C4A

Chr 6AR

complement C4A (Chido/Rodgers blood group)

Also known as: C4, C4A2, C4A3, C4A4, C4A6, C4AD, C4S, CO4

NCBI Gene: 720ENSG00000244731UniProt: P0C0L4

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]

Primary Disease Associations & Inheritance

[Blood group, Rodgers]MIM #614374
C4a deficiencyMIM #614380
AR
UniProtComplement component 4A deficiency
UniProtSystemic lupus erythematosus
0
Active trials
5
Pathogenic / LP
87
ClinVar variants
78
Pubs (1 yr)
1.9
Missense Z
1.45
LOEUF
Clinical Summary— C4A
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
5 Pathogenic / Likely Pathogenic· 57 VUS of 87 total submissions
📖
GeneReview available — C4A
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.45LOEUF
pLI 0.000
Z-score 0.14
OE 0.97 (0.66–1.45)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
1.92Z-score
OE missense 0.63 (0.54–0.72)
130 obs / 207.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.97 (0.66–1.45)
0≤0.351.4
Missense OE0.63 (0.54–0.72)
0≤0.61.4
Synonymous OE0.81
0≤1.21.6
LoF obs/exp: 17 / 17.6Missense obs/exp: 130 / 207.9Syn Z: 1.41

ClinVar Variant Classifications

87 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4
Likely Pathogenic1
VUS57
Likely Benign12
Benign13
4
Pathogenic
1
Likely Pathogenic
57
VUS
12
Likely Benign
13
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
4
0
4
Likely Pathogenic
0
0
1
0
1
VUS
0
51
5
1
57
Likely Benign
0
5
6
1
12
Benign
1
2
8
2
13
Total15824487

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

C4A · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Polymorphisms in intron 1 of HLA-DRA differentially associate with type 1 diabetes and celiac disease and implicate involvement of complement system genes C4A and C4B.
Aydemir O et al.·Elife
2026Open Access
Distinct Effects of Complement C4A and C4B Copy Numbers in Systemic Sclerosis Serological and Clinical Subtypes.
Martínez-López J et al.·Arthritis Rheumatol
2025
Multiphasic acute disseminated encephalomyelitis (MDEM) in a patient with systemic lupus erythematosus and C4A deficiency: case-based review.
Ljubicic J et al.·Rheumatol Int
2025Review
Complement component C4a binds to oxytocin and modulates plasma oxytocin concentrations and social behavior in male mice.
Yamamoto Y et al.·Biochem Biophys Res Commun
2025
Enantioselective Access to Decahydroquinolines Bearing a C4a or C8a Quaternary Stereocenter from a Common Intermediate Total Synthesis of (-)-Myrioxazine A.
Calbó A et al.·J Org Chem
2025Open Access
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients