C5 Gene (Complement C5): Structure, Function, and Clinical Significance

A comprehensive overview of the complement C5 gene, its protein product, associated diseases, and therapeutic relevance.

Gene Information Card

Symbol C5
Full Name Complement C5
Gene Type protein-coding
Chromosomal Location 9q33.2
NCBI Gene ID 727 ncbi.nlm.nih.gov/gene/727
Ensembl ID ENSG00000106804
UniProt ID P01031
OMIM ID 120900
HGNC ID 1331
Aliases CPAMD4, C5a, C5b

Description

The C5 gene encodes complement component 5, a key protein of the complement system that plays a central role in innate immunity. C5 is cleaved into C5a (an anaphylatoxin) and C5b (a component of the membrane attack complex), contributing to inflammation and pathogen lysis. Mutations in C5 can lead to complement deficiencies or dysregulation, associated with recurrent infections and autoimmune conditions.

Disease Associations

Disease category Pathophysiological mechanism Genomic evidence
Complement C5 deficiency Loss-of-function mutations in C5 impair formation of C5b and membrane attack complex, leading to increased susceptibility to Neisseria infections. OMIM 120900; PMID: 12324460
Atypical hemolytic uremic syndrome (aHUS) Gain-of-function variants in C5 can cause overactivation of the complement pathway, leading to endothelial damage and thrombotic microangiopathy. PMID: 23463675
Paroxysmal nocturnal hemoglobinuria (PNH) C5 mutations or autoantibodies can lead to complement-mediated hemolysis; anti-C5 therapy is used. PMID: 15699020
C3 glomerulopathy Dysregulation of complement, including C5, contributes to glomerular injury. PMID: 23463675

Expression Profile

Tissue Expression
Tissue nTPM level
Liver High (nTPM ~ 100) High
Plasma High (protein) High
Spleen Low (nTPM ~ 5) Low
Kidney Low (nTPM ~ 3) Low
Cell Line Expression
Cell Line nTPM Notes
HepG2 (liver) High Major source of C5
THP-1 (monocyte) Low Induced upon activation
Jurkat (T cell) Not detected No significant expression
Data source：Human Protein Atlas（proteinatlas.org）

Mutations & Variants

Hotspot Mutations
Variant Type Frequency Functional Description
c.2236C>T (p.Arg746Ter) Nonsense Rare Loss of function; leads to C5 deficiency
c.754C>T (p.Arg252Ter) Nonsense Rare Loss of function; C5 deficiency
c.2926A>G (p.Thr976Ala) Missense Rare Potential gain-of-function; associated with aHUS
c.481C>T (p.Arg161Trp) Missense Rare Uncertain; may affect C5 cleavage
Mutation functional classification

Loss of Function (LOF)

Nonsense or frameshift mutations that truncate the protein, leading to absence of functional C5 and impaired MAC formation.

Gain of Function (GOF)

Missense variants that enhance C5 convertase activity or resistance to regulation, leading to complement overactivation.

Dominant Negative (DN)

Rare; some missense mutations may interfere with C5 cleavage or binding, but dominant-negative effects are not well documented.
View complete mutation data：
ClinVar：https://www.clinvar.com/gene/727
COSMIC：https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=C5

Gene Ontology (GO)

• complement activation (GO:0006956) • complement activation, classical pathway (GO:0006958)
• complement activation, alternative pathway (GO:0006959) • complement activation, lectin pathway (GO:0001869)
• protein binding (GO:0005515) • extracellular space (GO:0005615)
• plasma membrane (GO:0005886)

Pathways

• Complement cascade (KEGG hsa04610)
• Immune response (Reactome R-HSA-166658)

Protein Summary

Complement C5 is a 1676-amino acid glycoprotein synthesized primarily in the liver. It is cleaved by C5 convertase into C5a (74 aa) and C5b (152 aa). C5a is a potent anaphylatoxin that recruits immune cells, while C5b initiates the assembly of the membrane attack complex (MAC) with C6, C7, C8, and C9, leading to cell lysis. C5 also plays roles in inflammation and immune regulation. Its structure includes multiple domains: an anaphylatoxin domain, a C345C domain, and a macroglobulin domain.

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Reference Databases

NCBI Gene https://www.ncbi.nlm.nih.gov/gene/727
OMIM https://www.omim.org/entry/120900
HGNC https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:1331
Ensembl https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000106804
UniProt https://www.uniprot.org/uniprotkb/P01031/entry
ClinVar https://www.ncbi.nlm.nih.gov/clinvar/?term=C5%5Bgene%5D
COSMIC https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=C5
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