C4A

Summary

C4A (complement C4A (Chido/Rodgers blood group), HGNC:1323) is a protein-coding gene on chromosome 6p21.33, encoding Complement C4-A (P0C0L4). 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 acidic form of complement factor 4, 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 is cleaved to release C4 anaphylatoxin, an antimicrobial peptide and a mediator of local inflammation. Deficiency of this protein is associated with systemic lupus erythematosus and type I diabetes mellitus. 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. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 720 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complement component 4a deficiency (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 40
• Clinical variants (ClinVar): 177 total — 1 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 124
• MANE Select transcript: NM_007293

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1323
Approved symbol	C4A
Name	complement C4A (Chido/Rodgers blood group)
Location	6p21.33
Locus type	gene with protein product
Status	Approved
Aliases	CPAMD2, C4S, CO4, C4, C4A3, C4A2, C4A4, C4A6, C4B, RG
Ensembl gene	ENSG00000244731
Ensembl biotype	protein_coding
OMIM	120810
Entrez	720

Gene structure

Transcript identifiers

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

ENST00000428956, ENST00000460060, ENST00000460841, ENST00000463034, ENST00000465724, ENST00000467749, ENST00000467948, ENST00000469975, ENST00000470365, ENST00000471624, ENST00000477424, ENST00000480795, ENST00000483974, ENST00000490663, ENST00000491876, ENST00000496659, ENST00000498271, ENST00000698442, ENST00000883667, ENST00000883668, ENST00000883669, ENST00000883670, ENST00000883671, ENST00000883672, ENST00000883673, ENST00000883674, ENST00000883675, ENST00000883676, ENST00000967848, ENST00000967849, ENST00000967850, ENST00000967851, ENST00000967852, ENST00000967853, ENST00000967854

RefSeq mRNA: 2 — MANE Select: NM_007293 NM_001252204, NM_007293

CCDS: CCDS47404, CCDS59005

Canonical transcript exons

ENST00000375295 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.82.

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	99.82	gold quality
liver	UBERON:0002107	99.73	gold quality
right adrenal gland cortex	UBERON:0035827	99.66	gold quality
left adrenal gland cortex	UBERON:0035825	99.60	gold quality
left adrenal gland	UBERON:0001234	99.56	gold quality
right adrenal gland	UBERON:0001233	99.55	gold quality
adrenal gland	UBERON:0002369	99.33	gold quality
right lobe of thyroid gland	UBERON:0001119	99.28	gold quality
left lobe of thyroid gland	UBERON:0001120	98.69	gold quality
adrenal tissue	UBERON:0018303	98.67	gold quality
right ovary	UBERON:0002118	98.62	gold quality
thyroid gland	UBERON:0002046	98.44	gold quality
tibial nerve	UBERON:0001323	98.07	gold quality
left ovary	UBERON:0002119	97.93	gold quality
adenohypophysis	UBERON:0002196	97.87	gold quality
ovary	UBERON:0000992	97.63	gold quality
spleen	UBERON:0002106	97.05	gold quality
pituitary gland	UBERON:0000007	96.97	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.86	gold quality
adult mammalian kidney	UBERON:0000082	96.79	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.66	gold quality
lower esophagus	UBERON:0013473	96.61	gold quality
left uterine tube	UBERON:0001303	96.35	gold quality
gall bladder	UBERON:0002110	95.95	gold quality
omental fat pad	UBERON:0010414	95.89	gold quality
substantia nigra	UBERON:0002038	95.85	gold quality
right atrium auricular region	UBERON:0006631	95.74	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.62	gold quality
hypothalamus	UBERON:0001898	95.43	gold quality
descending thoracic aorta	UBERON:0002345	95.19	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-8530	yes	602.88
E-HCAD-9	yes	66.25
E-GEOD-135922	yes	61.88
E-MTAB-6678	yes	27.25
E-MTAB-5061	yes	19.14
E-GEOD-130148	yes	11.30
E-HCAD-25	yes	7.27
E-ANND-3	yes	3.78
E-GEOD-75688	no	840.54

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, KLF3, NCOA3, PAX3, SP1, STAT5A

miRNA regulators (miRDB)

8 targeting C4A, 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)
• Data describe the 2.3A resolution structure of C4Ad, the C4d fragment derived from the human complement component C4A isotype. (PMID:12367531)
• determination of whether the levels of complement factors C3a, C4a, and C5a are elevated at the site of inflammation in chronic obstructive pulmonary disease and in asthma (PMID:15039137)
• In this study, capillary leak syndrome induced by cardiopulmonary bypass occurs only in patients with the homozygous C4A null phenotype. (PMID:15166556)
• C4A gene deletion is an independent susceptibility factor in patients with lupus erythematosus. (PMID:15794202)
• 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)
• 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)
• all of the C4 genes adjacent to the RP1 gene presented the long gene (PMID:16908004)
• Complement components C3a and C4a, but not C5a, display antimicrobial activity against P. aeruginosa, E. coli, B. subtilis, and C. albicans. (PMID:17132627)
• C4 gene deficiencies are associated with predisposition to chronic periodontitis. (PMID:17257223)
• Gene dosage variation and associated polymorphisms of C4A in systemic lupus erythematosus were studied. (PMID:17503323)
• C4A*Q0 was found in two out of the 130 control samples; overall, our results do not demonstrate a significant association to these known C4 mutations in the Malaysian SLE patients (PMID:17728371)
• partial or complete C4a deficiencies were found in juvenile idiopathic arthritis with histories of severe disease or infections (PMID:17921792)
• electron dense C4d (complement 4d) deposition in peritubular capillaries was observed in most Lupus Nephritis patients (PMID:17971360)
• The dominant types of C1q complexes that circulate in vivo are C1q-C3d and C1q-C4d complexes. (PMID:18054386)
• C4d positive chronic rejection is very common, associated with proteinuria, and has a poor outcome. (PMID:18091514)
• 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)
• hypercomplementemia in anti-AQP4 antibody-positive patients may reflect a systemic inflammatory reaction at relapse in multiple sclerosis (PMID:19028829)
• high frequency of autoimmune diseases and autoantibodies in systemic lupus erythematosus multicase families; PD-1.3A and C4AQ0 are part of a predisposing genetic background (PMID:19035512)
• demonstration of diversity associated with gene copy-number variation of complement C4, CYP21 & tenascin; also offers an explanation for low prevalence of systemic lupus erythematosus but high incidence of congenital adrenal hyperplasia in Asian-Indians (PMID:19135723)
• improved survival is seen in patients with C4A or C4B deficiency and renal cell carcinoma treated with cytokine therapy with or without surgery (PMID:19150565)
• produced by trophoblast cells, may be regulated by IFNgamma (PMID:19665237)
• Serum level of a fragment of complement C4 was increased at the time of clinical relapse in patients with relapsing-remitting multiple sclerosis (PMID:19923011)
• Data show that C1q, C4, C3, and C9 bind to thrombin receptor-activating peptide-activated platelets in lepirudin-anticoagulated platelet-rich plasma (PRP) and whole blood. (PMID:20139276)
• Intrathecal and systemic activation of complement, reflected in changes in cerebral spinal fluid and plasma C4a, suggest its role in the pathogenesis of multiple sclerosis and a systemic component to the disease. (PMID:20409594)
• Secretome analysis and protease inhibitor studies identified the secreted alkaline protease Alp1 as the central molecule responsible for the cleavage of human complement proteins C3, C4, and C5. (PMID:20498262)
• The reduction in olfactory function in these hereditary angioedema cases seems to correlate with complement C4 and CH50 levels. (PMID:20649895)
• The physiology and molecular basis of the Rodgers blood-group system is discussed. Review. (PMID:20795316)
• Data indicate that the deposition of both C4 and C3 showed a significant positive correlation with the serum concentration of Ficolin-3. (PMID:21085669)
• not demonstrate that C4 gene copy number associates with transplant outcome (PMID:21164027)
• C4 mRNA levels of the two isoforms (C4A and C4B) were significantly reduced in hepatocytes transfected with RNA from HCV genotype 1a or 2a. (PMID:21345967)
• The study shows the complement component C4A in the plasmas of sePE women is lower than the severe, late-onset PE women, and the Apolipoprotein A-I level is higher in sePE women than slPE women. (PMID:21677994)
• We showed no evidence for a role of hs-CRP, C3 and C4 in the association between BMI and asthma symptoms in overweight children. (PMID:21801245)
• Data show that in the UK cohort, total C4 GCN ranged from 2 to 6, with copy numbers from 0 to 4 observed for both C4A and C4B, while in the Spanish cohort, C4A GCN from 0 to 6 and C4B GCN from 0 to 5. (PMID:21857912)
• study concludes that the association of C4 gene copy with systemic lupus erythematosus(SLE)was replicated in Chinese Han population, which highlighted the importance of C4 in SLE pathogenesis of diverse populations (PMID:21904924)
• Individuals with 4, 2, and 2 copies of C4, C4A and C4B genes, especially those with A2B2 polymorphism may associate with the development of Graves’ disease (PMID:21943165)
• Complement 4a plasma protein was identified as increased in Alzheimer’s disease (PMID:22052466)
• C4A appears to associate with the protection of residual beta-cell function in new-onset type 1 diabetes. (PMID:22151770)

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), C4B (ENSG00000224389)

Protein

Protein identifiers

Complement C4-A — P0C0L4 (reviewed: P0C0L4)

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

All UniProt accessions (2): A0A8V8TLP6, P0C0L4

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-A isotype is responsible for effective binding to form amide bonds with immune aggregates or protein antigens, while complement C4b-B isotype catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate 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. Complement 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.

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. Ser-1236 of 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. Complement component 4A deficiency (C4AD) [MIM:614380] 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. 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.

Activity regulation. Specifically inhibited by nanobody hC4Nb8, inhibiting the classical complement pathway. Specifically inhibited by NbB5, NbE11 and NbH9 nanobodies, and to a lesser extent by NbH11 and NbE3 nanobodies.

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. 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. C4A6 allotype is deficient in hemolytic activity. Allotype C4A13 is infrequent. Common copy-number variants of C4A and C4B affecting expression of complement component C4 in the brain have been associated with schizophrenia risk.

Isoforms (2)

UniProt ID	Names	Canonical?
P0C0L4-1	1	yes
P0C0L4-2	2

RefSeq proteins (2): NP_001239133, NP_009224* (*=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 (216 total): strand 111, helix 31, disulfide bond 16, sequence variant 14, sequence conflict 14, turn 7, chain 6, glycosylation site 5, modified residue 4, domain 2, propeptide 2, signal peptide 1, site 1, cross-link 1, splice variant 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
1HZF	X-RAY DIFFRACTION	2.3
6YSQ	X-RAY DIFFRACTION	3.3
7B2M	ELECTRON MICROSCOPY	3.39
7B2P	ELECTRON MICROSCOPY	3.43
5JTW	X-RAY DIFFRACTION	3.5
9QJ5	ELECTRON MICROSCOPY	3.5
9QK2	ELECTRON MICROSCOPY	3.5
5JPN	X-RAY DIFFRACTION	3.6
5JPM	X-RAY DIFFRACTION	3.75
7B2Q	ELECTRON MICROSCOPY	3.76
9QJ4	ELECTRON MICROSCOPY	3.9
9QPY	ELECTRON MICROSCOPY	4.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0C0L4-F1	83.56	0.45

Antibody-complex structures (SAbDab): 4 — 6YSQ, 7B2M, 7B2P, 7B2Q

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 (1): 756–757 (cleavage; by c1s, masp2 and gzmk)

