C4A

protein-coding

complement C4A (Rodgers blood group), the group of Complement system activation components|Blood group antigens|C3 and PZP like, alpha-2-macroglobulin domain containing

Gene summary

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. [provided by RefSeq, Nov 2014]

MANE transcript

NM_007293.3

Inheritance

AR, BG

ClinVar variants

U:60B:10

Top phenotype

Blood group, Chido/Rodgers system

gnomAD constraint

pLI —, LoF o/e 0.97

Max pathogenic AF

—

Genomic locus

chr6:31,982,057-32,002,681

External References & Databases

Ensembl (ENSG00000244731)

Transcript & Mutation Effects

hg38 • Region Span ~20.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complement component 4a deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013721

Submitter: Labcorp Genetics (formerly Invitae)

complement component 4a deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013721

Submitter: Ambry Genetics

systemic lupus erythematosusSUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0007915

Submitter: Orphanet

systemic lupus erythematosus related to C4AMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0700323

Submitter: ClinGen

The *C4A* gene encodes the acidic isoform of complement factor 4, part of the classical pathway. C4 protein deficiency was first reported in relation to systemic lupus erythematosus (SLE) in the 1970’s, with specific C4A deficiency first reported in the 1980’s. Since then, many studies have investigated the evidence relating lower *C4A* copy number to increased risk of developing SLE. Genetic evidence includes case reports of homozygous loss of *C4A* or absence of C4A protein (often called C4AQ0), which were not curated due to the lack of information on and thus potential variability of the deletion boundaries and absence of genetic information, respectively. A recent report of an SLE patient with a homozygous predicted loss of function variant in *C4A* and confirmed location of the variant in the *C4A* gene (PMID 40788338) has been given the maximum score (3 points). A number of case-control studies of various cohort sizes and ancestries, as well as two meta-analyses (PMIDs 28205620, 32691186) have been published. Older case-control studies used allotyping/C4A protein detection and were therefore not scored. Nine case-control studies (PMIDs 7481564, 10529130, 12480675, 19287147, 23335107, 26800705, 29050534, 31387635, 35315244) show a statistically significant relationship between lower *C4A* copy number and increased risk of SLE. Six additional case-control studies (PMIDs 21904924, 22387014, 26814708, 29080553, 38594415) provide statistically significant support for the relationship between *C4A* and SLE, but lack gender matching between the case and control cohorts. Two large case-control studies (PMIDs 32499649, 40617727) used imputation to infer the copy number of *C4A* and also support the relationship. We awarded points to only a small number of these studies due to substantial uncertainty regarding the deletion boundaries. Three case-control studies (PMIDs 21695597, 34580371, 39800843) showed a lack of statistical significance. Experimental evidence includes a lupus mouse model where expression of the human *C4A* isotypic region leads to a reduction in autoimmunity relative to C4B-expressing mice (PMID 33147456). In summary, there is **moderate** evidence supporting the relationship between *C4A* and autosomal recessive systemic lupus erythematosus. This classification was approved by the ClinGen Monogenic Systemic and Incomplete Lupus Erythematosus GCEP on the meeting date December 10, 2025 (SOP Version 11).

Clinical Genomic Database (CGD)

Blood group, Chido/Rodgers systemBG

Manifestation: Allergy/Immunology/Infectious; Hematologic

Intervention: Hematologic

Rationale: Variants associated with a blood group may be important in specific situations (eg, related to transfusion)

Refs: 4190973; 6932037; 7451653; 2862466; 3260957; 2551816; 2295875; 2243578; 2289315; 2384609; 8473511; 7706484; 22387014; 29928053

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to C4A variants in ClinVar

4 Conditions Cataloged

Inborn genetic diseasesTotal: 52

not providedTotal: 9

not specifiedTotal: 7

Complement component 4a deficiencyTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007293.3. 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 clinvar	2 clinvar	2 clinvar	5
missense			54 clinvar	4 clinvar	1 clinvar	59
nonsense			2 clinvar			2
start loss						0
frameshift			1 clinvar		1 clinvar	2
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	60	6	4	70

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_007293.3	RefSeq	NP_009224.2	41	MANE Select
ENST00000428956.7	Ensembl	ENSP00000396688.2	41	MANE Select
NM_001252204.2	RefSeq	NP_001239133.1	40	Standard
ENST00000498271.1	Ensembl	ENSP00000420212.1	40	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
negative regulation of endopeptidase activity

Molecular Function

complement component C1q binding
serine-type endopeptidase activity
endopeptidase inhibitor activity

Cellular Component

extracellular region
extracellular space
endoplasmic reticulum lumen
plasma membrane
cell junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000428956
Coding exons: 41
Length: 20658
Individuals with no LoFs: 124261
Homozygous LoFs: 3
Heterozygous LoFs: 28
Defined: 124292
p: 0.000125

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.92	130	208	0.625	0.0000124	11177
Missense (PolyPhen)		35	62.201	0.56269		3004
Synonymous	1.41	76	93.3	0.815	0.00000601	3601
Loss of Function	0.135	17	17.6	0.965	8.23e-7	1030

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00032	0.00029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00017	0.00016	rare
Finnish	0.00016	0.000092	rare
European (Non-Finnish)	0.000079	0.000063	rare
South Asian	0.00029	0.00029	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Non-enzymatic component of 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: 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. {ECO:0000269|PubMed:8473511}. Note=The disease is caused by mutations affecting the gene represented in this entry.; 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.;

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.600

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium