C4B

Summary

C4B (complement C4B (Chido/Rodgers blood group), HGNC:1324) is a protein-coding gene on chromosome 6p21.33, encoding Complement C4-B (P0C0L5). Precursor of non-enzymatic components of the classical, lectin and GZMK complement pathways, which consist in a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system.

This gene encodes the basic form of complement factor 4, and together with the C4A gene, is part of the classical activation pathway. The protein is expressed as a single chain precursor which is proteolytically cleaved into a trimer of alpha, beta, and gamma chains prior to secretion. The trimer provides a surface for interaction between the antigen-antibody complex and other complement components. The alpha chain may be cleaved to release C4 anaphylatoxin, a mediator of local inflammation. Deficiency of this protein is associated with systemic lupus erythematosus. This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. Varying haplotypes of this gene cluster exist, such that individuals may have 1, 2, or 3 copies of this gene. In addition, this gene exists as a long form and a short form due to the presence or absence of a 6.4 kb endogenous HERV-K retrovirus in intron 9.

Source: NCBI Gene 721 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complement component 4b deficiency (Strong, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 91 total — 1 pathogenic, 2 likely-pathogenic
• MANE Select transcript: NM_001002029

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1324
Approved symbol	C4B
Name	complement C4B (Chido/Rodgers blood group)
Location	6p21.33
Locus type	gene with protein product
Status	Approved
Aliases	CPAMD3, C4F, CO4, C4B1, C4B3, CH
Ensembl gene	ENSG00000224389
Ensembl biotype	protein_coding
OMIM	120820
Entrez	721

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 19 protein_coding, 14 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000425700, ENST00000435363, ENST00000461632, ENST00000463249, ENST00000468237, ENST00000468936, ENST00000473957, ENST00000474912, ENST00000478388, ENST00000478438, ENST00000485263, ENST00000485543, ENST00000486992, ENST00000490071, ENST00000496065, ENST00000496560, ENST00000647698, ENST00000648821, ENST00000649658, ENST00000904229, ENST00000904230, ENST00000904231, ENST00000904232, ENST00000904233, ENST00000951109, ENST00000951110, ENST00000951111, ENST00000951112, ENST00000951113, ENST00000951114, ENST00000951115, ENST00000951116, ENST00000951117, ENST00000951118, ENST00000951119

RefSeq mRNA: 1 — MANE Select: NM_001002029 NM_001002029

CCDS: CCDS47405

Canonical transcript exons

ENST00000375177 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.85.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.85	gold quality
right adrenal gland cortex	UBERON:0035827	99.77	gold quality
liver	UBERON:0002107	99.76	gold quality
left adrenal gland cortex	UBERON:0035825	99.72	gold quality
right adrenal gland	UBERON:0001233	99.69	gold quality
left adrenal gland	UBERON:0001234	99.68	gold quality
adrenal gland	UBERON:0002369	99.48	gold quality
right lobe of thyroid gland	UBERON:0001119	99.39	gold quality
left lobe of thyroid gland	UBERON:0001120	98.98	gold quality
adrenal tissue	UBERON:0018303	98.96	gold quality
right ovary	UBERON:0002118	98.91	gold quality
thyroid gland	UBERON:0002046	98.71	gold quality
tibial nerve	UBERON:0001323	98.44	gold quality
left ovary	UBERON:0002119	98.32	gold quality
adenohypophysis	UBERON:0002196	98.25	gold quality
ovary	UBERON:0000992	97.84	gold quality
spleen	UBERON:0002106	97.80	gold quality
pituitary gland	UBERON:0000007	97.52	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.37	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.26	gold quality
lower esophagus	UBERON:0013473	97.22	gold quality
left uterine tube	UBERON:0001303	97.21	gold quality
adult mammalian kidney	UBERON:0000082	97.09	gold quality
omental fat pad	UBERON:0010414	96.51	gold quality
substantia nigra	UBERON:0002038	96.46	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.45	gold quality
right atrium auricular region	UBERON:0006631	96.31	gold quality
right coronary artery	UBERON:0001625	96.18	gold quality
hypothalamus	UBERON:0001898	96.11	gold quality
mucosa of stomach	UBERON:0001199	96.09	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-8530	yes	606.90
E-HCAD-9	yes	333.60
E-GEOD-135922	yes	61.99
E-MTAB-5061	yes	19.34
E-GEOD-130148	yes	11.17
E-ANND-3	yes	8.01
E-HCAD-25	yes	7.25

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTCF, IRF1, NFATC3, NFKBIA, REL, SP1, STAT5A, TBP

miRNA regulators (miRDB)

8 targeting C4B, 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-6764-5P	99.75	67.89	2304
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-1206	99.30	69.32	1016
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-124-5P	98.11	67.65	1095

Literature-anchored findings (GeneRIF, showing 40)

• Allelic distribution of complement components BF, C4A, C4B, and C3 in Psoriasis vulgaris. (PMID:11803045)
• C4A and C4B gene-dosage variations play in infectious and autoimmune diseases. (PMID:12224044)
• Genetic sophistication of human complement components C4A and C4B and RP-C4-CYP21-TNX (RCCX) modules in the major histocompatibility complex. (PMID:12226794)
• C4b and C3b do not undergo the same conformational changes upon binding to the C4BP mutants as during the interaction with the wild type C4BP, which then results in an observed loss of the cofactor activity (PMID:12893820)
• complex of C4b and protein S could act as a bridge between coagulation and inflammation due to the involvement of C4BP in regulating complement activation. (PMID:12907438)
• negative effect of C4B(*)Q0 on health or survival (PMID:15033778)
• C4b-binding protein-protein S complex inhibits the phagocytosis of apoptotic cells (PMID:15096498)
• Plasma-derived PROS-C4BP complex has direct anticoagulant activity; enhanced direct activity of PROS-Heerlen-C4BP may compensate for low free protein S levels and low cofactor activity in individuals with protein S-Heerlen. (PMID:15456488)
• Acute rejection of kidney transpl with C4d expression was diffuse and showed a higher proportionate elevation of serum creatinine at biopsy and 4 weeks after diagnosis. (PMID:15665772)
• C4 null alleles were significantly more common in Henoch-Schonlein purpura patients than in controls (PMID:15787745)
• multicenter analysis of C4d staining in protocol biopsies from renal allografts (PMID:15816885)
• The tertiary structures of C4A and C4B were compared using near and far-UV circular dichroism, ANS fluorescence, site-specific monoclonal antibodies and isoelectric focusing. (PMID:16098595)
• C4d is a possibe marker for the identification of humoral rejection in any clinical setting after kidney transplantation. (PMID:16386506)
• C4d peritubular capillary expression did not differentiate patients after kidney transplantation immunosuppression , but it predisposes to progression of chronic morphological findings during 1-year observation. (PMID:16504674)
• C3d was somewhat more predictive of margination than C4d in ABO-incompatible renal allografts (PMID:16889542)
• Results describe three distinct profiles of serum complement C4 proteins in pediatric systemic lupus erythematosus (SLE) patients, and show tight associations of complement C4 and C3 protein levels in SLE but not in healthy subjects. (PMID:16893076)
• 47% of the C4 genes adjacent to the RP2 gene were the short gene and 53% were the long gene (PMID:16908004)
• C4d could be used as a marker for rejection following hepatic transplantation. (PMID:16980082)
• Both galactose-specific and mannose-specific mannose-binding lectins isolated from common carp were found to associate with a serine protease that cleaves native human C4 into C4b but not C4i (PMID:17015733)
• suggest a direct role of lgtC expression in the inhibition of C4b deposition and consequent serum resistance of R2866 (PMID:17202363)
• C4 gene deficiencies are associated with predisposition to chronic periodontitis. (PMID:17257223)
• demonstrated a significant association between diffuse C4d staining, production of donor-specific antibodies, and graft failure (PMID:17318071)
• findings indicate that the C4B*Q0 genotype can be considered as a major covariate of smoking in precipitating the risk for acute myocardial infarction and associated deaths (PMID:17425651)
• Gene dosage variation and associated polymorphisms of C4B in systemic lupus erythematosus were studied. (PMID:17503323)
• C4B*Q0 was present in two out of the 130 SLE patients; overall, our results do not demonstrate a significant association to these known C4 mutations in the Malaysian scenario (PMID:17728371)
• the binding of Factor H and C4bp to Aspergillus spp. appears to be even stronger than to Candida spp. and different, albeit possibly nearby, binding moieties mediate this surface attachment. (PMID:17915330)
• partial or complete C4b deficiencies were found in oligoarthritis and polyarthritis patients (PMID:17921792)
• electron dense C4d (complement 4d) deposition in peritubular capillaries was observed in most Lupus Nephritis patients (PMID:17971360)
• The binding of complement components C4b and C3b to the proteins of Neisseria gonorrhoeae and Neisseria meningitidis is reported. (PMID:17984207)
• This observation indicates that low C4B copy number is a strong risk factor for short-term mortality after acute myocardial infarction (AMI) in smoking Icelandic patients. (PMID:18032375)
• C4d immunostaining for the diagnosis of acute antibody-mediated rejection in renal transplant recipients (PMID:18065805)
• Establish reproducible procedure for C4d detection with a polyclonal antibody. (PMID:18085389)
• C4d positive chronic rejection is very common, associated with proteinuria, and has a poor outcome. (PMID:18091514)
• In 2,250 genetic typings of autistic subjects, only one individual carried a chromosome containing both C4B null allele and CYP21A2 mutations. (PMID:18179706)
• Confirmed the independent prognostic value of peritubular capillary C4d staining on renal allograft survival in Chinese. (PMID:18315707)
• omplement C4d region staining in peritubular capillaries in kidney allograft biopsies is a hallmark of antibody-mediated rejection. (PMID:18347532)
• The finding of diffuse C4d on follow-up biopsy is significantly associated with kidney graft loss at 1 year, regardless of index biopsy C4d results. [C4d, complement 4d] (PMID:18360261)
• Complement 4d in renal transplant biopsy is indicative of chronic graft rejection. (PMID:18365397)
• HLA-specific antibodies are associated with vascular C4d deposition and soluble C4d in broncho-alveolar lavage of lung allografts (PMID:18645500)
• C4BP binds to jeopardized cardiomyocytes early after acute myocardial infarct and co-localizes to other well known markers such as complemenb 3b. (PMID:18682851)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	c4	ENSDARG00000015065
mus_musculus	C4a	ENSMUSG00000015451
mus_musculus	C4b	ENSMUSG00000073418
rattus_norvegicus		ENSRNOG00000072842
rattus_norvegicus	C4b	ENSRNOG00000080491
drosophila_melanogaster	Tep4	FBGN0041180
drosophila_melanogaster	Tep3	FBGN0041181
drosophila_melanogaster	Tep2	FBGN0041182
drosophila_melanogaster	Tep1	FBGN0041183
caenorhabditis_elegans	tep-1	WBGENE00013969

Paralogs (8): C5 (ENSG00000106804), C3 (ENSG00000125730), PZP (ENSG00000126838), CD109 (ENSG00000156535), CPAMD8 (ENSG00000160111), A2ML1 (ENSG00000166535), A2M (ENSG00000175899), C4A (ENSG00000244731)

Protein

Protein identifiers

Complement C4-B — P0C0L5 (reviewed: P0C0L5)

Alternative names: Basic complement C4, C3 and PZP-like alpha-2-macroglobulin domain-containing protein 3

All UniProt accessions (4): P0C0L5, A0A3B3ISA6, A0A3B3ISD7, F5GXS0

UniProt curated annotations — full annotation on UniProt →

Function. Precursor of non-enzymatic components of the classical, lectin and GZMK complement pathways, which consist in a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system. Non-enzymatic component of C3 and C5 convertases. Generated following cleavage by complement proteases (C1S, MASP2 or GZMK, depending on the complement pathway), it covalently attaches to the surface of pathogens, where it acts as an opsonin that marks the surface of antigens for removal. It then recruits the serine protease complement C2b to form the C3 and C5 convertases, which cleave and activate C3 and C5, respectively, the next components of the complement pathways. Complement C4b-B isotype catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens, while C4b-A isotype is responsible for effective binding to form amide bonds with immune aggregates or protein antigens. Putative humoral mediator released following cleavage by complement proteases (C1S, MASP2 or GZMK, depending on the complement pathway). While it is strongly similar to anaphylatoxins, its role is unclear. Was reported to act as a mediator of local inflammatory process; however these effects were probably due to contamination with C3a and/C5a anaphylatoxins in biological assays.

