CR2

Summary

CR2 (complement C3d receptor 2, HGNC:2336) is a protein-coding gene on chromosome 1q32.2, encoding Complement receptor type 2 (P20023). Serves as a receptor for various ligands including complement component CD3d, HNRNPU OR IFNA1.

This gene encodes a membrane protein, which functions as a receptor for Epstein-Barr virus (EBV) binding on B and T lymphocytes. Genetic variations in this gene are associated with susceptibility to systemic lupus erythematosus type 9 (SLEB9). Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 1380 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency, common variable, 7 (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 868 total — 41 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 79
• MANE Select transcript: NM_001006658

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2336
Approved symbol	CR2
Name	complement C3d receptor 2
Location	1q32.2
Locus type	gene with protein product
Status	Approved
Aliases	CD21, C3DR
Ensembl gene	ENSG00000117322
Ensembl biotype	protein_coding
OMIM	120650
Entrez	1380

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 10 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000367057, ENST00000367058, ENST00000367059, ENST00000475194, ENST00000479186, ENST00000485707, ENST00000640301, ENST00000699620, ENST00000699621, ENST00000699640, ENST00000864103, ENST00000923186, ENST00000923187

RefSeq mRNA: 2 — MANE Select: NM_001006658 NM_001006658, NM_001877

CCDS: CCDS1478, CCDS31007

Canonical transcript exons

ENST00000367057 — 20 exons

Exon	Start	End
ENSE00000882439	207469695	207470102
ENSE00000882440	207470740	207470916
ENSE00000882441	207470997	207471087
ENSE00001069650	207466526	207466912
ENSE00001167855	207479978	207480053
ENSE00001167866	207479257	207479280
ENSE00001167878	207477885	207478070
ENSE00001167890	207476234	207476419
ENSE00001167899	207474824	207475216
ENSE00001167908	207474241	207474323
ENSE00001167916	207473801	207473885
ENSE00001246608	207485464	207485572
ENSE00001381764	207472772	207473179
ENSE00001385266	207473545	207473721
ENSE00003517027	207469150	207469232
ENSE00003517877	207468800	207468899
ENSE00003631293	207471423	207471499
ENSE00003898484	207454328	207454476
ENSE00003898726	207489142	207489892
ENSE00003977200	207468527	207468715

Expression profiles

Bgee: expression breadth ubiquitous, 150 present calls, max score 95.83.

FANTOM5 (CAGE): breadth broad, TPM avg 10.8865 / max 750.3476, expressed in 214 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
8251	10.5367	200
8252	0.2791	80
8250	0.0706	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	95.83	gold quality
oocyte	CL:0000023	94.56	gold quality
spleen	UBERON:0002106	94.09	gold quality
vermiform appendix	UBERON:0001154	93.52	gold quality
lymph node	UBERON:0000029	93.20	gold quality
ileal mucosa	UBERON:0000331	92.88	gold quality
caecum	UBERON:0001153	88.47	gold quality
epithelium of nasopharynx	UBERON:0001951	85.85	gold quality
tonsil	UBERON:0002372	84.49	gold quality
superficial temporal artery	UBERON:0001614	82.17	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.44	gold quality
rectum	UBERON:0001052	73.31	gold quality
granulocyte	CL:0000094	72.63	gold quality
nephron tubule	UBERON:0001231	72.16	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.02	gold quality
metanephric glomerulus	UBERON:0004736	69.71	silver quality
small intestine Peyer’s patch	UBERON:0003454	69.60	gold quality
gall bladder	UBERON:0002110	67.43	gold quality
small intestine	UBERON:0002108	67.02	gold quality
renal glomerulus	UBERON:0000074	66.78	silver quality
thymus	UBERON:0002370	65.91	silver quality
kidney epithelium	UBERON:0004819	65.79	silver quality
bone marrow cell	CL:0002092	64.43	silver quality
colonic epithelium	UBERON:0000397	63.75	silver quality
duodenum	UBERON:0002114	62.36	gold quality
colonic mucosa	UBERON:0000317	61.95	gold quality
mucosa of sigmoid colon	UBERON:0004993	61.27	silver quality
blood	UBERON:0000178	61.10	gold quality
mucosa of transverse colon	UBERON:0004991	60.12	gold quality
adult mammalian kidney	UBERON:0000082	59.92	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.68

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ARID1B, ARID3A, CEBPB, CREB1, CUX1, FOS, FOXC1, IRF6, JUN, MYC, NFATC3, NFKB1, NFKB2, NFKB, NOTCH1, PAX5, POU2F1, POU2F2, RBPJ, REL, RELA, RFX5, SATB1, TCF3, YY1

miRNA regulators (miRDB)

