CR1

Summary

CR1 (complement C3b/C4b receptor 1 (Knops blood group), HGNC:2334) is a protein-coding gene on chromosome 1q32.2, encoding Complement receptor type 1 (P17927). Membrane immune adherence receptor that plays a critical role in the capture and clearance of complement-opsonized pathogens by erythrocytes and monocytes/macrophages.

This gene is a member of the receptors of complement activation (RCA) family and is located in the ‘cluster RCA’ region of chromosome 1. The genome is polymorphic at this locus with allele-specific splice variants encoding different isoforms, based on the presence/absence of long homologous repeats (LHRs). The gene encodes a monomeric single-pass type I membrane glycoprotein found on erythrocytes, leukocytes, glomerular podocytes, and splenic follicular dendritic cells. The Knops blood group system is a system of antigens located on this protein. The protein mediates cellular binding to particles and immune complexes that have activated complement. Decreases in expression of this protein and/or mutations in this gene have been associated with gallbladder carcinomas, mesangiocapillary glomerulonephritis, systemic lupus erythematosus, sarcoidosis and Alzheimer’s disease. Mutations in this gene have also been associated with a reduction in Plasmodium falciparum rosetting, conferring protection against severe malaria.

Source: NCBI Gene 1378 — RefSeq curated summary.

At a glance

• GWAS associations: 19
• Clinical variants (ClinVar): 296 total
• Druggable target: yes
• MANE Select transcript: NM_000651

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2334
Approved symbol	CR1
Name	complement C3b/C4b receptor 1 (Knops blood group)
Location	1q32.2
Locus type	gene with protein product
Status	Approved
Aliases	CD35, KN
Ensembl gene	ENSG00000203710
Ensembl biotype	protein_coding
OMIM	120620
Entrez	1378

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 7 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000367049, ENST00000367050, ENST00000367051, ENST00000367052, ENST00000367053, ENST00000400960, ENST00000434033, ENST00000436595, ENST00000450439, ENST00000529814, ENST00000530487, ENST00000534202, ENST00000896237

RefSeq mRNA: 3 — MANE Select: NM_000651 NM_000573, NM_000651, NM_001381851

CCDS: CCDS44308

Canonical transcript exons

ENST00000367049 — 47 exons

Exon	Start	End
ENSE00001443316	207496157	207496388
ENSE00001443328	207639397	207641765
ENSE00001443329	207630517	207630621
ENSE00001443332	207619880	207620065
ENSE00001443333	207618071	207618247
ENSE00001443338	207609290	207609688
ENSE00002334337	207621973	207621996
ENSE00002334777	207611677	207611853
ENSE00002340329	207539981	207540066
ENSE00002390209	207611939	207612041
ENSE00002403204	207616575	207616802
ENSE00002409546	207622993	207623068
ENSE00002425493	207614404	207614489
ENSE00002429069	207534197	207534296
ENSE00003474365	207564132	207564234
ENSE00003489348	207533409	207533588
ENSE00003490843	207505904	207506083
ENSE00003495210	207506714	207506813
ENSE00003504449	207523611	207524009
ENSE00003550575	207542182	207542580
ENSE00003552727	207532180	207532398
ENSE00003561485	207552752	207552851
ENSE00003561988	207560739	207561137
ENSE00003593863	207527021	207527123
ENSE00003613886	207567824	207568042
ENSE00003638821	207551964	207552143
ENSE00003641563	207565838	207565923
ENSE00003656886	207526753	207526929
ENSE00003663878	207563864	207564040
ENSE00003664078	207511569	207511654
ENSE00003672220	207528716	207528801
ENSE00003673461	207545576	207545678
ENSE00003681581	207558538	207558623
ENSE00003684705	207545308	207545484
ENSE00003691170	207550735	207550953
ENSE00003692631	207547271	207547356
ENSE00003712429	207581918	207582003
ENSE00003713173	207575595	207575680
ENSE00003720350	207584649	207584876
ENSE00003729025	207580240	207580416
ENSE00003730519	207577805	207578203
ENSE00003731201	207607251	207607336
ENSE00003734817	207588675	207588774
ENSE00003738575	207569847	207569946
ENSE00003739595	207569059	207569238
ENSE00003742297	207587386	207587565
ENSE00003750106	207580511	207580613

Expression profiles

Bgee: expression breadth ubiquitous, 184 present calls, max score 92.40.

FANTOM5 (CAGE): breadth broad, TPM avg 2.0714 / max 411.0970, expressed in 284 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
8254	1.4930	263
8253	0.3800	137
8255	0.1776	68
201928	0.0207	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood	UBERON:0000178	92.40	gold quality
monocyte	CL:0000576	91.05	gold quality
mononuclear cell	CL:0000842	90.34	gold quality
leukocyte	CL:0000738	90.13	gold quality
spleen	UBERON:0002106	88.63	gold quality
vermiform appendix	UBERON:0001154	85.93	gold quality
lymph node	UBERON:0000029	84.00	gold quality
bone marrow	UBERON:0002371	83.41	gold quality
trabecular bone tissue	UBERON:0002483	82.36	gold quality
granulocyte	CL:0000094	80.50	gold quality
superficial temporal artery	UBERON:0001614	80.42	gold quality
bone marrow cell	CL:0002092	79.25	gold quality
caecum	UBERON:0001153	78.72	gold quality
renal glomerulus	UBERON:0000074	74.93	gold quality
epithelium of nasopharynx	UBERON:0001951	74.00	gold quality
metanephric glomerulus	UBERON:0004736	73.60	gold quality
right lung	UBERON:0002167	73.15	gold quality
ileal mucosa	UBERON:0000331	72.98	gold quality
buccal mucosa cell	CL:0002336	72.97	gold quality
tonsil	UBERON:0002372	72.60	gold quality
parietal pleura	UBERON:0002400	71.97	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	70.84	gold quality
endometrium epithelium	UBERON:0004811	70.71	gold quality
frontal pole	UBERON:0002795	70.59	gold quality
pleura	UBERON:0000977	70.51	gold quality
colonic epithelium	UBERON:0000397	70.37	silver quality
paraflocculus	UBERON:0005351	70.30	gold quality
middle frontal gyrus	UBERON:0002702	70.05	gold quality
sural nerve	UBERON:0015488	69.65	gold quality
upper lobe of left lung	UBERON:0008952	69.05	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	29.56
E-ANND-3	yes	16.32
E-MTAB-9801	yes	5.71
E-CURD-112	no	2.84

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ETS1, ETV6, NR5A2, NR6A1, PAX5, RUNX1, SP1, SP3, TCF3, ZNF699

miRNA regulators (miRDB)

127 targeting CR1, 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-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 40)

