, Q6XKD3, Q76JU8, Q76JU9, Q76JV1, Q86VZ1, Q8BUD0, Q8BYC4, Q8HYC3, Q8K3T4, Q8TDS5, Q8TDU9, Q920E0, Q924U0, Q96G91

Diamond homologs: A1ZAX0, B2ZI34, F1MV99, O00270, O08858, O09047, O15974, O42179, O54798, O54799, O62709, O88855, O97666, O97967, P21451, P21729, P24053, P24530, P25101, P26684, P28088, P28336, P30550, P30937, P31391, P32247, P35346, P35370, P35371, P35377, P35414, P35463, P47211, P47748, P47751, P48302, P49660, P49683, P52500, P56479

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
C5	up-regulates	C5AR2	binding
C5AR2	up-regulates	Chemotaxis
Avacopan	“down-regulates activity”	C5AR2	binding
C5AR2	up-regulates	Inflammation
C5AR2	“up-regulates quantity by expression”	ITGAM
C5AR2	“up-regulates quantity by expression”	CR1
C5AR2	“down-regulates quantity by repression”	SELL
C5AR2	“up-regulates quantity by expression”	superoxide

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	73
Likely benign	10
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

422 predictions. Top by Δscore:

Variant	Effect	Δscore
19:47332346:GACG:G	donor_gain	1.0000
19:47332347:ACGGT:A	donor_loss	1.0000
19:47332348:CGGTA:C	donor_loss	1.0000
19:47332349:GGT:G	donor_loss	1.0000
19:47332350:G:GG	donor_gain	1.0000
19:47332350:GTA:G	donor_loss	1.0000
19:47332351:T:G	donor_loss	1.0000
19:47332348:CG:C	donor_gain	0.9900
19:47332349:GG:G	donor_gain	0.9900
19:47332355:G:GT	donor_gain	0.9900
19:47340778:T:TA	acceptor_gain	0.9900
19:47332341:G:GT	donor_gain	0.9800
19:47332345:AGACG:A	donor_gain	0.9800
19:47332346:GACGG:G	donor_gain	0.9800
19:47332347:ACG:A	donor_gain	0.9800
19:47340783:A:AG	acceptor_gain	0.9800
19:47340784:G:GG	acceptor_gain	0.9800
19:47340784:GA:G	acceptor_gain	0.9800
19:47340780:CCCA:C	acceptor_loss	0.9700
19:47340781:CCA:C	acceptor_loss	0.9700
19:47340783:A:AC	acceptor_loss	0.9700
19:47340784:GAC:G	acceptor_gain	0.9700
19:47340784:GACA:G	acceptor_gain	0.9700
19:47332256:G:GT	donor_gain	0.9600
19:47340784:GACAC:G	acceptor_gain	0.9500
19:47341401:C:G	donor_gain	0.9400
19:47340780:CCCAG:C	acceptor_gain	0.9300
19:47340781:CCAG:C	acceptor_gain	0.9300
19:47340782:CAG:C	acceptor_gain	0.9300
19:47340783:AGACA:A	acceptor_gain	0.9300

AlphaMissense

2132 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:47341099:G:C	W100C	0.988
19:47341099:G:T	W100C	0.988
19:47341523:T:C	F242L	0.982
19:47341525:T:A	F242L	0.982
19:47341525:T:G	F242L	0.982
19:47341355:T:A	C186S	0.972
19:47341356:G:C	C186S	0.972
19:47341424:T:C	F209L	0.969
19:47341426:C:A	F209L	0.969
19:47341426:C:G	F209L	0.969
19:47341118:T:A	C107S	0.967
19:47341119:G:C	C107S	0.967
19:47341097:T:A	W100R	0.957
19:47341097:T:C	W100R	0.957
19:47341355:T:C	C186R	0.957
19:47341649:A:C	S284R	0.955
19:47341651:C:A	S284R	0.955
19:47341651:C:G	S284R	0.955
19:47341274:T:A	W159R	0.949
19:47341274:T:C	W159R	0.949
19:47341119:G:A	C107Y	0.945
19:47341118:T:C	C107R	0.942
19:47341184:A:C	S129R	0.942
19:47341186:T:A	S129R	0.942
19:47341186:T:G	S129R	0.942
19:47341357:T:G	C186W	0.939
19:47340958:T:A	N53K	0.936
19:47340958:T:G	N53K	0.936
19:47341356:G:A	C186Y	0.935
19:47341652:T:C	C285R	0.934

dbSNP variants (sampled 300 via entrez): RS1000005554 (19:47335310 G>A), RS1000065751 (19:47334721 C>A), RS1000498952 (19:47335033 C>T), RS1001224443 (19:47333984 T>C), RS1001252451 (19:47344836 C>T), RS1001359281 (19:47339462 C>T), RS1001390450 (19:47339781 C>T), RS1001456639 (19:47344899 G>A,C), RS1001621626 (19:47344618 G>A,T), RS1001897451 (19:47337986 T>G), RS1001951835 (19:47330479 G>C,T), RS1002178641 (19:47345543 T>A,C), RS1002293133 (19:47345304 A>G), RS1002312037 (19:47335652 G>A), RS1002642855 (19:47339751 C>A,G,T)

Disease associations

OMIM: gene MIM:609949 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4523478 (SINGLE PROTEIN), CHEMBL4523605 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 59,532 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1707	LOPERAMIDE HYDROCHLORIDE	4	59,532

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Complement peptide receptors

Most potent curated ligand interactions (8 total), top 8:

Ligand	Action	Affinity	Parameter
C5a	Full agonist	8.6	pIC50
C5a des-Arg	Partial agonist	7.9	pIC50
CHIPS-(28-149)	Antagonist	6.6	pIC50
C5apep	Partial agonist	6.15	pEC50
A8Δ71-73	Antagonist	6.0	pIC50
C5a hexapeptide analogue	Agonist	4.74	pIC50
P59 [PMID: 27108698]	Biased agonist	4.19	pKi
P32 [PMID: 27108698]	Biased agonist	3.65	pKi

ChEMBL bioactivities

7 potent at pChembl≥5 of 8 total, top 7 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.69	Kd	203	nM	CHEMBL5594087
6.69	Kd	203	nM	CHEMBL5594178
6.52	Kd	299	nM	CHEMBL5594087
6.52	Kd	299	nM	CHEMBL5594178
5.90	EC50	1251	nM	LOPERAMIDE HYDROCHLORIDE
5.23	EC50	5900	nM	CHEMBL4518532
5.12	EC50	7600	nM	CHEMBL4550325

PubChem BioAssay actives

4 with measured affinity, of 6 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(4S)-4-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]-4-amino-4-oxobutanoyl]amino]-4-carboxybutanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-3-methylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-carboxypropanoyl]amino]-5-amino-5-oxopentanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]pyrrolidine-2-carbonyl]amino]acetyl]amino]-4-methylpentanoyl]amino]-3-carboxypropanoyl]amino]-4-carboxybutanoyl]amino]-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-6-aminohexanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-carboxypropanoyl]amino]-3-phenylpropanoyl]pyrrolidine-2-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-5-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-amino-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-5-oxopentanoic acid	2113416: Binding affinity to N-terminal peptide SR12 of C5aR2 (6 to 32 residues)(unknown origin) assessed as dissociation constant by fluorescence based analysis	kd	0.2030	uM
(4R)-4-[[(2S)-2-[[(2S)-1-[(2R)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2R)-1-[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]-4-amino-4-oxobutanoyl]amino]-4-carboxybutanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-3-methylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-carboxypropanoyl]amino]-5-amino-5-oxopentanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]pyrrolidine-2-carbonyl]amino]acetyl]amino]-4-methylpentanoyl]amino]-3-carboxypropanoyl]amino]-4-carboxybutanoyl]amino]-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-6-aminohexanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-carboxypropanoyl]amino]-3-phenylpropanoyl]pyrrolidine-2-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-5-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-amino-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-5-oxopentanoic acid	2113416: Binding affinity to N-terminal peptide SR12 of C5aR2 (6 to 32 residues)(unknown origin) assessed as dissociation constant by fluorescence based analysis	kd	0.2030	uM

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
Tetrachlorodibenzodioxin	increases expression	2
aristolochic acid I	increases expression	1
ginger extract	decreases expression, increases abundance	1
triphenyl phosphate	affects expression	1
ferrous chloride	increases expression	1
di-n-butylphosphoric acid	affects expression	1
obeticholic acid	decreases expression	1
abrine	decreases expression	1
licochalcone B	decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	increases expression	1
Estradiol	increases expression	1
Oils, Volatile	decreases expression, increases abundance	1
Quercetin	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	increases expression	1
Valproic Acid	increases methylation	1
Cadmium Chloride	decreases expression	1
Lactic Acid	decreases expression	1
Endocannabinoids	affects binding, increases activity, increases reaction	1

ChEMBL screening assays

17 unique, capped per target: 16 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4482492	Binding	Displacement of [125I]-C5a from C5a2 receptor (unknown origin) expressed in Flp-In CHO cell membranes at 100 uM incubated for 1 hr by microbeta scintillation counting assay	Discovery of the first selective c5a2 receptor (c5l2/c5ar2) ligands
CHEMBL5442714	Functional	GPCR PRESTO-Tango dose-response in antagonist mode with target: C5AR2	EUbOPEN Chemogenomics Library - GPCR Dose-Respose

Cellosaurus cell lines

2 cell lines: 1 spontaneously immortalized cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_KW46	PathHunter CHO-K1 C5L2 beta-arrestin	Spontaneously immortalized cell line	Female
CVCL_KZ86	PathHunter U2OS C5L2 Activated GPCR Internalization	Cancer cell line	Female

Clinical trials (associated diseases)

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