46 targeting CR2, 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-3646	100.00	73.56	5283
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-3913-3P	99.74	66.53	938
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868
HSA-MIR-519C-3P	99.67	71.67	1870
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-567	99.63	68.57	1219
HSA-MIR-802	99.61	67.70	1254
HSA-MIR-4728-3P	99.47	68.94	981
HSA-MIR-7849-3P	99.47	68.17	1224
HSA-MIR-548AV-3P	99.43	68.50	1721
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-4293	99.22	65.46	1263
HSA-MIR-122B-3P	99.21	68.90	1333

Literature-anchored findings (GeneRIF, showing 40)

• The binding of CR2 to EBV surface glycoprotein gp350/220 follows a simple 1:1 interaction, whereas that of the receptor’s natural ligands C3d and iC3b is more complex and involves more than one intramolecular component. (PMID:11466369)
• promoter activity is critically dependent on a cell type-specific repressor (PMID:11739509)
• Redox control of EBV infection: prevention by thiol-dependent modulation of functional CD21/EBV receptor expression. (PMID:11813981)
• 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)
• crystal structure of human CD21; implications for epstein-barr virus and c3d binding (PMID:12122212)
• The percentage of T cells expressing CD21 from all gestations was significantly higher than the adult and the percentage positive decreased with increasing gestational age. (PMID:12149502)
• NF-kappaB signaling pathway enhances the expression of the CR2 gene, as a result of NF-kappaB proteins binding to two CR2 promoter elements. (PMID:12444129)
• CR2 is shed mainly as a soluble CR2 complex, in which the CR2 units link covalently and react with nucleophilic agents (PMID:12713795)
• Complement receptor 2-mediated targeting of complement inhibitors to sites of complement activation. (PMID:12813023)
• Coligation of CD21 with the B cell antigen receptor lowers the antigen concentration threshold for eliciting protection from Fas apoptosis by 2-3 orders of magnitude. (PMID:14607925)
• 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)
• electrostatic calculations provide global and site-specific explanations of the physical causes that underlie the ionic strength dependence of C3d-CR2 association (PMID:15187133)
• The activation of MAPKs is independently mediated by CR2 and that anti-CR2 McAb, PD98059, and Wortmanin block the activation of MAPKs, respectively. (PMID:15603708)
• characterized the interaction between the first two short consensus repeats (SCR1-2) of complement receptor type 2 (CR2, CD21) and C3d (PMID:15713467)
• the open V-shaped structures formed by CR2 SCR 1-2, both when free and when bound to C3d, are optimal for the formation of a tight two-domain interaction with its ligand C3d (PMID:15713468)
• CD21 and CD23a are common targets for B lymphotropic gammaherpesviruses. (PMID:15795251)
• Unresponsiveness to T-dependent antigen (sheep red blood cells) displayed by transgenic CR2-positive B cells is linked to increase in the stimulus level required to propel the B cell into a fully activated state, a normal humoral immune response. (PMID:15905540)
• CD21 activation triggered Cbl tyrosine phosphorylation, which interacts with SH2 domains of p85 subunit, SH2 domains of Crk-L and with tyrosine phosphorylated Syk kinase. CD21 activation triggers dissociation of Cbl-Vav complex. (PMID:16289966)
• Results describe the domain structure of complement receptor 2 engineered with the Fc fragment of a mouse IgG1 in solution. (PMID:16375923)
• shedding of CD21 and CD62L is mediated via the P2X7R. (PMID:16740600)
• CR2 binds interferon-alpha in the same affinity range as the other three well-characterized ligands studied in parallel: CD23, C3d, and Epstein-Barr virus glycoprotein 350. (PMID:16785534)
• CD21 shedding is a redox-regulated process inducible by oxidation presumably through activation of a tyrosine kinase-mediated signal pathway involving protein kinase C (PKC). (PMID:16803874)
• factor I in concert with CR1 on E and factor H in serum due to their cofactor activity are likely to be important contributors (PMID:16920989)
• CD4, complement receptors, and CXCR4 chemokine receptors are required for complement mediated antibody dependent enhanced entry of HIV into MT2 cells. (PMID:16987062)
• Four novel partners that are involved in intracellular trafficking, sorting or cytoskeleton remodeling were identified and the hCD21 transmembrane and tail subdomains they interact with, were mapped. (PMID:17118449)
• Premature transgenic CR2 expression and the consequences thereof during B cell development intrinsically alters the way mature B cells develop and subsequently respond to antigen through the B cell receptor signaling complex. (PMID:17301948)
• CR2 participates in the pathogenesis of systemic lupus erythematosus (PMID:17360460)
• no strong association between variation in the CR2 receptor gene and risk in multiple sclerosis (PMID:17881405)
• The serum sCD21 levels during pregnancy are significantly lower as compared to that of the healthy controls;Restoration of sCD21 levels to normal values takes between 6 weeks and 1 year (PMID:18500464)
• REVIEW: comparison of CR2 protein structure, gene structure and function for mouse nad human (PMID:18713965)
• This is the first solution structural study of a large multidomain short complement regulator protein CR2 bound to its physiological ligand C3d. (PMID:18804116)
• members of the Staphylococcus aureus extracellular fibrinogen-binding protein family inhibit the interaction of C3d with complement receptor 2 (PMID:19017934)
• C3dp1 interacts at the same CR2 site as C3d (PMID:19164292)
• mice expressing hCR2 on their B cells during bone marrow development display a higher degree of apoptosis which may lead to a deletion of autoreactive B cells and be protective against the development of autoimmune disease. (PMID:19187965)
• CD21-dependent viral entry plays a crucial role in type 2 alveolar epithelial cells, indicative of an IL-4 response EBV infection in idiopathic pulmonary fibrosis. (PMID:19193442)
• Analysis of aged hCR2(high) mice (1 year plus) showed that both B cell numbers, B cell sub-population distribution including expansion of a newly described B regulatory cell subset, and immune responses were comparable with age-matched hCR2 negative mice. (PMID:19359041)
• CD21 is tightly related to LFA-1 expression in B-cell lymphoma (BCL) and the absence of CD21/LFA-1 expression is associated with pleural/peritoneal fluid involvement by BCL (PMID:19360456)
• Study confirms previous association of rs3813946, rs1048971, and rs17615 with systemic lupus erythematosus (SLE) susceptibility, and show association of 2 additional CR2 SNPs with SLE, identify a protective CR2 haplotype containing these SNPs. (PMID:19387458)
• Both CBF1 and C/EBP-beta bind the CR2 promoter in B cells raising the possibility that these factors facilitate or respond to alterations in chromatin structure to control the timing and/or level of CR2 transcription. (PMID:19487031)
• Data show that B cell activation led to increased CD21-CTF levels, suggesting a functional role for the CD21-CTFs in B cell activation and maintenance of B cell homeostasis. (PMID:19524299)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	csmd2	ENSDARG00000001559
mus_musculus	Cr2	ENSMUSG00000026616
rattus_norvegicus	Cr2	ENSRNOG00000034164

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), 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), CR1 (ENSG00000203710), CFB (ENSG00000243649), CFHR1 (ENSG00000244414)

Protein

Protein identifiers

Complement receptor type 2 — P20023 (reviewed: P20023)

Alternative names: Complement C3d receptor, Epstein-Barr virus receptor

All UniProt accessions (6): A0A1W2PPV2, A0A8V8TNI2, A0A8V8TPX6, A0A8V8TQA3, P20023, Q5SR47

UniProt curated annotations — full annotation on UniProt →

Function. Serves as a receptor for various ligands including complement component CD3d, HNRNPU OR IFNA1. When C3d is bound to antigens, attaches to C3d on B-cell surface and thereby facilitates the recognition and uptake of antigens by B-cells. This interaction enhances B-cell activation and subsequent immune responses. Forms a complex with several partners on the surface of B-cells including CD19, FCRL5 and CD81, to form the B-cell coreceptor complex that plays a crucial role in B-cell activation and signaling. Also induces specific intracellular signaling separately from the BCR and CD19 by activating the tyrosine kinase SRC, which then phosphorylates nucleolin/NCL and triggers AKT and GSK3 kinase activities in a SYK/CD19-independent manner. Acts as a ligand for CD23 (FcepsilonRII), a low-affinity receptor for IgE, which is expressed on B-cells and other immune cells, and thus participates in the regulation of IgE production. (Microbial infection) Acts as a receptor for Epstein-Barr virus.

Subunit / interactions. Interacts (via Sushi domain 1 and 2) with C3. Interacts with CD19. Part of a complex composed of CD19, CR2/CD21, CD81 and IFITM1/CD225 in the membrane of mature B-cells. Interacts (via Sushi domain 1 and 2) with FCER2 (via the C-terminus). Interacts with CD23. Interacts with FCRL5. Interacts with CR1. Interacts with INFNA1. (Microbial infection) Interacts with Epstein-Barr virus gp350 protein.

Subcellular location. Cell membrane.

Tissue specificity. Mature B-lymphocytes, T-lymphocytes, pharyngeal epithelial cells, astrocytes and follicular dendritic cells of the spleen.

Disease relevance. Systemic lupus erythematosus 9 (SLEB9) [MIM:610927] A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. Disease susceptibility is associated with variants affecting the gene represented in this entry. Immunodeficiency, common variable, 7 (CVID7) [MIM:614699] A primary immunodeficiency characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B-cells is usually in the normal range, but can be low. The disease is caused by variants affecting the gene represented in this entry.

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

Isoforms (4)

UniProt ID	Names	Canonical?
P20023-1	A	yes
P20023-2	B
P20023-3	C
P20023-4	D

RefSeq proteins (2): NP_001006659, NP_001868 (=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 (97 total): disulfide bond 30, domain 15, strand 15, glycosylation site 11, sequence conflict 11, splice variant 4, sequence variant 3, mutagenesis site 3, topological domain 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
8SM0	X-RAY DIFFRACTION	1.68
1LY2	X-RAY DIFFRACTION	1.8
1GHQ	X-RAY DIFFRACTION	2.04
3OED	X-RAY DIFFRACTION	3.16
8ZNI	ELECTRON MICROSCOPY	3.29
1W2R	SOLUTION SCATTERING
1W2S	SOLUTION SCATTERING
2ATY	SOLUTION SCATTERING
2GSX	SOLUTION SCATTERING

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P20023-F1	75.18	0.02

Functional residue map

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

Disulfide bonds (30): 23–65, 51–82, 91–132, 118–146, 154–197, 183–210, 215–256, 242–271, 276–325, 305–342, 351–393, 379–406, 410–453, 439–466, 471–509, 495–522, 527–576, 556–593, 602–644, 630–657 …

Glycosylation sites (11): 121, 127, 294, 372, 492, 623, 682, 800, 823, 861, 911

Mutagenesis-validated functional residues (3):

Position	Phenotype
103	no effect on affinity for c3.
112	reduced affinity for c3.
128	strongly reduced affinity for c3.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-977606	Regulation of Complement cascade

MSigDB gene sets: 403 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, BENPORATH_ES_WITH_H3K27ME3, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, MODULE_169, GOBP_RESPONSE_TO_PEPTIDE, GOBP_B_CELL_ACTIVATION, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, CHIARETTI_T_ALL_REFRACTORY_TO_THERAPY, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_MEDIATED_IMMUNITY, MODULE_64, GOBP_RESPONSE_TO_TYPE_I_INTERFERON, GOBP_B_CELL_PROLIFERATION, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_B_CELL_MEDIATED_IMMUNITY, WANG_ESOPHAGUS_CANCER_VS_NORMAL_DN

GO Biological Process (14): T cell mediated immunity (GO:0002456), immune response (GO:0006955), complement activation, alternative pathway (GO:0006957), complement activation, classical pathway (GO:0006958), B cell differentiation (GO:0030183), B cell proliferation (GO:0042100), B cell activation (GO:0042113), negative regulation of complement activation, classical pathway (GO:0045959), symbiont entry into host cell (GO:0046718), type I interferon-mediated signaling pathway (GO:0060337), immune system process (GO:0002376), complement receptor mediated signaling pathway (GO:0002430), innate immune response (GO:0045087), antiviral innate immune response (GO:0140374)

GO Molecular Function (8): virus receptor activity (GO:0001618), complement binding (GO:0001848), DNA binding (GO:0003677), complement receptor activity (GO:0004875), transmembrane signaling receptor activity (GO:0004888), immunoglobulin receptor binding (GO:0034987), protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (5): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), membrane (GO:0016020), signaling receptor complex (GO:0043235), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Complement cascade	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
complement activation	2
innate immune response	2
B cell activation	2
lymphocyte mediated immunity	1
adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
immune system process	1
response to stimulus	1
humoral immune response mediated by circulating immunoglobulin	1
lymphocyte differentiation	1
lymphocyte proliferation	1
lymphocyte activation	1
negative regulation of humoral immune response mediated by circulating immunoglobulin	1
complement activation, classical pathway	1
regulation of complement activation, classical pathway	1
negative regulation of complement activation	1
viral life cycle	1
symbiont entry into host	1
cellular response to type I interferon	1
interferon-mediated signaling pathway	1
biological_process	1
immune response-activating cell surface receptor signaling pathway	1
immune response	1
defense response to symbiont	1
defense response to virus	1
symbiont entry into host cell	1
exogenous protein binding	1
protein binding	1
nucleic acid binding	1
complement binding	1
complement receptor mediated signaling pathway	1
transmembrane signaling receptor activity	1
immune receptor activity	1
signaling receptor activity	1
signaling receptor binding	1
identical protein binding	1
protein dimerization activity	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1458 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CR2	CD19	P15391	999
CR2	CD81	P18582	997
CR2	IFITM1	P13164	994
CR2	C3	P01024	983
CR2	IFNA13	P01562	941
CR2	FCER2	P06734	936
CR2	CD5	P06127	909
CR2	CD27	P26842	891
CR2	CD79A	P11912	829
CR2	CD22	P20273	822
CR2	ITIH4	Q14624	822
CR2	PTPRC	P08575	806
CR2	SPN	P16150	804
CR2	MME	P08473	791
CR2	CD4	P01730	787

IntAct

10 interactions, top by confidence:

A	B	Type	Score
C3	CR2	psi-mi:“MI:0407”(direct interaction)	0.720
LGALS1	LAMA5	psi-mi:“MI:0914”(association)	0.530
C3	C3	psi-mi:“MI:0407”(direct interaction)	0.440
CR2	FCER2	psi-mi:“MI:0407”(direct interaction)	0.440
MFSD2B	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
SLC44A1	UPK3BL1	psi-mi:“MI:0914”(association)	0.350
CR2		psi-mi:“MI:0915”(physical association)	0.000

BioGRID (16): CR2 (Affinity Capture-Western), CD81 (Affinity Capture-Western), IFITM1 (Affinity Capture-Western), FCER2 (Reconstituted Complex), CR2 (Affinity Capture-RNA), CR2 (Affinity Capture-Western), ANXA6 (Reconstituted Complex), CR2 (Affinity Capture-Western), CR2 (Reconstituted Complex), CR2 (Affinity Capture-MS), NCOA1 (Reconstituted Complex), CR2 (Proximity Label-MS), CR2 (Proximity Label-MS), CR2 (Affinity Capture-MS), CR2 (Affinity Capture-MS)

ESM2 similar proteins: O02839, O08569, O19124, O62685, O62837, O88174, P02749, P04003, P05160, P08607, P14151, P15529, P16109, P17690, P19070, P20023, P26644, P27113, P30836, P42201, P49457, P70105, P79138, P98107, P98109, P98131, Q01102, Q03472, Q07968, Q28065, Q28768, Q2VPA4, Q5R4D0, Q60401, Q60736, Q61475, Q61476, Q63135, Q63514, Q64735

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

3 interactions.

A	Effect	B	Mechanism
TCF3	“down-regulates quantity by repression”	CR2	“transcriptional regulation”
BLLF1	“up-regulates activity”	CR2	binding
CR2	“up-regulates activity”	CD19	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	41
Likely pathogenic	15
Uncertain significance	410
Likely benign	305
Benign	40

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1017238	NM_001006658.3(CR2):c.592_595del (p.Ser199fs)	Pathogenic
1018003	NM_001006658.3(CR2):c.1191del (p.Thr398fs)	Pathogenic
1047654	NM_001006658.3(CR2):c.2176_2177dup (p.Gln726fs)	Pathogenic
1061097	NM_001006658.3(CR2):c.2204C>G (p.Ser735Ter)	Pathogenic
1469632	NM_001006658.3(CR2):c.2864_2865del (p.His955fs)	Pathogenic
1903089	NM_001006658.3(CR2):c.2244C>A (p.Tyr748Ter)	Pathogenic
2041808	NM_001006658.3(CR2):c.1231C>T (p.Gln411Ter)	Pathogenic
2086090	NM_001006658.3(CR2):c.412del (p.Trp138fs)	Pathogenic
2128585	NM_001006658.3(CR2):c.1877_1878del (p.Val626fs)	Pathogenic
2169328	NM_001006658.3(CR2):c.2423del (p.Asp808fs)	Pathogenic
2756144	NM_001006658.3(CR2):c.1458del (p.Phe486fs)	Pathogenic
2781409	NM_001006658.3(CR2):c.40dup (p.Val14fs)	Pathogenic
2880311	NM_001006658.3(CR2):c.3230T>G (p.Leu1077Ter)	Pathogenic
2954886	NM_001006658.3(CR2):c.1518T>A (p.Tyr506Ter)	Pathogenic
2987740	NM_001006658.3(CR2):c.3070_3088del (p.Leu1024fs)	Pathogenic
3022333	NM_001006658.3(CR2):c.2275C>T (p.Gln759Ter)	Pathogenic
35453	NM_001006658.3(CR2):c.2297G>A (p.Trp766Ter)	Pathogenic
35454	NM_001006658.3(CR2):c.1225+1G>C	Pathogenic
3616630	NM_001006658.3(CR2):c.909C>G (p.Tyr303Ter)	Pathogenic
3622853	NM_001006658.3(CR2):c.739C>T (p.Arg247Ter)	Pathogenic
3629192	NM_001006658.3(CR2):c.2479G>T (p.Gly827Ter)	Pathogenic
3643091	NM_001006658.3(CR2):c.630T>A (p.Cys210Ter)	Pathogenic
3653659	NM_001006658.3(CR2):c.909C>A (p.Tyr303Ter)	Pathogenic
3663085	NM_001006658.3(CR2):c.52del (p.Val18fs)	Pathogenic
3664550	NM_001006658.3(CR2):c.2608dup (p.Ile870fs)	Pathogenic
3696802	NM_001006658.3(CR2):c.2454dup (p.Leu819fs)	Pathogenic
4725530	NM_001006658.3(CR2):c.3111T>A (p.Cys1037Ter)	Pathogenic
4775945	NM_001006658.3(CR2):c.1741C>T (p.Gln581Ter)	Pathogenic
540314	NM_001006658.3(CR2):c.424C>T (p.Arg142Ter)	Pathogenic
573311	NM_001006658.3(CR2):c.3238C>T (p.Arg1080Ter)	Pathogenic

SpliceAI

3358 predictions. Top by Δscore:

Variant	Effect	Δscore
1:207468798:A:AG	acceptor_gain	1.0000
1:207468799:G:GG	acceptor_gain	1.0000
1:207468898:GG:G	donor_gain	1.0000
1:207468899:GG:G	donor_gain	1.0000
1:207474238:TA:T	acceptor_loss	1.0000
1:207474239:AGGT:A	acceptor_loss	1.0000
1:207474324:G:GA	donor_loss	1.0000
1:207474325:T:A	donor_loss	1.0000
1:207477883:A:AG	acceptor_gain	1.0000
1:207477884:G:GG	acceptor_gain	1.0000
1:207478066:ATCCC:A	donor_gain	1.0000
1:207478067:TCCC:T	donor_gain	1.0000
1:207478071:G:GG	donor_gain	1.0000
1:207485462:A:AG	acceptor_gain	1.0000
1:207485463:G:GG	acceptor_gain	1.0000
1:207485463:GC:G	acceptor_gain	1.0000
1:207485463:GCA:G	acceptor_gain	1.0000
1:207485463:GCAA:G	acceptor_gain	1.0000
1:207485463:GCAAT:G	acceptor_gain	1.0000
1:207485570:GTG:G	donor_gain	1.0000
1:207485574:TAT:T	donor_loss	1.0000
1:207468794:TTTTA:T	acceptor_loss	0.9900
1:207468795:TTTA:T	acceptor_loss	0.9900
1:207468798:A:AT	acceptor_loss	0.9900
1:207468799:G:T	acceptor_loss	0.9900
1:207468799:GA:G	acceptor_gain	0.9900
1:207468895:GAAGG:G	donor_gain	0.9900
1:207469684:A:AG	acceptor_gain	0.9900
1:207470016:T:G	acceptor_gain	0.9900
1:207470101:GG:G	donor_gain	0.9900

AlphaMissense

7141 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:207466692:G:C	W75C	0.999
1:207466692:G:T	W75C	0.999
1:207466881:G:C	W138C	0.999
1:207466881:G:T	W138C	0.999
1:207466861:T:A	C132S	0.998
1:207466862:G:C	C132S	0.998
1:207468690:G:C	W203C	0.998
1:207468690:G:T	W203C	0.998
1:207478042:G:C	W961C	0.998
1:207478042:G:T	W961C	0.998
1:207466660:T:A	C65S	0.997
1:207466661:G:C	C65S	0.997
1:207475185:G:C	W836C	0.997
1:207475185:G:T	W836C	0.997
1:207466711:T:A	C82S	0.996
1:207466712:G:C	C82S	0.996
1:207466879:T:A	W138R	0.996
1:207466879:T:C	W138R	0.996
1:207466819:T:A	C118S	0.995
1:207466820:G:C	C118S	0.995
1:207466903:T:A	C146S	0.995
1:207466904:G:C	C146S	0.995
1:207469210:G:C	W265C	0.995
1:207469210:G:T	W265C	0.995
1:207473151:G:C	W650C	0.995
1:207473151:G:T	W650C	0.995
1:207476394:G:C	W900C	0.995
1:207476394:G:T	W900C	0.995
1:207466690:T:A	W75R	0.994
1:207466690:T:C	W75R	0.994

dbSNP variants (sampled 300 via entrez): RS1000037978 (1:207467191 A>G), RS1000326173 (1:207453925 G>A), RS1000422777 (1:207461714 T>G), RS1000521922 (1:207454036 T>A,C), RS1000598361 (1:207455099 A>G), RS1000697680 (1:207459913 C>A,G), RS1001011663 (1:207465114 G>T), RS1001063925 (1:207465411 A>G), RS1001074159 (1:207479682 C>A,T), RS1001372917 (1:207486700 A>G), RS1001577471 (1:207458601 A>G), RS1001608601 (1:207479810 C>A), RS1001709271 (1:207483056 G>A,T), RS1002036592 (1:207454355 C>A,G,T), RS1002067872 (1:207463836 A>G)