Subunit / interactions. In absence of complement activation, circulates in blood as a disulfide-linked trimer of an alpha, beta and gamma chain. Complement C4b is composed of complement C4b-A, complement C4 beta and complement C4 gamma chains that are associated via disulfide bonds. Non-enzymatic component of the C3 convertase, also named C4bC2b, composed of the serine protease complement C2b (C2), as well as complement C4b. Non-enzymatic component of the C5 convertase, also named C4bC2bC3b, composed of the serine protease complement C2b (C2), complement C3b, as well as complement C4b. Interacts with CR1 (via Sushi 1 and Sushi 2 domains). (Microbial infection) Binds B.burgdorferi OspC, the interaction is inhibited by complement factor C2. This binding may inhibit the complement cascade and allow the bacteria to survive in the host bloodstream.

Subcellular location. Secreted. Synapse. Cell projection. Axon. Dendrite Secreted Secreted. Cell surface.

Tissue specificity. Complement component C4 is expressed at highest levels in the liver, at moderate levels in the adrenal cortex, adrenal medulla, thyroid gland, and the kidney, and at lowest levels in the heart, ovary, small intestine, thymus, pancreas and spleen. The extra-hepatic sites of expression may be important for the local protection and inflammatory response.

Post-translational modifications. Prior to secretion, the single-chain precursor is enzymatically cleaved by plasminogen (PLG) to yield non-identical chains alpha, beta and gamma. During activation of the complement systems, the alpha chain is cleaved into C4a and C4b by different proteases depending on the complement pathway: C4b stays linked to the beta and gamma chains, while C4a is released in the plasma. The alpha chain is cleaved by C1S to generate C4a and C4b following activation by the classical complement system. The alpha chain is cleaved to generate C4a and C4b by MASP2 following activation by the lectin complement system. The alpha chain is cleaved by GZMK to generate C4a and C4b following activation by the GZMK complement system. Further degradation of C4b by C1 into the inactive fragments C4c and C4d blocks the generation of C3 convertase. The proteolytic cleavages often are incomplete so that many structural forms can be found in plasma. Upon activation, the internal thioester bond reacts with carbohydrate antigens on the target surface to form amide or ester bonds, leading to covalent association with the surface of pathogens. Complement C4b interacts with complement C3b via a thioester linkage. N- and O-glycosylated. O-glycosylated with a core 1 or possibly core 8 glycan.

Disease relevance. Systemic lupus erythematosus (SLE) [MIM:152700] 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. Interindividual copy-number variation (CNV) of complement component C4 and associated polymorphisms result in different susceptibilities to SLE. The risk of SLE susceptibility has been shown to be significantly increased among subjects with only two copies of total C4. A high copy number is a protective factor against SLE. Complement component 4B deficiency (C4BD) [MIM:614379] A rare defect of the complement classical pathway associated with the development of autoimmune disorders, mainly systemic lupus with or without associated glomerulonephritis. The disease is caused by variants affecting the gene represented in this entry.

Polymorphism. The complement component C4 is the most polymorphic protein of the complement system. It is the product of 2 closely linked and highly homologous genes, C4A and C4B. Once polymorphic variation is discounted, the 2 isotypes differ by only 4 amino acids at positions 1120-1125: PCPVLD for C4A and LSPVIH for C4B. The 2 isotypes bear several antigenic determinants defining Chido/Rodgers blood group system [MIM:614374]. Rodgers determinants are generally associated with C4A allotypes, and Chido with C4B. Variations at these loci involve not only nucleotide polymorphisms, but also gene number and gene size. The second copy of C4B gene present in some individuals has been called C4B_2 by the HUGO Gene Nomenclature Committee (HGNC). Some individuals may lack either C4A, or C4B gene. Partial deficiency of C4A or C4B is the most commonly inherited immune deficiency known in humans with a combined frequency over 31% in the normal Caucasian population. Common copy-number variants of C4A and C4B affecting expression of complement component C4 in the brain have been associated with schizophrenia risk.

