Complement component 3 deficiency

Summary

Complement component 3 deficiency (MONDO:0013417) is a disease caused by C3 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: C3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 509

Clinical features

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

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: 509 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

Related subtypes (12): C1 inhibitor deficiency, complement component C1r/C1s 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

Genetics & variants

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.

Variant details and genetic-evidence tiers

ClinVar germline variants

509 retrieved; paginated sample, class counts are floors:

283 uncertain significance, 78 conflicting classifications of pathogenicity, 45 benign, 39 likely benign, 25 benign/likely benign, 18 likely pathogenic, 17 pathogenic, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1455261	NM_000064.4(C3):c.373dup (p.Leu125fs)	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
17060	NM_000064.4(C3):c.1775G>A (p.Arg592Gln)	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
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
4280287	NM_000064.4(C3):c.305dup (p.Asn103fs)	C3	Pathogenic	criteria provided, single submitter
4819735	NM_000064.4(C3):c.1005_1015del	C3	Pathogenic	criteria provided, single submitter
599117	NM_000064.4(C3):c.169_170del (p.Val57fs)	C3	Pathogenic	criteria provided, single submitter
992385	NM_000064.4(C3):c.3737_3738del (p.Asp1245_Phe1246insTer)	C3	Pathogenic	criteria provided, multiple submitters, no conflicts
17064	NM_000064.4(C3):c.4631-2A>G	C3	Likely pathogenic	criteria provided, single submitter
2506048	NM_000064.4(C3):c.4030-2A>G	C3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
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
3584120	NM_000064.4(C3):c.2863+1G>T	C3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3584127	NM_000064.4(C3):c.2615del (p.Phe872fs)	C3	Likely pathogenic	criteria provided, single submitter
3584178	NM_000064.4(C3):c.1003+1G>A	C3	Likely pathogenic	criteria provided, single submitter
3584182	NM_000064.4(C3):c.774-1G>T	C3	Likely pathogenic	criteria provided, single submitter

Genes & proteins

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.

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

Orphanet rare-disease linkage (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 (full)

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

Cohort function summary

Lead sentence per gene, UniProt-curated.

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 families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Complement	1	268.0×	0.004

Per-gene assignment

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

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

Per-gene tissue summary (top 30)

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	3,199

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
C3	P01024	75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Alternative complement activation	1	2284.0×	0.004	C3
Activation of C3 and C5	1	1268.9×	0.004	C3
Purinergic signaling in leishmaniasis infection	1	423.0×	0.008	C3
Regulation of Complement cascade	1	233.1×	0.011	C3
Post-translational protein phosphorylation	1	100.2×	0.017	C3
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	87.2×	0.017	C3
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.017	C3
Peptide ligand-binding receptors	1	74.2×	0.017	C3
G alpha (i) signalling events	1	39.0×	0.029	C3
Neutrophil degranulation	1	23.1×	0.043	C3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of triglyceride biosynthetic process	1	8426.0×	9e-04	C3
complement-dependent cytotoxicity	1	8426.0×	9e-04	C3
positive regulation of type IIa hypersensitivity	1	5617.3×	9e-04	C3
positive regulation of activation of membrane attack complex	1	5617.3×	9e-04	C3
oviduct epithelium development	1	5617.3×	9e-04	C3
vertebrate eye-specific patterning	1	5617.3×	9e-04	C3
complement-mediated synapse pruning	1	4213.0×	0.001	C3
positive regulation of apoptotic cell clearance	1	2407.4×	0.002	C3
positive regulation of D-glucose transmembrane transport	1	2106.5×	0.002	C3
positive regulation of lipid storage	1	1404.3×	0.002	C3
positive regulation of phagocytosis, engulfment	1	1296.3×	0.002	C3
complement activation, GZMK pathway	1	1296.3×	0.002	C3
neuron remodeling	1	1203.7×	0.002	C3
complement receptor mediated signaling pathway	1	1123.5×	0.002	C3
positive regulation of G protein-coupled receptor signaling pathway	1	1053.2×	0.002	C3
complement activation, alternative pathway	1	991.3×	0.002	C3
amyloid-beta clearance	1	936.2×	0.002	C3
positive regulation of receptor-mediated endocytosis	1	802.5×	0.002	C3
complement activation	1	624.1×	0.003	C3
complement activation, classical pathway	1	543.6×	0.003	C3
positive regulation of vascular endothelial growth factor production	1	495.6×	0.003	C3
B cell activation	1	455.5×	0.003	C3
positive regulation of protein phosphorylation	1	276.3×	0.005	C3
fatty acid metabolic process	1	193.7×	0.006	C3
response to bacterium	1	193.7×	0.006	C3
positive regulation of angiogenesis	1	115.4×	0.010	C3
immune response	1	47.1×	0.024	C3
inflammatory response	1	37.7×	0.028	C3
G protein-coupled receptor signaling pathway	1	36.2×	0.029	C3
signal transduction	1	16.1×	0.062	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 (full, sorted by assay count)

Symbol	Assays	Type breakdown
C3	15	Binding:15

Cohort enzymes (BRENDA EC)

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).

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.