Disease associations

OMIM: gene MIM:120650 | disease phenotypes: MIM:614699, MIM:240500, MIM:610927, MIM:614615

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency, common variable, 7	Definitive	Autosomal recessive
common variable immunodeficiency	Supportive	Autosomal dominant
systemic lupus erythematosus	Supportive	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
immunodeficiency, common variable, 7	Definitive	AR

Mondo (6): immunodeficiency, common variable, 7 (MONDO:0013862), immunodeficiency, common variable, 2 (MONDO:0009413), systemic lupus erythematosus, susceptibility to, 9 (MONDO:0012584), Joubert syndrome 17 (MONDO:0013824), common variable immunodeficiency (MONDO:0015517), systemic lupus erythematosus (MONDO:0007915)

Orphanet (3): OBSOLETE: Common variable immunodeficiency (Orphanet:1572), Common variable immunodeficiency phenotype due to CD21 deficiency (Orphanet:696894), Isolated Joubert syndrome (Orphanet:475)

HPO phenotypes

79 total (30 of 79 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000093	Proteinuria
HP:0000155	Oral ulcer
HP:0000403	Recurrent otitis media
HP:0000488	Retinopathy
HP:0000509	Conjunctivitis
HP:0000716	Depression
HP:0000790	Hematuria
HP:0000822	Hypertension
HP:0000992	Cutaneous photosensitivity
HP:0001250	Seizure
HP:0001287	Meningitis
HP:0001369	Arthritis
HP:0001596	Alopecia
HP:0001744	Splenomegaly
HP:0001824	Weight loss
HP:0001873	Thrombocytopenia
HP:0001878	Hemolytic anemia
HP:0001882	Decreased total leukocyte count
HP:0001945	Fever
HP:0002014	Diarrhea
HP:0002028	Chronic diarrhea
HP:0002039	Anorexia
HP:0002072	Chorea
HP:0002110	Bronchiectasis
HP:0002205	Recurrent respiratory infections
HP:0002240	Hepatomegaly
HP:0002664	Neoplasm

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001033_10	Type 2 diabetes	7.000000e-06
GCST005554_3	Systemic sclerosis	2.000000e-06
GCST007826_1	Alzheimer’s disease or fasting insulin levels (pleiotropy)	4.000000e-15
GCST010002_375	Refractive error	2.000000e-54

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D017074	Common Variable Immunodeficiency	C20.673.330
D008180	Lupus Erythematosus, Systemic	C17.300.480; C20.111.590

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
entinostat	increases expression, affects cotreatment	2
Panobinostat	increases expression, affects cotreatment	2
Valproic Acid	increases expression	2
triphenyl phosphate	affects expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
gardiquimod	increases expression, decreases reaction	1
theaflavin-3,3’-digallate	affects expression	1
Resveratrol	affects cotreatment, decreases expression	1
Ascorbic Acid	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation	1
Copper	affects cotreatment, decreases expression	1
Pesticides	decreases methylation	1
Tretinoin	decreases expression, affects cotreatment	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	decreases expression	1
Copper Sulfate	affects expression	1
Protein Kinase Inhibitors	decreases reaction, increases expression	1

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8DZ	Abcam HCT 116 CR2 KO	Cancer cell line	Male
CVCL_B9G7	Abcam A-549 CR2 KO	Cancer cell line	Male
CVCL_D2EJ	Abcam MCF-7 CR2 KO	Cancer cell line	Female
CVCL_E2W8	SCC12F-CR2	Cancer cell line	Male
CVCL_YD67	SVK-CR2	Transformed cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00520494	PHASE4	COMPLETED	Efficacy and Safety of Vivaglobin® in Previously Untreated Patients With Primary Immunodeficiency
NCT01289847	PHASE4	COMPLETED	A Study to Find Out How Safe and Effective Gammaplex® is in Young People With Primary Immunodeficiency
NCT01946906	PHASE4	COMPLETED	The Rifaximin Study in CVID
NCT05193552	PHASE4	RECRUITING	Usage of Spirometry in Managing IgG Therapy in CVID With Airway Disease
NCT00120887	PHASE4	COMPLETED	Lupus Atherosclerosis Prevention Study
NCT00125307	PHASE4	COMPLETED	Tacrolimus for the Treatment of Systemic Lupus Erythematosus With Membranous Nephritis
NCT00188188	PHASE4	UNKNOWN	Study of Endothelial Dysfunction in Systemic Lupus and Its Role in Heart Disease
NCT00371501	PHASE4	COMPLETED	Aspirin and Statins for Prevention of Atherosclerosis and Arterial Thromboembolism in Systemic Lupus Erythematosus
NCT00392093	PHASE4	COMPLETED	Effect of Hormone Replacement Therapy on Lupus Activity
NCT00413361	PHASE4	COMPLETED	The Reduction of Systemic Lupus Erythematosus Flares :Study PLUS
NCT00508898	PHASE4	WITHDRAWN	The Efficacy and Safety of Calcitriol for the Treatment of Lupus Nephritis and Persistent Proteinuria
NCT00668330	PHASE4	COMPLETED	Steroid Induced Osteoporosis in Patients With Systemic Lupus Erythematosus
NCT00739050	PHASE4	TERMINATED	Effect of Simvastatin on Endothelial Function in Premenopausal Women With Systemic Lupus Erythematosus (0733-271)(TERMINATED)
NCT00815282	PHASE4	COMPLETED	Immune Response After Human Papillomavirus Vaccination in Patients With Autoimmune Disease
NCT00828178	PHASE4	COMPLETED	Efficacy of Fish Oil in Lupus Patients
NCT00866229	PHASE4	UNKNOWN	Efficacy and Adverse Effect of Simvastatin Compare to Rosuvastatin in Systemic Lupus Erythematosus (SLE) Patients With Corticosteroid Therapy and High Low-Density Lipoprotein (LDL) Cholesterol Level
NCT00911521	PHASE4	COMPLETED	Immunogenicity and Safety of a Quadrivalent Human Papillomavirus (HPV) Vaccine in Patients With SLE: a Controlled Study
NCT01101802	PHASE4	COMPLETED	Mycophenolate Mofetil in Systemic Lupus Erythematosus (MISSILE)
NCT01112215	PHASE4	COMPLETED	Enteric-coated Mycophenolate Sodium Versus Azathioprine for the Extra-renal Lupus Manifestations
NCT01151644	PHASE4	UNKNOWN	Safety and Efficacy of Anti-Pandemic H1N1 Vaccination in Rheumatic Diseases
NCT01276782	PHASE4	WITHDRAWN	Levothyroxine in Pregnant SLE Patients
NCT01322308	PHASE4	COMPLETED	Effect of Pioglitazone on Endothelial Function in Premenopausal Women With Uncomplicated Systemic Lupus Erythematosus
NCT01359826	PHASE4	WITHDRAWN	The Effect of Milnacipran on Fatigue and Quality of Life in Lupus Patients
NCT01597492	PHASE4	COMPLETED	A Study to Evaluate the Effect of Belimumab on Vaccine Responses in Subjects With Systemic Lupus Erythematosus (SLE)
NCT01632241	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in Black Race Patients With Systemic Lupus Erythematosus (SLE)
NCT01705977	PHASE4	COMPLETED	Belimumab Assessment of Safety in SLE
NCT01753401	PHASE4	COMPLETED	Acthar for the Treatment of Systemic Lupus Erythematosus (SLE) in Patients With a History of Persistently Active Disease
NCT02270970	PHASE4	UNKNOWN	Evaluation of Belimumab Impact on a BLyS Activity Signature Test in the Absence of Confounding Polypharmacy
NCT02477150	PHASE4	COMPLETED	Safety and Immunogenicity of a Zoster Vaccine in SLE
NCT02741960	PHASE4	COMPLETED	The Effect of Metformin on Reducing Lupus Flares
NCT02779153	PHASE4	WITHDRAWN	Acthar SLE (Systemic Lupus Erythematosus)
NCT02953821	PHASE4	COMPLETED	Acthar Gel for Active Systemic Lupus Erythematosus (SLE)
NCT03042260	PHASE4	UNKNOWN	Prophylactic Trimethoprim/Sulfamethoxazole to Prevent Severe Infections in Patients With Lupus Erythematous
NCT03098823	PHASE4	COMPLETED	A Crossover Study to Compare RAYOS to IR Prednisone to Improve Fatigue and Morning Symptoms for SLE
NCT03122431	PHASE4	COMPLETED	Relevance of Monitoring Blood and Salivar Levels of Drugs Used in Rheumatic Autoimmune Diseases
NCT03543839	PHASE4	RECRUITING	Trial of Belimumab in Early Lupus
NCT04447053	PHASE4	UNKNOWN	Sequential Belimumab and T-cell Based Therapy in SLE
NCT04515719	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in SLE Patients
NCT04893161	PHASE4	UNKNOWN	A Model About the Response of Belimumab in SLE
NCT04908865	PHASE4	COMPLETED	Open-label Study of Belimumab Plus Standard Therapy in Chinese Pediatric Participants With Active Systemic Lupus Erythematosus (SLE)