RefSeq proteins (1): NP_001002029* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000020	Anaphylatoxin/fibulin	Domain
IPR001134	Netrin_domain	Domain
IPR001599	Macroglobln_a2	Domain
IPR001840	Anaphylatoxn_comp_syst_dom	Domain
IPR002890	MG2	Domain
IPR008930	Terpenoid_cyclase/PrenylTrfase	Homologous_superfamily
IPR008993	TIMP-like_OB-fold	Homologous_superfamily
IPR009048	A-macroglobulin_rcpt-bd	Domain
IPR011625	A2M_N_BRD	Domain
IPR011626	Alpha-macroglobulin_TED	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR018081	Anaphylatoxin_comp_syst	Homologous_superfamily
IPR018933	Netrin_module_non-TIMP	Domain
IPR019742	MacrogloblnA2_CS	Conserved_site
IPR036595	A-macroglobulin_rcpt-bd_sf	Homologous_superfamily
IPR040839	MG4	Domain
IPR041555	MG3	Domain
IPR047565	Alpha-macroglob_thiol-ester_cl	Conserved_site
IPR048847	C4_MG1	Domain
IPR050473	A2M/Complement_sys	Family
IPR054587	CO4A-B_CUB_C	Domain

Pfam: PF00207, PF01759, PF01821, PF01835, PF07677, PF07678, PF07703, PF17789, PF17791, PF21145, PF22661

UniProt features (143 total): strand 68, disulfide bond 16, helix 13, sequence conflict 9, sequence variant 8, chain 6, mutagenesis site 5, modified residue 4, glycosylation site 4, domain 2, site 2, propeptide 2, turn 2, signal peptide 1, cross-link 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
9U60	ELECTRON MICROSCOPY	2.9
9U5Z	ELECTRON MICROSCOPY	3.1
9U61	ELECTRON MICROSCOPY	3.1
6YSQ	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0C0L5-F1	83.50	0.44

Antibody-complex structures (SAbDab): 1 — 6YSQ

Functional residue map

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

Catalytic / active sites (2): 756–757 (cleavage; by c1s, masp2 and gzmk); 1125 (responsible for effective binding to form amide bonds with immune aggregates or protein antigens)

Post-translational modifications (5): 918, 1417, 1420, 1422, 1010–1013

Disulfide bonds (16): 68–97, 567, 635–669, 702–728, 703–735, 716–736, 820, 876, 1394, 1471–1535, 1566, 1583–1588, 1590, 1595–1673, 1618–1742, 1718–1727

Glycosylation sites (4): 226, 862, 1328, 1391

Mutagenesis-validated functional residues (5):

Position	Phenotype
1120	no effect on hemolytic activity, nor on c1-dependent binding to igg.
1121	30-40% decrease in hemolytic activity and c1-dependent binding to igg.
1124	50-60% decrease in hemolytic activity and c1-dependent binding to igg.
1125	20% decrease in hemolytic activity, 2-fold increase in c1-dependent binding to igg.
1125	2.5-3 fold-decrease in hemolytic activity, 3-fold increase in c1-dependent binding to igg.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-166663	Initial triggering of complement
R-HSA-174577	Activation of C3 and C5
R-HSA-977606	Regulation of Complement cascade
R-HSA-9920588	Dengue virus activates/modulates innate and adaptive immune responses

MSigDB gene sets: 253 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_INFLAMMATORY_RESPONSE, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOCC_CELL_SURFACE, GOBP_APOPTOTIC_CELL_CLEARANCE, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, HUMMERICH_SKIN_CANCER_PROGRESSION_DN, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, COUP_01, GOBP_B_CELL_MEDIATED_IMMUNITY, GOBP_REGULATION_OF_IMMUNE_RESPONSE, MODULE_75

GO Biological Process (11): inflammatory response (GO:0006954), complement activation (GO:0006956), complement activation, classical pathway (GO:0006958), opsonization (GO:0008228), detection of molecule of bacterial origin (GO:0032490), complement activation, GZMK pathway (GO:0160257), positive regulation of apoptotic cell clearance (GO:2000427), activation of immune response (GO:0002253), immune system process (GO:0002376), immune response (GO:0006955), innate immune response (GO:0045087)