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 (5): 226, 862, 1244, 1328, 1391

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-166663	Initial triggering of complement
R-HSA-174577	Activation of C3 and C5
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-8957275	Post-translational protein phosphorylation
R-HSA-977606	Regulation of Complement cascade
R-HSA-9920588	Dengue virus activates/modulates innate and adaptive immune responses

MSigDB gene sets: 435 (showing top): SHEPARD_BMYB_MORPHOLINO_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, MCLACHLAN_DENTAL_CARIES_UP, GOBP_INFLAMMATORY_RESPONSE, GOZGIT_ESR1_TARGETS_DN, 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

GO Biological Process (7): inflammatory response (GO:0006954), complement activation (GO:0006956), complement activation, classical pathway (GO:0006958), complement activation, GZMK pathway (GO:0160257), positive regulation of apoptotic cell clearance (GO:2000427), immune system process (GO:0002376), innate immune response (GO:0045087)

GO Molecular Function (4): complement component C1q complex binding (GO:0001849), endopeptidase inhibitor activity (GO:0004866), complement binding (GO:0001848), protein binding (GO:0005515)

GO Cellular Component (12): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), plasma membrane (GO:0005886), cell surface (GO:0009986), axon (GO:0030424), dendrite (GO:0030425), neuronal cell body (GO:0043025), synapse (GO:0045202), extracellular exosome (GO:0070062), blood microparticle (GO:0072562), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Complement cascade	3
Metabolism of proteins	1
Post-translational protein modification	1
Dengue Virus-Host Interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
complement activation	2
neuron projection	2
defense response	1
immune effector process	1
activation of immune response	1
humoral immune response	1
protein activation cascade	1
humoral immune response mediated by circulating immunoglobulin	1
innate immune response	1
apoptotic cell clearance	1
positive regulation of phagocytosis	1
regulation of apoptotic cell clearance	1
biological_process	1
immune response	1
defense response to symbiont	1
opsonin binding	1
complement binding	1
protein-containing complex binding	1
endopeptidase activity	1
peptidase inhibitor activity	1
endopeptidase regulator activity	1
protein binding	1
binding	1
endoplasmic reticulum	1
intracellular organelle lumen	1
membrane	1
cell periphery	1
dendritic tree	1
somatodendritic compartment	1
cell body	1
cell junction	1
extracellular vesicle	1
extracellular region	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

107 interactions, top by confidence:

A	B	Type	Score
CFHR4	CRP	psi-mi:“MI:0915”(physical association)	0.800
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
SCN2B	EXOC5	psi-mi:“MI:0914”(association)	0.640
VSIG1	TTI1	psi-mi:“MI:0914”(association)	0.640
TMEM89	C4A	psi-mi:“MI:0915”(physical association)	0.590
CFHR1	CRP	psi-mi:“MI:0915”(physical association)	0.540
SLC15A1	METTL15	psi-mi:“MI:0914”(association)	0.530
FAM171B	FAM171A2	psi-mi:“MI:0914”(association)	0.530
OCLN	DNAJC13	psi-mi:“MI:0914”(association)	0.530
CCL5	C4A	psi-mi:“MI:0914”(association)	0.530
CD226	MEN1	psi-mi:“MI:0914”(association)	0.530
VSIG1	TNPO2	psi-mi:“MI:0914”(association)	0.530
LAMP1	FZD7	psi-mi:“MI:0914”(association)	0.530
CRP	QSOX1	psi-mi:“MI:0914”(association)	0.530
DNAJC3	DEDD	psi-mi:“MI:0914”(association)	0.530
C4A	ESR1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (115): C4A (Affinity Capture-MS), C4A (Affinity Capture-MS), C4A (Affinity Capture-MS), C4A (Affinity Capture-MS), C4A (Affinity Capture-MS), C4A (Affinity Capture-MS), C4A (Affinity Capture-MS), C4A (Affinity Capture-MS), C4A (Affinity Capture-MS), C4A (Affinity Capture-MS), C4B (Affinity Capture-MS), C4A (Affinity Capture-MS), C4A (Affinity Capture-MS), C4A (Affinity Capture-MS), C4A (Affinity Capture-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

10 interactions.