• CR1 multimeric ligand inhibits the proliferation of tonsil B cells activated with a suboptimal dose of anti-IgM F(ab’)2. (PMID:11884446)
• The structure of the principal C3b/C4b binding site (residues 901-1095) of CR1 is reported, revealing three complement control protein modules (modules 15-17) in an extended head-to-tail arrangement with flexibility at the 16-17 junction (PMID:11955431)
• relative contributions of CR1 and CR2 to the deposition of C3 fragments and MAC on B lymphocytes under circumstances where all complement pathways are operational (PMID:11981823)
• The presence of CR1 (CD35) and CR4 (CD1c/CD18) on HUVEC indicates that endothelial cells (EC) have the potential to bind C3b and iC3b, respectively, which both mediate biological effects in the course of complement activation. (PMID:12083416)
• CR1 gene as a possible susceptibility factor in sarcoidosis. (PMID:12091241)
• No relationship has been found between erythrocyte CR1 expression level and genotype for the HindIII restriction fragment length polymorphism when correlated with malaria susceptibility in West Africa. (PMID:12486610)
• data suggest that erythrocyte cell surface domains rich in CR1, but not in DAF, are specifically lost in factor I deficiency (PMID:12490287)
• Complement receptors type 1 (CR1, CD35) and 2 (CR2, CD21) cooperate in the binding of hydrolyzed complement factor 3 (C3i) to human B lymphocytes. (PMID:14635039)
• CR1 deficiency occurs in up to 80% of healthy individuals from the malaria-endemic regions of Papua New Guinea. This CR1 deficiency is associated with polymorphisms in the CR1 gene and, with alpha-thalassemia, a common genetic disorder in Melanesia. (PMID:14694201)
• Reduced CR1 synthesis causes the low cell-surface CR1 expression in SLE. Increased proteolytic cleavage of leukocyte cell-surface CR1 may occur. Low leukocyte CR1 impairs phagocyte-mediated immune complex clearance & increase complement consumption. (PMID:15163541)
• Urinary CR1 is a potential marker for glomerular involvement in systemic lupus erythematosus (PMID:15176657)
• process in which C3b-opsonized substrates, bound to erythrocyte CR1 by immune adherence, are transferred to acceptor phagocytes (PMID:15388259)
• The changes in CR1 quantitative expression and adhering activity are consanguineously related to the development and metastasis in gallbladder carcinoma. (PMID:15526369)
• abnormally high levels of erythrocyte C4d and low levels of erythrocyte CR1 are characteristic of systemic lupus erythematosus (PMID:15529364)
• Several CR1-truncated soluble proteins were prepared and tested for their ability to prevent complement-mediated RBC destruction in vitro and in mice. (PMID:15660833)
• In an in vitro model in which red cells with antibodies and complement bound to CR1 are incubated with THP-1 model macrophages, an unusual binding pattern is characterized by rearrangement and unclustering of CR1. (PMID:15728520)
• The expression of leukocyte CR1 at transcriptional level was correlated with the levels of serum CIC, C3 and anti dsDNA antibodies in SLE. (PMID:15864913)
• The effect of the presence of the Sl2 and McCb alleles of the Swain-Langley and McCoy blood group antigens of CR1 on plasmodium malaria resistance are reported. (PMID:16277654)
• Occurrence of a reduced number/density of CR1 on erythrocytes of systemic lupus erythematosus (SLE) patients does not appear related to disease activity in SLE; coating of the complexes with complement is sufficient to bind them preferentially to CR1. (PMID:16289666)
• triggering CR1 inhibits proliferation of T-lymphocytes by a mechanism operating downstream of the initial signalling events (PMID:16360013)
• We identified several novel polymorphisms; however, the mutations did not segregate with erythrocyte CR1 expression level or the H and L alleles. (PMID:16426237)
• The expression of CR1 on neutrophils of patients with community-acquired viral or bacterial pneumonia is reported. (PMID:16433910)
• A CR1 single nucleotide polymorphism (1597C>T) was identified that results in an additional cysteine (483R>C) in short consensus repeats 8 of the N-terminal C3b/C4b binding domain. (PMID:17467802)
• Susceptibility to sarcoidosis or its clinical course is not associated with the presence of the complement receptor 1 (CR1)5507*G allele in Czech and Dutch patients. (PMID:17999656)
• The partly folded back solution structure of the 30 SCR domains in human CR1 permits access to its C3b and C4b ligands. (PMID:18028942)
• A reduced erythrocyte CR1 level may be a risk factor for reduced host defense and can be used as a predicting factor for poor prognosis in hemodialysis patients. (PMID:18075277)
• We demonstrate that the expression of the inhibitory receptors Fc gamma RII and CR1 is up-regulated on peripheral memory B cells of healthy controls, whereas this up-regulation is considerably impaired on the memory B cells of SLE patients. (PMID:18182380)
• HH genotype is high in pulmonary tuberculosis patients and the reduced complement receptor 1 in patients may be an acquired phenomenon related to disease pathogenesis. (PMID:18434253)
• erythrocyte CR1 ligation induces its clustering in complex with scaffolding protein FAP-1 (PMID:18684861)
• Within the SLE population, there was no association with disease activity and erythrocyte surface Complement Receptor 1 (CR1) (PMID:18709693)
• REVIEW: comparison of CR1 protein structure, gene structure and function for mouse nad human (PMID:18713965)
• Measurement of the complement C4d/erythrocyte complement receptor 1 ratio may be a noninvasive method for detecting acute rejection after cardiac transplantation. (PMID:18929826)
• the association of the CR1 C5507G polymorphism with susceptibility to IPF was not reproducible in Czech and English populations. (PMID:18937792)
• A CR1 promoter allele, associated with higher E-CR1 expression, that conferred protection against cerebral malaria, is described. (PMID:18954261)
• Expression levels of CD47, CD35, CD55, and CD59 on red blood cells and signal-regulatory protein-alpha,beta on monocytes from patients with warm autoimmune hemolytic anemia. (PMID:18954403)
• Genetic polymorphisms in CR1 genes are not associated with malaria resistance in patients from Baixo Amazonas region, Brazil (PMID:19048480)
• Human erythrocytes bind and inactivate type 5 adenovirus by presenting Coxsackie virus-adenovirus receptor and complement receptor 1. (PMID:19131551)
• Resutls show that populations of the endemic region have very low red blood cell surface CR1 levels and higher frequencies of the exon 22 and intron 27 mutant L alleles. (PMID:19480840)
• Data showed a possible involvement of CR1 gene polymorphisms in the predisposition to the development of CAD. (PMID:19578791)
• Two loci gave replicated evidence of association with Alzheimer’s disease: one within CLU on chromosome 8 and the other within CR1 on chromosome 1. (PMID:19734903)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cr1l	ENSMUSG00000016481
rattus_norvegicus	Cd46	ENSRNOG00000008193

Paralogs (39): CFH (ENSG00000000971), SELE (ENSG00000007908), C8B (ENSG00000021852), C6 (ENSG00000039537), SEZ6 (ENSG00000063015), CFHR2 (ENSG00000080910), APOH (ENSG00000091583), SEZ6L (ENSG00000100095), SUSD6 (ENSG00000100647), SRPX (ENSG00000101955), SRPX2 (ENSG00000102359), C7 (ENSG00000112936), C9 (ENSG00000113600), PAPPA2 (ENSG00000116183), CFHR3 (ENSG00000116785), CR2 (ENSG00000117322), CD46 (ENSG00000117335), CSMD2 (ENSG00000121904), C4BPA (ENSG00000123838), C4BPB (ENSG00000123843), CFHR4 (ENSG00000134365), CFHR5 (ENSG00000134389), F13B (ENSG00000143278), SUSD4 (ENSG00000143502), C8A (ENSG00000157131), SUSD3 (ENSG00000157303), CSMD3 (ENSG00000164796), SVEP1 (ENSG00000165124), C2 (ENSG00000166278), SELP (ENSG00000174175), SEZ6L2 (ENSG00000174938), PRF1 (ENSG00000180644), PAPPA (ENSG00000182752), CSMD1 (ENSG00000183117), SELL (ENSG00000188404), CD55 (ENSG00000196352), CR1L (ENSG00000197721), CFB (ENSG00000243649), CFHR1 (ENSG00000244414)