GO Molecular Function (4): complement binding (GO:0001848), endopeptidase inhibitor activity (GO:0004866), carbohydrate binding (GO:0030246), protein binding (GO:0005515)

GO Cellular Component (11): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), cell surface (GO:0009986), axon (GO:0030424), dendrite (GO:0030425), synapse (GO:0045202), extracellular exosome (GO:0070062), blood microparticle (GO:0072562), symbiont cell surface (GO:0106139), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Complement cascade	3
Dengue Virus-Host Interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
immune effector process	2
complement activation	2
immune system process	2
binding	2
neuron projection	2
defense response	1
activation of immune response	1
humoral immune response	1
protein activation cascade	1
humoral immune response mediated by circulating immunoglobulin	1
phagocytosis, recognition	1
response to molecule of bacterial origin	1
detection of chemical stimulus	1
detection of external biotic stimulus	1
innate immune response	1
apoptotic cell clearance	1
positive regulation of phagocytosis	1
regulation of apoptotic cell clearance	1
positive regulation of immune response	1
biological_process	1
response to stimulus	1
immune response	1
defense response to symbiont	1
protein binding	1
endopeptidase activity	1
peptidase inhibitor activity	1
endopeptidase regulator activity	1
membrane	1
cell periphery	1
dendritic tree	1
cell junction	1
extracellular vesicle	1
extracellular region	1
other organism part	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

36 interactions, top by confidence:

A	B	Type	Score
CFHR4	CRP	psi-mi:“MI:0915”(physical association)	0.800
KIF22	KPNA4	psi-mi:“MI:0914”(association)	0.730
C4B	C4A	psi-mi:“MI:0915”(physical association)	0.720
MASP2	C4A	psi-mi:“MI:0407”(direct interaction)	0.680
C4A	MASP2	psi-mi:“MI:0570”(protein cleavage)	0.680
CFHR1	CRP	psi-mi:“MI:0915”(physical association)	0.540
MASP1	C4A	psi-mi:“MI:0915”(physical association)	0.400
	C4A	psi-mi:“MI:0915”(physical association)	0.400
MASP2	C4A	psi-mi:“MI:0915”(physical association)	0.400
	CD5L	psi-mi:“MI:0915”(physical association)	0.400
	LECT2	psi-mi:“MI:0915”(physical association)	0.400
C4B	BNLF2	psi-mi:“MI:0915”(physical association)	0.370
Tor1aip1	PEX10	psi-mi:“MI:0914”(association)	0.350
Naa10	MYO9A	psi-mi:“MI:0914”(association)	0.350
Zbtb7a	C4B	psi-mi:“MI:0914”(association)	0.350
Uso1	GOLGA2	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
GNG8	POTEF	psi-mi:“MI:0914”(association)	0.350
PPP2R2B	A2ML1	psi-mi:“MI:0914”(association)	0.350
CCR1	UBA6	psi-mi:“MI:0914”(association)	0.350
C18orf21	A2ML1	psi-mi:“MI:0914”(association)	0.350
AGPAT1	A2ML1	psi-mi:“MI:0914”(association)	0.350
PHF11	A2ML1	psi-mi:“MI:0914”(association)	0.350

BioGRID (19): C4B (Affinity Capture-MS), C4B (Affinity Capture-MS), C4B (Affinity Capture-MS), C4B (Affinity Capture-MS), C2 (Reconstituted Complex), C2 (Reconstituted Complex), C4B (Affinity Capture-MS), C4B (Affinity Capture-MS), C4B (Affinity Capture-MS), C4B (Affinity Capture-MS), C4B (Proximity Label-MS), C4B (Affinity Capture-MS), C4B_2 (Affinity Capture-MS), C3 (Cross-Linking-MS (XL-MS)), C4B (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0AAQ4VMX2, A0M8R7, A1X150, I2C090, O02668, P01029, P01030, P01031, P06238, P06684, P08581, P08649, P08650, P0C0L4, P0C0L5, P14046, P16056, P19069, P19823, P28665, P28666, P79263, P97523, P98093, P98094, Q00685, Q03626, Q07DY1, Q07DZ1, Q07E48, Q09YN5, Q108U6, Q14624, Q2IBA6, Q2IBC0, Q2IBD8, Q2IBF2, Q2IBG7, Q2QL89, Q2QLA9

Diamond homologs: A0AAQ4VMX2, P01029, P01030, P08649, P0C0L4, P0C0L5, P19069, P23667, Q2UVX4, Q6IE37, A0RZC6, I2C090, J3S836, P01024, P01025, P01026, P01027, P12247, P12387, P98093, P98094, Q00685, Q01833, Q0ZZJ6, Q6ZMU1, Q91132, P12082, P01032, P01023, P06238, P14046, P20740, P20742, P28666, Q03626, Q3UU35, Q5R4N8, Q61838, Q63041, Q6GQT1

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
CSMD1	“down-regulates quantity”	C4B	binding
C4B	“form complex”	“C3 convertase complex”	binding
MASP2	“up-regulates activity”	C4B	cleavage
MASP1	“up-regulates activity”	C4B	cleavage
“Complement C1 complex”	“up-regulates activity”	C4B	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	72
Likely benign	3
Benign	4

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
987922	NM_001002029.3:c.(?3231)(3387_?)del	Pathogenic
1299253	NM_001002029.4(C4B):c.3676+1G>A	Likely pathogenic
4539488	NM_001002029.4(C4B):c.3893dup (p.Phe1299fs)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1001158549 (6:31980963 G>A), RS1003761200 (6:32027148 T>A), RS1006636511 (6:31980195 A>C), RS1009388336 (6:31980931 T>A), RS1009407914 (6:31980525 G>C,T), RS1012400686 (6:32027039 C>G,T), RS1016876596 (6:32030374 T>C), RS1017526214 (6:31981026 C>A,T), RS1020820448 (6:31980952 T>C), RS1020851383 (6:31980551 A>G), RS1022362121 (6:32027490 T>G), RS1023015049 (6:31980238 G>A,C), RS1023879145 (6:32013343 C>G,T), RS1025931829 (6:32030131 A>C,G), RS1027152766 (6:32013179 G>A,T)

Disease associations

OMIM: gene MIM:120820 | disease phenotypes: MIM:614379

GenCC curated gene-disease

Disease	Classification	Inheritance
complement component 4b deficiency	Strong	Autosomal recessive
systemic lupus erythematosus	Supportive	Unknown

Mondo (2): complement component 4b deficiency (MONDO:0013720), systemic lupus erythematosus (MONDO:0007915)

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
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

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	decreases expression	3
Benzo(a)pyrene	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
Asian ginseng	affects cotreatment, decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
2-aminothiophenol	affects binding, decreases reaction	1
bisphenol A	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
Olanzapine	affects phosphorylation	1
Arsenic Trioxide	decreases expression	1
Acrolein	increases abundance, affects cotreatment, increases oxidation	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Allergens	affects cotreatment, increases expression	1
Vehicle Emissions	affects cotreatment, increases expression	1
Cadmium	affects binding	1
Copper	affects binding	1
Diethylhexyl Phthalate	affects cotreatment, decreases expression	1
Estradiol	decreases expression, affects cotreatment	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Nickel	affects binding	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Penicillamine	affects binding, decreases reaction	1
Zinc	affects binding	1
Cadmium Chloride	increases expression	1
Okadaic Acid	decreases expression	1
Nanotubes, Carbon	decreases expression	1
Volatile Organic Compounds	affects cotreatment, increases oxidation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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)
NCT04956484	PHASE4	COMPLETED	Belimumab In Early Systemic Lupus Erythematosus
NCT05559671	PHASE4	RECRUITING	Safety of the Herpes Zoster Subunit Vaccine in Lupus
NCT05666336	PHASE4	UNKNOWN	Multi-omics Studies on the Efficacy of Telitacicept in Chinese SLE Patients
NCT05748925	PHASE4	COMPLETED	Cardio Renal Effects of SGLT2 Inhibitors Among Lupus Nephritis Patients