A	Effect	B	Mechanism
C4A	“form complex”	“C3 convertase complex”	binding
MASP2	“up-regulates activity”	C4A	cleavage
MASP1	“up-regulates activity”	C4A	cleavage
“Complement C1 complex”	“up-regulates activity”	C4A	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 118 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Post-translational protein phosphorylation	7	9.9×	3e-03
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	7	8.5×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	126
Likely benign	13
Benign	17

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

12445 predictions. Top by Δscore:

Variant	Effect	Δscore
6:31982915:GCGGG:G	donor_gain	1.0000
6:31982916:CGGGG:C	donor_loss	1.0000
6:31982917:GGG:G	donor_gain	1.0000
6:31982918:GG:G	donor_gain	1.0000
6:31982918:GGG:G	donor_gain	1.0000
6:31982918:GGGTG:G	donor_loss	1.0000
6:31982919:GG:G	donor_gain	1.0000
6:31982919:GGT:G	donor_loss	1.0000
6:31982920:G:GG	donor_gain	1.0000
6:31982921:TGAG:T	donor_loss	1.0000
6:31983121:A:AG	acceptor_gain	1.0000
6:31983122:C:G	acceptor_gain	1.0000
6:31983125:CCA:C	acceptor_loss	1.0000
6:31983126:CAGTT:C	acceptor_loss	1.0000
6:31983127:A:AG	acceptor_gain	1.0000
6:31983127:A:T	acceptor_loss	1.0000
6:31983127:AGTTC:A	acceptor_gain	1.0000
6:31983128:G:GG	acceptor_gain	1.0000
6:31983128:GT:G	acceptor_gain	1.0000
6:31983128:GTTC:G	acceptor_gain	1.0000
6:31983128:GTTCG:G	acceptor_gain	1.0000
6:31983200:G:GA	donor_loss	1.0000
6:31983201:T:G	donor_loss	1.0000
6:31983365:GA:G	donor_gain	1.0000
6:31983367:G:GG	donor_gain	1.0000
6:31983826:A:AG	acceptor_gain	1.0000
6:31983830:T:A	acceptor_gain	1.0000
6:31983831:G:A	acceptor_gain	1.0000
6:31983834:TCA:T	acceptor_loss	1.0000
6:31983836:A:AG	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000726010 (6:31995990 C>T), RS1001158549 (6:31980963 G>A), RS1001324282 (6:31998009 C>A,T), RS1002089632 (6:31996854 T>C), RS1004522192 (6:31996675 A>C,G), RS1006636511 (6:31980195 A>C), RS1009388336 (6:31980931 T>A), RS1009407914 (6:31980525 G>C,T), RS1016397819 (6:31996738 C>T), RS1017526214 (6:31981026 C>A,T), RS1020568425 (6:31997356 G>A), RS1020820448 (6:31980952 T>C), RS1020851383 (6:31980551 A>G), RS1023015049 (6:31980238 G>A,C), RS1030024956 (6:31994183 G>A)

Disease associations

OMIM: gene MIM:120810 | disease phenotypes: MIM:614380, MIM:614379

GenCC curated gene-disease

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

Mondo (3): complement component 4a deficiency (MONDO:0013721), complement component 4b deficiency (MONDO:0013720), systemic lupus erythematosus (MONDO:0007915)

Orphanet (0):

