C4B
protein-codingcomplement C4B (Chido blood group), the group of C3 and PZP like, alpha-2-macroglobulin domain containing|Complement system activation components|Blood group antigens
Gene summary
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. [provided by RefSeq, May 2020]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~20.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0007915
Submitter: ClinGen
*C4B* was first reported in relation to autosomal recessive systemic lupus erythematous (SLE) in 1984 (Voigtländer et al., PMID: 6084933). Early proband reports used allotyping (a protein-based assay) to report *C4B* copy number and can therefore not be used as evidence (PMIDs: 6084933, 3265961, 7814456). The relationship between *C4B* copy number variation and SLE has been assessed in a number of case-control studies with various cohort sizes and ancestries. The genotyping techniques used in these case-control studies generally did not support the detection and evaluation of precise deletion/duplication boundaries. Overall, 14 case-control studies found no statistically significant difference in *C4B* copy number between cases and controls (PMIDs: 12480675, 17503323, 19287147, 21904924, 23335107, 26814708, 27274095, 29050534, 29080553, 34580371, 35315244, 38594415, 39800843, 40617727). Five case-control studies found a significantly lower (PMIDs: 9777334, 22387014, 26800705, 31387635, 32499649), while one cohort/study found a significantly higher *C4B* copy number in cases compared to controls (PMIDs: 22387014). Two meta-analyses found no effect of *C4B* copy number on SLE risk (PMIDs: 28205620, 32691186). In summary, there is **limited** evidence supporting the relationship between *C4B* and autosomal recessive systemic lupus erythematosus. This classification was approved by the ClinGen Monogenic Systemic and Incomplete Lupus Erythematosus GCEP on the meeting date March 11, 2026 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0013720
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: Unknown
Disease ID:MONDO:0007915
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013720
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to C4B variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001002029.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 1 | ||||
| missense | 72 | 7 | 79 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 1 | 2 | 3 | |||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 3 | 74 | 8 | 0 | 85 |
Highest pathogenic variant AF is 0.000013011159
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001002029.3 | 41 | MANE Select | |
| Ensembl | ENSP00000415941.2 | 41 | MANE Select | |
| Ensembl | ENSP00000391933.2 | 40 | Standard | |
| Ensembl | ENSP00000497270.1 | 31 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Complement and coagulation cascades - Homo sapiens (human)
- Pertussis - Homo sapiens (human)
- Systemic lupus erythematosus - Homo sapiens (human)
- Staphylococcus aureus infection - Homo sapiens (human)
- Allograft Rejection
Biological Process
- proteolysis
- inflammatory response
- complement activation
- complement activation, classical pathway
- opsonization
Molecular Function
- complement binding
- serine-type endopeptidase activity
- endopeptidase inhibitor activity
- carbohydrate binding
Cellular Component
- extracellular region
- extracellular space
- plasma membrane
- cell junction
- axon
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000435363
- Coding exons
- 41
- Length
- 20657
- Individuals with no LoFs
- 123351
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 9
- Defined
- 123360
- p
- 0.0000365
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.02 | 140 | 225 | 0.622 | 0.0000128 | 11186 |
| Missense (PolyPhen) | 50 | 76.079 | 0.65721 | 3093 | ||
| Synonymous | 2.91 | 61 | 97.6 | 0.625 | 0.00000594 | 3602 |
| Loss of Function | 3.41 | 3 | 19.1 | 0.157 | 8.50e-7 | 1023 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00012 | rare |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000055 | 0.000055 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000019 | 0.000018 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Non-enzymatic component of the C3 and C5 convertases and thus essential for the propagation of the classical complement pathway. Covalently binds to immunoglobulins and immune complexes and enhances the solubilization of immune aggregates and the clearance of IC through CR1 on erythrocytes. C4A isotype is responsible for effective binding to form amide bonds with immune aggregates or protein antigens, while C4B isotype catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens.;
- Disease
- DISEASE: 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. {ECO:0000269|PubMed:10092831, ECO:0000269|PubMed:17503323}. Note=Disease susceptibility is associated with variations 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.; DISEASE: 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. {ECO:0000269|PubMed:3265961}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.539
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |