Complement component 3 deficiency

Summary

Complement component 3 deficiency (MONDO:0013417) is a disease caused by C3 (GenCC Definitive), inherited in an autosomal recessive pattern. It is a rare, genetic, primary immunodeficiency characterized by susceptibility to infection (mainly by gram negative bacteria) due to extremely low C3 plasma levels (Orphanet). This page aggregates 1 associated gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: C3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 514
• Phenotypes (HPO): 9

Clinical features

Clinical description

Orphanet: Complement component 3 deficiency is a rare, genetic, primary immunodeficiency characterized by susceptibility to infection (mainly by gram negative bacteria) due to extremely low C3 plasma levels. Patients typically present recurrent episodes of sinusitis, tonsillitis, and/or otitis, as well as upper and lower respiratory tract infections (including pneumonia) and skin infections, such as erythema multiforme. Autoimmune disease resembling systemic lupus erythematosus and mesangiocapillary or membranoproliferative glomerulonephritis may develop, resulting in renal failure.

Mondo: A rare genetic disorder with an autosomal recessive pattern of inheritance. It is caused by the ineffective or decreased biosynthesis of the third complement component, C3. C3 deficiency may also be acquired acutely post-infection or chronically from co-morbid autoimmune disorders. If C3 is adequately synthesized, its rapid depletion may result in a functional deficiency. Clinical signs of the inherited deficiency present within the first decade of life and are consistent with the signs of recurrent systemic infection or immune complex disease. Deficiency of serum C3 and its major cleavage product, C3b, will decrease the effective humoral immune response to encapsulated bacteria. Deficiency of C3 also impairs clearance of circulating immune complexes and therefore predisposes to rheumatic and renal disease.

Inheritance: Autosomal recessive · Onset: Childhood

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		27	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (curated from Orphanet + OMIM; top 9 shown, Orphanet frequencies first):

HPO ID	Term	Frequency
HP:0000083	Renal insufficiency	—
HP:0000100	Nephrotic syndrome	—
HP:0000793	Membranoproliferative glomerulonephritis	—
HP:0001954	Recurrent fever	—
HP:0002718	Recurrent bacterial infections	—
HP:0002725	Systemic lupus erythematosus	—
HP:0005421	Decreased circulating complement C3 concentration	—
HP:0006532	Recurrent pneumonia	—
HP:0011110	Recurrent tonsillitis	—

Identifiers

Disease identifiers

Field	Value
Canonical name	complement component 3 deficiency
Mondo ID	MONDO:0013417
MeSH	C565169
OMIM	613779
Orphanet	280133
DOID	DOID:8354
NCIT	C9468
UMLS	C3151071
MedGen	462421
GARD	0016489
Is cancer (heuristic)	no

Also known as: C3 classic complement early component deficiency · C3 deficiency · C3d · classic complement early component deficiency caused by mutation in C3 · complement component 3 deficiency, autosomal recessive

Data availability: 514 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › complement deficiency › classic complement early component deficiency › complement component 3 deficiency

Sibling subtypes (12): C1 inhibitor deficiency, complement component 2 deficiency, complement component 5 deficiency, complement component 7 deficiency, complement component 6 deficiency, complement component C1s deficiency, type II complement component 8 deficiency, type I complement component 8 deficiency, complement component 9 deficiency, complement component 4b deficiency, complement component 4a deficiency, … (+1 more under the parent term)

Genetics & variants

Variant details and genetic-evidence tiers

ClinVar germline variants

514 retrieved; paginated sample, class counts are floors:

286 uncertain significance, 79 conflicting classifications of pathogenicity, 46 benign/likely benign, 40 likely benign, 24 benign, 17 likely pathogenic, 16 pathogenic, 6 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
17060	NM_000064.4(C3):c.1775G>A (p.Arg592Gln)	C3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
992385	NM_000064.4(C3):c.3737_3738del (p.Asp1245_Phe1246insTer)	C3	Pathogenic	criteria provided, multiple submitters, no conflicts
1455261	NM_000064.4(C3):c.373dup (p.Leu125fs)	C3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2972902	NM_000064.4(C3):c.2290C>T (p.Arg764Ter)	C3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3584123	NM_000064.4(C3):c.2825_2826del (p.Val942fs)	C3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3584178	NM_000064.4(C3):c.1003+1G>A	C3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4280287	NM_000064.4(C3):c.305dup (p.Asn103fs)	C3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17058	NM_000064.4(C3):c.2354+1G>A	C3	Pathogenic	criteria provided, single submitter
599117	NM_000064.4(C3):c.169_170del (p.Val57fs)	C3	Pathogenic	criteria provided, single submitter
4280162	NM_000064.4(C3):c.2002del (p.Arg668fs)	C3	Pathogenic	criteria provided, single submitter
4280170	NM_000064.4(C3):c.2696del (p.Val899fs)	C3	Pathogenic	criteria provided, single submitter
4280175	NM_000064.4(C3):c.3116dup (p.Glu1040fs)	C3	Pathogenic	criteria provided, single submitter
4280184	NM_000064.4(C3):c.3997del (p.Thr1333fs)	C3	Pathogenic	criteria provided, single submitter
4280242	NM_000064.4(C3):c.1432C>T (p.Arg478Ter)	C3	Pathogenic	criteria provided, single submitter
4280243	NM_000064.4(C3):c.1656G>A (p.Trp552Ter)	C3	Pathogenic	criteria provided, single submitter
4280244	NM_000064.4(C3):c.2542C>T (p.Arg848Ter)	C3	Pathogenic	criteria provided, single submitter
4280245	NM_000064.4(C3):c.3243C>G (p.Tyr1081Ter)	C3	Pathogenic	criteria provided, single submitter
4280246	NM_000064.4(C3):c.4258C>T (p.Gln1420Ter)	C3	Pathogenic	criteria provided, single submitter
4280249	NM_000064.4(C3):c.1004-2A>T	C3	Pathogenic	criteria provided, single submitter
4280250	NM_000064.4(C3):c.1119+1G>T	C3	Pathogenic	criteria provided, single submitter
4280252	NM_000064.4(C3):c.1480-1G>T	C3	Pathogenic	criteria provided, single submitter
4976826	NM_000064.4(C3):c.1811del (p.Val604fs)	C3	Pathogenic	criteria provided, single submitter
2506048	NM_000064.4(C3):c.4030-2A>G	C3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3584120	NM_000064.4(C3):c.2863+1G>T	C3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
17064	NM_000064.4(C3):c.4631-2A>G	C3	Likely pathogenic	criteria provided, single submitter
830031	NM_000064.4(C3):c.2061dup (p.Lys688fs)	C3	Likely pathogenic	criteria provided, single submitter
2690556	NM_000064.4(C3):c.3813dup (p.Thr1272fs)	C3	Likely pathogenic	criteria provided, single submitter
3584072	NM_000064.4(C3):c.4918del (p.Glu1640fs)	C3	Likely pathogenic	criteria provided, single submitter
3584099	NM_000064.4(C3):c.3687del (p.Asn1229fs)	C3	Likely pathogenic	criteria provided, single submitter
3584127	NM_000064.4(C3):c.2615del (p.Phe872fs)	C3	Likely pathogenic	criteria provided, single submitter

Pathogenic / likely-pathogenic variants link to their full per-variant reference — ACMG evidence, calibrated predictors, gnomAD frequency — on Sugi Variant.

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Genes & proteins

Molecular basis

The molecular function of this disease’s causal gene(s), from UniProt. Attributed to the gene/protein — reporting UniProt’s curation, not an assertion about this disease’s clinical phenotype.

C3 — Complement C3 (P01024) · GenCC Definitive Function: Precursor of non-enzymatic components of the classical, alternative, 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. Localization / cofactor: Secreted Secreted UniProt gene–disease: Complement component 3 deficiency (C3D) [MIM:613779] A rare defect of the complement classical pathway. Patients develop recurrent, severe, pyogenic infections because of ineffective opsonization of pathogens. Some patients may also develop autoimmune …

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

1 cohort genes:

Gene	Classification	Inheritance	Disease	Records
C3	Definitive	Autosomal recessive	complement component 3 deficiency	6

Orphanet rare-disease linkage (cohort genes)

2 cohort genes:

Gene	Orphanet ID	Rare disease
C3	Orphanet:280133	Complement component 3 deficiency
C3	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes

1 cohort genes:

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
C3	HGNC:1318	ENSG00000125730	P01024	Complement C3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

1 cohort genes:

Symbol	Protein name	Function (lead sentence)
C3	Complement C3	Precursor of non-enzymatic components of the classical, alternative, 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 adapt…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort has 1 family-classified gene — counts only (too few for over-representation statistics).

Family	Genes
Complement	1

Per-gene assignment

1 cohort genes:

Symbol	Family	Druggable?	EC	InterPro (top 3)
C3	Complement	yes	3.4.21.47	Anaphylatoxin/fibulin, Netrin_domain, Macroglobln_a2

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

3 tissues:

Tissue	Cohort genes
palpebral conjunctiva	1
parietal pleura	1
right lobe of liver	1

Per-gene tissue summary

1 cohort genes:

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
C3	289	ubiquitous	marker	parietal pleura, right lobe of liver, palpebral conjunctiva

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
C3	3,028

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures

1 cohort genes:

Symbol	UniProt	PDB entries
C3	P01024	80

Alliance gene associations

Curated gene–disease associations from the Alliance of Genome Resources (Disease Ontology) — distinct from the cohort above: implicated (causal/mechanistic) vs biomarker (a marker for the disease).

Implicated genes (1): C3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 28. Cohort has 1 gene with Reactome annotation — too few for over-representation statistics, so the pathways below are membership (what the cohort gene participates in), not enrichment.

Pathways by enrichment

Cohort has 1 annotated gene — membership only (too few for over-representation statistics).

28 pathways:

Pathway	Genes	Sample cohort genes
Alternative complement activation	1	C3
Activation of C3 and C5	1	C3
Cell recruitment (pro-inflammatory response)	1	C3
Complement cascade	1	C3
Initial triggering of complement	1	C3
Purinergic signaling in leishmaniasis infection	1	C3
Regulation of Complement cascade	1	C3
Leishmania infection	1	C3
Parasitic Infection Pathways	1	C3
Post-translational protein phosphorylation	1	C3
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	C3
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	C3
Class A/1 (Rhodopsin-like receptors)	1	C3
Peptide ligand-binding receptors	1	C3
GPCR ligand binding	1	C3
GPCR downstream signalling	1	C3
Signaling by GPCR	1	C3
G alpha (i) signalling events	1	C3
Adaptive Immune System	1	C3
Innate Immune System	1	C3
Infectious disease	1	C3
Neutrophil degranulation	1	C3
Post-translational protein modification	1	C3
Disease	1	C3
Immune System	1	C3
Metabolism of proteins	1	C3
Signal Transduction	1	C3
Affinity selection of immunoglobulins	1	C3

GO biological processes by enrichment

Cohort has 1 annotated gene — membership only (too few for over-representation statistics).

26 GO terms:

GO term	Genes	Sample cohort genes
regulation of triglyceride biosynthetic process	1	C3
positive regulation of activation of membrane attack complex	1	C3
vertebrate eye-specific patterning	1	C3
complement-mediated synapse pruning	1	C3
positive regulation of apoptotic cell clearance	1	C3
positive regulation of D-glucose transmembrane transport	1	C3
positive regulation of lipid storage	1	C3
positive regulation of phagocytosis, engulfment	1	C3
complement activation, GZMK pathway	1	C3
neuron remodeling	1	C3
complement receptor mediated signaling pathway	1	C3
positive regulation of G protein-coupled receptor signaling pathway	1	C3
complement activation, alternative pathway	1	C3
amyloid-beta clearance	1	C3
positive regulation of receptor-mediated endocytosis	1	C3
complement activation	1	C3
complement activation, classical pathway	1	C3
positive regulation of vascular endothelial growth factor production	1	C3
B cell activation	1	C3
positive regulation of protein phosphorylation	1	C3
fatty acid metabolic process	1	C3
positive regulation of angiogenesis	1	C3
immune response	1	C3
inflammatory response	1	C3
G protein-coupled receptor signaling pathway	1	C3
signal transduction	1	C3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
C3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity

1 cohort genes by assay count:

Symbol	Assays	Type breakdown
C3	15	Binding:15

Cohort enzymes (BRENDA EC)

1 cohort enzymes:

Symbol	EC numbers	Names
C3	3.4.21.47	alternative-complement-pathway C3/C5 convertase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	C3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

1 cohort genes:

Symbol	ChEMBL assays	Drugged partners (top 3)
C3	15	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.