HPO phenotypes

124 total (30 of 124 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000031	Epididymitis
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000099	Glomerulonephritis
HP:0000155	Oral ulcer
HP:0000488	Retinopathy
HP:0000518	Cataract
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000737	Irritability
HP:0000790	Hematuria
HP:0000822	Hypertension
HP:0000979	Purpura
HP:0000992	Cutaneous photosensitivity
HP:0001061	Acne
HP:0001097	Keratoconjunctivitis sicca
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001269	Hemiparesis
HP:0001287	Meningitis
HP:0001288	Gait disturbance
HP:0001289	Confusion
HP:0001347	Hyperreflexia
HP:0001369	Arthritis
HP:0001482	Subcutaneous nodule
HP:0001596	Alopecia
HP:0001637	Abnormal myocardium morphology

GWAS associations

40 associations (top):

Study	Trait	p-value
GCST001679_7	Complement C3 and C4 levels	6.000000e-97
GCST001679_8	Complement C3 and C4 levels	1.000000e-22
GCST001942_21	Prostate cancer	5.000000e-09
GCST004131_25	Inflammatory bowel disease	2.000000e-31
GCST004133_79	Ulcerative colitis	5.000000e-65
GCST004521_114	Autism spectrum disorder or schizophrenia	3.000000e-17
GCST004521_117	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_118	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_126	Autism spectrum disorder or schizophrenia	2.000000e-10
GCST004521_154	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST004521_17	Autism spectrum disorder or schizophrenia	2.000000e-12
GCST004521_170	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_173	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_209	Autism spectrum disorder or schizophrenia	5.000000e-16
GCST004521_211	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_213	Autism spectrum disorder or schizophrenia	5.000000e-13
GCST004521_227	Autism spectrum disorder or schizophrenia	4.000000e-12
GCST004521_296	Autism spectrum disorder or schizophrenia	6.000000e-18
GCST004521_45	Autism spectrum disorder or schizophrenia	2.000000e-16
GCST004521_81	Autism spectrum disorder or schizophrenia	1.000000e-14
GCST005964_2	Neuromyelitis optica	7.000000e-12
GCST006937_2	Neuromyelitis optica (AQP4-IgG-positive)	3.000000e-16
GCST006940_137	Neurociticism	4.000000e-08
GCST006950_15	Feeling worry	3.000000e-08
GCST006950_67	Feeling worry	2.000000e-10
GCST008916_30	Asthma	1.000000e-09
GCST011833_1	Complement C4 levels	2.000000e-33
GCST011833_10	Complement C4 levels	2.000000e-10
GCST011833_11	Complement C4 levels	1.000000e-14
GCST011833_12	Complement C4 levels	7.000000e-11

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004984	complement C4 measurement
EFO:0009584	AQP4-IgG-positive neuromyelitis optica
EFO:0007660	neuroticism measurement
EFO:0009589	worry measurement
EFO:0007986	reticulocyte count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008180	Lupus Erythematosus, Systemic	C17.300.480; C20.111.590
C565167	Complement Component 4a Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases reaction, increases abundance	2
Doxorubicin	decreases expression	2
Ozone	affects cotreatment, increases oxidation, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
ginger extract	decreases expression, decreases reaction, increases abundance	1
tremortin	increases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
2-aminothiophenol	affects binding, decreases reaction	1
deoxynivalenol	decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
nivalenol	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
corosolic acid	increases expression	1
3’,4’-dimethoxy-alpha-naphthoflavone	decreases reaction, increases expression	1
Olanzapine	decreases phosphorylation	1
Acetaminophen	decreases expression	1
Acrolein	increases oxidation, increases abundance, affects cotreatment	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Arsenic	increases expression	1
Benzo(a)pyrene	decreases expression	1
Diethylhexyl Phthalate	affects cotreatment, affects expression, decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Colforsin	affects cotreatment, affects expression	1
Hydralazine	affects cotreatment, increases expression	1
Lead	affects expression	1
Oils, Volatile	decreases expression, decreases reaction, increases abundance	1
Penicillamine	affects binding, decreases reaction	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	affects expression	1
Valproic Acid	increases expression, affects cotreatment	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