Protein

Protein identifiers

Complement receptor type 1 — P17927 (reviewed: P17927)

Alternative names: C3b/C4b receptor

All UniProt accessions (5): E9PDY4, E9PQN4, P17927, H0YE06, Q5SR44

UniProt curated annotations — full annotation on UniProt →

Function. Membrane immune adherence receptor that plays a critical role in the capture and clearance of complement-opsonized pathogens by erythrocytes and monocytes/macrophages. Mediates the binding by these cells of particles and immune complexes that have activated complement to eliminate them from the circulation. Also acts in the inhibition of spontaneous complement activation by impairing the formation and function of the alternative and classical pathway C3/C5 convertases, and by serving as a cofactor for the cleavage by factor I of C3b to iC3b, C3c and C3d,g, and of C4b to C4c and C4d. Also plays a role in immune regulation by contributing, upon ligand binding, to the generation of regulatory T cells from activated helper T cells. (Microbial infection) Acts as a receptor for Epstein-Barr virus.

Subunit / interactions. Interacts (via Sushi 1 and Sushi 2 domains) with complement factor C4b. Interacts (via Sushi 8 and Sushi 9 domains) with complement factor C3b. Interacts (via Sushi 24 and Sushi 25 domains) with MBL2. Interacts with FCN2. Interacts (via Sushi 24 and Sushi 25 domains) with C1QA. Interacts with CR2. (Microbial infection) Interacts with Epstein-Barr virus gp350.

Subcellular location. Membrane.

Tissue specificity. Present on erythrocytes, a subset of T cells, mature B cells, follicular dendritic cells, monocytes and granulocytes.

Polymorphism. CR1 contains a system of antigens called the Knops blood group system. Polymorphisms within this system are involved in malarial rosetting, a process associated with cerebral malaria, the major cause of mortality in Plasmodium falciparum malaria. Common Knops system antigens include McCoy (McC) and Sl(a)/Vil (Kn4, or Swain-Langley; Vil or Villien). Sl(a-) phenotype is more common in persons of African descent and may protect against fatal malaria. Other polymorphic forms of CR1 contain 23, 37 or 44 Sushi (CCP/SCR) domains instead of the 30 Sushi (CCP/SCR) domains. The most frequent alleles are the F allotype (shown here) and the S allotype (37 repeat Sushi domains). The gene frequencies of the F allotype and S allotype are 0.87 and 0.11 in Caucasians, 0.82 and 0.11 in African Americans, 0.89 and 0.11 in Mexicans. Genetic variations in CR1 resulting in CR1 deficiency are involved in protection against severe malaria [MIM:611162]. Parasitized red blood cells (RBCs) from children suffering from severe malaria often adhere to complement receptor 1 (CR1) on uninfected RBCs to form clumps of cells known as rosettes. CR1-deficient red blood cells show greatly reduced rosetting and CR1 deficiency occurs in healthy individuals from malaria-endemic regions.

Similarity. Belongs to the receptors of complement activation (RCA) family.

RefSeq proteins (3): NP_000564, NP_000642, NP_001368780 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000436	Sushi_SCR_CCP_dom	Domain
IPR035976	Sushi/SCR/CCP_sf	Homologous_superfamily
IPR051277	SEZ6_CSMD_C4BPB_Regulators	Family

Pfam: PF00084

UniProt features (164 total): disulfide bond 60, strand 33, domain 30, glycosylation site 20, sequence variant 11, sequence conflict 2, topological domain 2, signal peptide 1, chain 1, turn 1, transmembrane region 1, region of interest 1, modified residue 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
5FO9	X-RAY DIFFRACTION	3.3
1GKG	SOLUTION NMR
1GKN	SOLUTION NMR
1PPQ	SOLUTION NMR
2MCY	SOLUTION NMR
2MCZ	SOLUTION NMR
2Q7Z	SOLUTION SCATTERING

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P17927-F1	65.53	0.00

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): 42

Disulfide bonds (60): 1426–1452, 1457–1498, 1484–1514, 1519–1568, 1548–1585, 1591–1633, 1619–1646, 1650–1693, 1679–1706, 1711–1753, 1739–1769, 1774–1823, 1803–1840, 1848–1891, 1877–1904, 1909–1952, 1938–1965, 43–86, 73–99, 104–145 …

Glycosylation sites (20): 56, 252, 410, 447, 509, 578, 702, 860, 897, 959, 1028, 1152, 1310, 1481, 1504, 1534, 1540, 1605, 1763, 1908

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-8877330	RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)
R-HSA-977606	Regulation of Complement cascade

MSigDB gene sets: 321 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_B_CELL_ACTIVATION, GOCC_SECRETORY_GRANULE, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_PRODUCTION_OF_MOLECULAR_MEDIATOR_OF_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_NEGATIVE_REGULATION_OF_HYDROLASE_ACTIVITY, GOBP_PLASMA_MEMBRANE_ORGANIZATION

GO Biological Process (32): positive regulation of activation of membrane attack complex (GO:0001970), negative regulation of activation of membrane attack complex (GO:0001971), organ or tissue specific immune response (GO:0002251), complement receptor mediated signaling pathway (GO:0002430), immune complex clearance (GO:0002434), immune complex clearance by erythrocytes (GO:0002435), T cell mediated immunity (GO:0002456), negative regulation of immunoglobulin production (GO:0002638), complement activation (GO:0006956), complement activation, alternative pathway (GO:0006957), complement activation, classical pathway (GO:0006958), plasma membrane organization (GO:0007009), positive regulation of cell population proliferation (GO:0008284), negative regulation of type II interferon production (GO:0032689), negative regulation of interleukin-2 production (GO:0032703), glomerulus development (GO:0032835), negative regulation of T cell proliferation (GO:0042130), positive regulation of regulatory T cell differentiation (GO:0045591), negative regulation of complement activation (GO:0045916), negative regulation of complement activation, alternative pathway (GO:0045957), negative regulation of complement activation, classical pathway (GO:0045959), negative regulation of serine-type endopeptidase activity (GO:1900004), positive regulation of serine-type endopeptidase activity (GO:1900005), negative regulation of plasma cell differentiation (GO:1900099), negative regulation of complement-dependent cytotoxicity (GO:1903660), ATP export (GO:1904669), immune system process (GO:0002376), regulation of complement activation (GO:0030449), innate immune response (GO:0045087), symbiont entry into host cell (GO:0046718), response to other organism (GO:0051707), regulation of complement-dependent cytotoxicity (GO:1903659)

GO Molecular Function (8): virus receptor activity (GO:0001618), complement component C3b binding (GO:0001851), complement component C4b binding (GO:0001855), complement component C4b receptor activity (GO:0001861), complement component C3b receptor activity (GO:0004877), complement binding (GO:0001848), complement receptor activity (GO:0004875), protein binding (GO:0005515)

GO Cellular Component (9): obsolete extracellular space (GO:0005615), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), cell surface (GO:0009986), secretory granule membrane (GO:0030667), plasma membrane raft (GO:0044853), extracellular exosome (GO:0070062), ficolin-1-rich granule membrane (GO:0101003), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Innate Immune System	1
Transcriptional regulation by RUNX1	1
Complement cascade	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
complement activation	3
complement binding	3
activation of membrane attack complex	2
regulation of activation of membrane attack complex	2
negative regulation of complement activation	2
immune effector process	2
negative regulation of cytokine production	2
opsonin binding	2
opsonin receptor activity	2
complement receptor activity	2
cellular anatomical structure	2
positive regulation of complement activation	1
immune response	1
immune response-activating cell surface receptor signaling pathway	1
immune complex clearance	1
lymphocyte mediated immunity	1
adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
immunoglobulin production	1
regulation of immunoglobulin production	1
negative regulation of production of molecular mediator of immune response	1
activation of immune response	1
humoral immune response	1
protein activation cascade	1
innate immune response	1
humoral immune response mediated by circulating immunoglobulin	1
endomembrane system organization	1
membrane organization	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
type II interferon production	1
regulation of type II interferon production	1
interleukin-2 production	1
regulation of interleukin-2 production	1
anatomical structure development	1
nephron development	1
T cell proliferation	1
regulation of T cell proliferation	1
negative regulation of lymphocyte proliferation	1
negative regulation of T cell activation	1

Protein interactions and networks

STRING

1184 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CR1	C3	P01024	999
CR1	C4A	P01028	999
CR1	C4A	P01028	998
CR1	CD59	P13987	824
CR1	MBL2	P11226	805
CR1	ITGAM	P11215	737
CR1	CEACAM8	P31997	736
CR1	FCGR2A	P12318	729
CR1	C5AR1	P21730	724
CR1	FCGR3B	O75015	723
CR1	FCGR3A	P08637	720
CR1	FCGR2B	P31994	712
CR1	CD19	P15391	704
CR1	ITGAX	P20702	690
CR1	CFI	P05156	687

IntAct

31 interactions, top by confidence:

A	B	Type	Score
C3	C3	psi-mi:“MI:0915”(physical association)	0.700
MBL2	CR1	psi-mi:“MI:0407”(direct interaction)	0.620
CR1	MASP1	psi-mi:“MI:0407”(direct interaction)	0.620
CR1	MBL2	psi-mi:“MI:0407”(direct interaction)	0.620
C3	CR1	psi-mi:“MI:0407”(direct interaction)	0.440
CR1	FCN2	psi-mi:“MI:0407”(direct interaction)	0.440
CR1	FCN3	psi-mi:“MI:0407”(direct interaction)	0.440
C3	C3	psi-mi:“MI:0915”(physical association)	0.400
CR1L	ACTL6B	psi-mi:“MI:0914”(association)	0.350
purL	CR1	psi-mi:“MI:0915”(physical association)	0.000
CR1	bioB	psi-mi:“MI:0915”(physical association)	0.000
	CR1	psi-mi:“MI:0915”(physical association)	0.000
CR1	lexA	psi-mi:“MI:0915”(physical association)	0.000
CR1		psi-mi:“MI:0915”(physical association)	0.000
ubiF	CR1	psi-mi:“MI:0915”(physical association)	0.000
CR1	pgl	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (3): CR1 (Affinity Capture-MS), CR2 (Affinity Capture-Western), CR1 (Affinity Capture-RNA)

ESM2 similar proteins: P08519, P0CG48, P0CG50, P0CG63, P0CG66, P0CG68, P0CG69, P0CG72, P0CG74, P0CG75, P0CG76, P0CG78, P0CG79, P0CG80, P0CG81, P0CG82, P0CG84, P0CG85, P0CG88, P0CH04, P0CH05, P0CH27, P0CH28, P0CH32, P14417, P17927, P18337, P42739, P42740, P59669, P62976, P69315, P69322, Q06852, Q26678, Q3E7K8, Q58G87, Q60997, Q63135, Q63429

Diamond homologs: A0A1D5NSM8, A2AVA0, B3EWY9, B3EWZ3, B3EWZ8, C0HL12, C5IAW9, D3YXF5, D3YXG0, D3ZTD8, E9Q6D8, F1LW30, G1FC92, G5ECS8, O08721, O08722, P10643, P13671, P16109, P17927, P19070, P20023, P35440, P35448, P58397, P61134, P61135, P68638, P68639, P98136, Q03472, Q13591, Q28065, Q29RQ1, Q29RU4, Q2PC93, Q3UHD1, Q4LDE5, Q5RAD0, Q62217

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
C5AR2	“up-regulates quantity by expression”	CR1
C5AR1	“up-regulates quantity by expression”	CR1

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	229
Likely benign	28
Benign	10

Top pathogenic / likely-pathogenic (0)

SpliceAI

7123 predictions. Top by Δscore:

Variant	Effect	Δscore
1:207506084:G:GG	donor_gain	1.0000
1:207506812:GG:G	donor_gain	1.0000
1:207506813:GG:G	donor_gain	1.0000
1:207511655:G:GG	donor_gain	1.0000
1:207523605:TTCCA:T	acceptor_loss	1.0000
1:207523607:CCAG:C	acceptor_loss	1.0000
1:207523608:CAG:C	acceptor_loss	1.0000
1:207523609:A:AG	acceptor_gain	1.0000
1:207523609:A:C	acceptor_loss	1.0000
1:207523609:AG:A	acceptor_gain	1.0000
1:207523610:G:GG	acceptor_gain	1.0000
1:207523610:GG:G	acceptor_gain	1.0000
1:207523610:GGA:G	acceptor_gain	1.0000
1:207524007:GGG:G	donor_gain	1.0000
1:207524008:GGG:G	donor_gain	1.0000
1:207526751:A:AG	acceptor_gain	1.0000
1:207526751:AGTAT:A	acceptor_gain	1.0000
1:207526752:G:GA	acceptor_gain	1.0000
1:207526752:GT:G	acceptor_gain	1.0000
1:207526752:GTA:G	acceptor_gain	1.0000
1:207526752:GTAT:G	acceptor_gain	1.0000
1:207526752:GTATG:G	acceptor_gain	1.0000
1:207526925:TGAAG:T	donor_loss	1.0000
1:207526927:A:T	donor_gain	1.0000
1:207526928:AGGTG:A	donor_loss	1.0000
1:207526930:GTG:G	donor_loss	1.0000
1:207526931:T:G	donor_loss	1.0000
1:207527013:A:AG	acceptor_gain	1.0000
1:207527014:T:G	acceptor_gain	1.0000
1:207527015:CTCCA:C	acceptor_loss	1.0000

AlphaMissense

16464 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:207533563:G:C	W542C	0.999
1:207533563:G:T	W542C	0.999
1:207552118:G:C	W542C	0.999
1:207552118:G:T	W542C	0.999
1:207523981:G:C	W286C	0.998
1:207523981:G:T	W286C	0.998
1:207540041:G:C	W604C	0.998
1:207540041:G:T	W604C	0.998
1:207542552:G:C	W286C	0.998
1:207542552:G:T	W286C	0.998
1:207558598:G:C	W604C	0.998
1:207558598:G:T	W604C	0.998
1:207560926:G:C	W675C	0.998
1:207560926:G:T	W675C	0.998
1:207561109:G:C	W736C	0.998
1:207561109:G:T	W736C	0.998
1:207568011:G:C	W930C	0.998
1:207568011:G:T	W930C	0.998
1:207577992:G:C	W1125C	0.998
1:207577992:G:T	W1125C	0.998
1:207578175:G:C	W1186C	0.998
1:207578175:G:T	W1186C	0.998
1:207609477:G:C	W1578C	0.998
1:207609477:G:T	W1578C	0.998
1:207506058:G:C	W92C	0.997
1:207506058:G:T	W92C	0.997
1:207523798:G:C	W225C	0.997
1:207523798:G:T	W225C	0.997
1:207532367:G:C	W480C	0.997
1:207532367:G:T	W480C	0.997

dbSNP variants (sampled 300 via entrez): RS1000004285 (1:207635244 A>G), RS1000049986 (1:207631818 A>G), RS1000095350 (1:207587193 T>TA), RS1000141437 (1:207632115 T>C), RS1000172124 (1:207622155 TAA>T), RS1000222265 (1:207640202 T>C), RS1000274161 (1:207637077 T>C), RS1000334251 (1:207594267 G>C,T), RS1000343043 (1:207496773 T>G), RS1000363200 (1:207575765 C>T), RS1000464218 (1:207641910 G>A,T), RS1000527305 (1:207609742 G>A,T), RS1000604451 (1:207580768 G>C), RS1000659948 (1:207592843 A>T), RS1000684165 (1:207603302 G>C)

Disease associations

OMIM: gene MIM:120620 | disease phenotypes: MIM:611162, MIM:607834

GenCC curated gene-disease

Mondo (4): malaria, susceptibility to (MONDO:0021024), hypothyroidism (MONDO:0005420), anxiety (MONDO:0011918), polyarticular arthritis (MONDO:0024280)

Orphanet (1): Malaria (Orphanet:673)

HPO phenotypes

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

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST000480_2	Alzheimer’s disease	3.000000e-10
GCST001025_3	Alzheimer’s disease	4.000000e-14
GCST001026_3	Alzheimer’s disease (late onset)	5.000000e-10
GCST001120_1	Erythrocyte sedimentation rate	2.000000e-28
GCST001385_1	Inflammatory biomarkers	9.000000e-14
GCST002245_5	Alzheimer’s disease (late onset)	6.000000e-24
GCST002813_11	Alzheimer’s disease in APOE e4+ carriers	4.000000e-09
GCST005549_4	Alzheimer’s disease (late onset)	7.000000e-11
GCST005554_3	Systemic sclerosis	2.000000e-06
GCST007319_17	Alzheimer’s disease (late onset)	1.000000e-17
GCST007320_107	Alzheimer’s disease or family history of Alzheimer’s disease	4.000000e-18
GCST007320_66	Alzheimer’s disease or family history of Alzheimer’s disease	1.000000e-18
GCST007321_12	Family history of Alzheimer’s disease	4.000000e-09
GCST007321_21	Family history of Alzheimer’s disease	9.000000e-10
GCST007826_1	Alzheimer’s disease or fasting insulin levels (pleiotropy)	4.000000e-15
GCST009021_17	Alzheimer’s disease	2.000000e-14
GCST009391_1918	Metabolite levels	3.000000e-06
GCST009496_14	Alzheimer’s disease (onset between ages 58 and 79)	5.000000e-09
GCST010002_375	Refractive error	2.000000e-54

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:1001870	late-onset Alzheimers disease
EFO:0009268	family history of Alzheimer’s disease
EFO:0010464	beta-aminoisobutyric acid measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D001007	Anxiety	F01.470.132
D007037	Hypothyroidism	C19.874.482

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3713643 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2274567	Efficacy	3	eculizumab	Paroxysmal nocturnal hemoglobinuria

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2274567	CR1	3	2.75	1	eculizumab
rs3811381	CR1		0.00	0
rs6691117	CR1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Nickel	increases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, decreases methylation	1
titanium dioxide	decreases expression	1
terbufos	decreases methylation	1
trichostatin A	increases expression	1
manganese chloride	increases expression	1
butylbenzyl phthalate	increases expression	1
maleic acid	increases expression	1
ceric oxide	decreases expression	1
Ribomunyl	increases expression, decreases expression, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
Fulvestrant	affects cotreatment, decreases methylation	1
Norethindrone Acetate	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Fonofos	decreases methylation	1
Estradiol	affects cotreatment, increases expression	1
Heparin	decreases expression	1
Hydrogen Peroxide	increases expression	1
Malathion	increases expression	1
Manganese	increases expression	1
Methotrexate	decreases expression	1
Parathion	decreases methylation	1
Perfume	increases expression	1
Phthalic Acids	increases methylation	1
Puromycin Aminonucleoside	affects binding, decreases reaction, increases expression	1
Tretinoin	increases expression	1
Valproic Acid	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_6356	CHO-DXB11 35.6	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00001730	PHASE4	COMPLETED	Study of Radioiodine (131-I) Uptake Following Administration of Thyrogen and Hypothyroid States During Thyroid Hormone Withdrawal.
NCT00111735	PHASE4	UNKNOWN	Thyroxine Titration Study
NCT00206375	PHASE4	TERMINATED	Growth Hormone and GnRH Agonist in Adolescents With Acquired Hypothyroidism
NCT00565864	PHASE4	COMPLETED	Neurocognitive and Metabolic Effects of Mild Hypothyroidism
NCT01379170	PHASE4	UNKNOWN	Thyroid Study Type 2 Diabetes Mellitus (T2DM)
NCT01536678	PHASE4	COMPLETED	Bioequivalence of Two Levothyroxine Tablet Formulations in Healthy Indian Volunteers
NCT01647750	PHASE4	COMPLETED	Study of Optimal Replacement of Thyroxine in the Elderly
NCT01769157	PHASE4	COMPLETED	Effects of L-carnitine on Hypothyroidism
NCT01831869	PHASE4	UNKNOWN	Effect of L-Thyroxine on Lipid Profiles and Atherosclerosis in Subclinical Hypothyroidism
NCT01848171	PHASE4	UNKNOWN	Effects of L-thyroxine Replacement on Serum Lipid and Atherosclerosis in Hypothyroidism
NCT01921452	PHASE4	COMPLETED	Study to Verify Clinical Utility of Point-of-Care (POC) Thyroid Stimulating Hormone (TSH) Test Kits as Compared to Third Generation TSH Test Kit
NCT02280330	PHASE4	COMPLETED	Iodine Status of Preschoolers Given Micronutrient Powder for 6 Months
NCT02512978	PHASE4	UNKNOWN	Thyroid Hormone Replacement for Hypothyroidism and Acute Myocardial Infarction(ThyroHeart-AMI)
NCT02577367	PHASE4	WITHDRAWN	Mean Percentage of Levothyroxine Dosage Increase in Patients With Hypothyroidism Started on Enteral Feeding
NCT02917863	PHASE4	UNKNOWN	Randomized Crossover Trial for the Evaluation of the Possible Effects in the Intestine of Two Different Pharmaceutical Forms of L - Thyroxine in Patients With Primary Acquired Hypothyroidism
NCT03342001	PHASE4	COMPLETED	Hypothyroidism Treated With Calcitonin
NCT03631771	PHASE4	WITHDRAWN	Pediatric Risk of Hypothyroidism With Iodinated Contrast Media
NCT03779906	PHASE4	TERMINATED	Thyroid Function of Pediatric Subjects Following Isovue® Administration
NCT04747275	PHASE4	TERMINATED	Use of Liquid Stable Levothyroxine in Trisomy 21 Pediatric Patients
NCT04878614	PHASE4	TERMINATED	Comparison of Levothyroxine Formulation in Hypothyroid Patients With Enteral Feeding
NCT05247476	PHASE4	UNKNOWN	Type 2 Deiodinase Gene Polymorphism and the Treatment of Hypothyroidism Caused by Thyroidectomy in Thyroid Cancer Patients.
NCT06073665	PHASE4	RECRUITING	Dosing of LT4 in Older Individuals
NCT06096454	PHASE4	UNKNOWN	Effect of Life Style Modification and Metformin on Hypothyroidism With Insulin Resistance
NCT00174850	PHASE4	COMPLETED	Switching From an SSRI to Tiagabine(GABITRIL) in Order to Alleviate SSRI Induced Sexual Dysfunction
NCT00302107	PHASE4	COMPLETED	A Placebo-Controlled Study of Mirtazapine for PTSD
NCT00596414	PHASE4	COMPLETED	Sedation and Analgesia for Transjugular Liver Biopsy: A Randomized Double Blind Placebo Controlled Trial
NCT00623454	PHASE4	COMPLETED	Non Cardiac Chest Pain and Benign Palpitations
NCT00676364	PHASE4	COMPLETED	Randomized Control Trial of a Topical Anesthetic to Evaluate Pain and Anxiety During Venipuncture
NCT00762099	PHASE4	UNKNOWN	Perioperative Pregabalin Use, Rehabilitation, Pain Outcomes and Anxiety Following Hip Surgery
NCT00826111	PHASE4	COMPLETED	The Effects of Eszopiclone and Lexapro on Prefrontal Glutamate and GABA in Depression With Anxiety and Insomnia
NCT00928772	PHASE4	TERMINATED	Cranial Electro Therapy Stimulation in Reducing Perioperative Anxiety
NCT00951483	PHASE4	COMPLETED	Cardiovascular Biomarkers and Quetiapine in Depression and Anxiety Patients
NCT01081249	PHASE4	COMPLETED	Effects of Oxytocin on Behavior and Physiology in a Psychotherapy Setting
NCT01148186	PHASE4	TERMINATED	An Intervention Study to Reduce the Use and Impact of Potentially Inappropriate Medications Among Older Adults
NCT01155804	PHASE4	UNKNOWN	Assessment of the Effectiveness of a Program of Preparation to Pregnancy and Delivery
NCT01285284	PHASE4	UNKNOWN	Effect of Music Over the Tolerance to Colonoscopy.
NCT01309074	PHASE4	WITHDRAWN	Does Pregabalin Improve Symptoms of Anxiety in Patients With Epilepsy? A Comparison With Sertraline
NCT01411709	PHASE4	COMPLETED	A Study On The Effect Of Vitano® On Physiological And Psychological Responses To Psychological Stress
NCT01441843	PHASE4	COMPLETED	Resistance Under the Microscope
NCT01486615	PHASE4	COMPLETED	Premedication With Melatonin and Alprazolam Combination Versus Alprazolam or Melatonin Alone