C3 glomerulonephritis

Summary

C3 glomerulonephritis (MONDO:0013892) is a disease caused by variants in CFH and CFHR5, with 6 cohort genes and 11 clinical trials. The dominant Reactome pathway is Regulation of Complement cascade (6 cohort genes). Top therapeutic interventions include pegcetacoplan, danicopan, and enalapril.

At a glance

• Causal genes: CFH (GenCC Definitive), CFHR5 (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 296
• Clinical trials: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	C3 glomerulonephritis
Mondo ID	MONDO:0013892
OMIM	614809
Orphanet	329931
NCIT	C123043
UMLS	C4055342
MedGen	884569
GARD	0016487
Is cancer (heuristic)	no

Also known as: complement-mediated membranoproliferative glomerulonephritis · nephropathy due to CFHR5 deficiency

Data availability: 296 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › urinary system disorder › kidney disorder › nephritis › hereditary nephritis › C3 glomerulonephritis

Related subtypes (6): IgA glomerulonephritis, Balkan nephropathy, complement factor H deficiency, karyomegalic interstitial nephritis, immunoglobulin-mediated membranoproliferative glomerulonephritis, Alport syndrome

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

296 retrieved; paginated sample, class counts are floors:

220 uncertain significance, 31 conflicting classifications of pathogenicity, 19 benign, 9 not provided, 5 likely benign, 5 benign/likely benign, 4 likely pathogenic, 2 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1163121	NM_000064.4(C3):c.481C>T (p.Arg161Trp)	C3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17060	NM_000064.4(C3):c.1775G>A (p.Arg592Gln)	C3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
37236	NM_030787.4(CFHR5):c.59-1806_430+3225dup	CFHR5	Pathogenic	no assertion criteria provided
3063665	NM_000064.4(C3):c.1774C>T (p.Arg592Trp)	C3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4279900	NM_000064.4(C3):c.683-1G>T	C3	Likely pathogenic	criteria provided, single submitter
4280265	NM_000064.4(C3):c.2768_2773del (p.Asp923_Gly924del)	C3	Likely pathogenic	criteria provided, single submitter
633673	NM_030787.4(CFHR5):c.1303C>T (p.Arg435Ter)	CFHR5	Likely pathogenic	criteria provided, single submitter
1678090	NM_000064.4(C3):c.387C>G (p.Tyr129Ter)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2986104	NM_000064.4(C3):c.3188G>A (p.Ser1063Asn)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330281	NM_000064.4(C3):c.4535G>A (p.Arg1512His)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330284	NM_000064.4(C3):c.4319A>C (p.Asp1440Ala)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330292	NM_000064.4(C3):c.3671G>A (p.Gly1224Asp)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330310	NM_000064.4(C3):c.2203C>T (p.Arg735Trp)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330316	NM_000064.4(C3):c.1855G>A (p.Val619Met)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330337	NM_000064.4(C3):c.681C>T (p.Tyr227=)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
381739	NM_000064.4(C3):c.193A>C (p.Lys65Gln)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
625901	NM_000064.4(C3):c.2951-5_2951-3del	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
636934	NM_000064.4(C3):c.4100T>C (p.Ile1367Thr)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
737356	NM_000064.4(C3):c.4369G>C (p.Asp1457His)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
872465	NM_000064.4(C3):c.26T>C (p.Leu9Pro)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
892936	NM_000064.4(C3):c.835G>A (p.Glu279Lys)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
894696	NM_000064.4(C3):c.3953T>G (p.Leu1318Arg)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
92162	NM_000064.4(C3):c.463A>C (p.Lys155Gln)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1163772	NM_030787.4(CFHR5):c.206G>A (p.Arg69His)	CFHR5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1712441	NM_030787.4(CFHR5):c.683G>C (p.Gly228Ala)	CFHR5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2514771	NM_030787.4(CFHR5):c.669A>C (p.Arg223Ser)	CFHR5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2514796	NM_030787.4(CFHR5):c.1640C>T (p.Ala547Val)	CFHR5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2883984	NM_030787.4(CFHR5):c.700G>A (p.Glu234Lys)	CFHR5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
294547	NM_030787.4(CFHR5):c.880G>A (p.Glu294Lys)	CFHR5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3575798	NM_030787.4(CFHR5):c.349G>A (p.Gly117Arg)	CFHR5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · Orphanet: 18 · 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
CFH	Definitive	Autosomal recessive	C3 glomerulonephritis	9
CFHR5	Strong	Autosomal dominant	C3 glomerulonephritis	2
C3	Moderate	Autosomal dominant	C3 glomerulonephritis	6
CFI	Moderate	Autosomal dominant	C3 glomerulonephritis	9

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
CFHR5	Orphanet:329931	C3 glomerulonephritis
CFH	Orphanet:200421	Immunodeficiency with factor H anomaly
CFH	Orphanet:244242	HELLP syndrome
CFH	Orphanet:244275	De novo thrombotic microangiopathy after kidney transplantation
CFH	Orphanet:329903	Immunoglobulin-mediated membranoproliferative glomerulonephritis
CFH	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality
CFH	Orphanet:75376	Familial drusen
CFH	Orphanet:93571	Dense deposit disease
CFI	Orphanet:200418	Immunodeficiency with factor I anomaly
CFI	Orphanet:244242	HELLP syndrome
CFI	Orphanet:244275	De novo thrombotic microangiopathy after kidney transplantation
CFI	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality
CFI	Orphanet:75376	Familial drusen
CFHR1	Orphanet:329931	C3 glomerulonephritis
CFHR1	Orphanet:93571	Dense deposit disease
CFHR2	Orphanet:329931	C3 glomerulonephritis

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
C3	HGNC:1318	ENSG00000125730	P01024	Complement C3	gencc,clinvar
CFHR5	HGNC:24668	ENSG00000134389	Q9BXR6	Complement factor H-related protein 5	gencc,clinvar
CFH	HGNC:4883	ENSG00000000971	P08603	Complement factor H	gencc,clinvar
CFI	HGNC:5394	ENSG00000205403	P05156	Complement factor I	gencc,clinvar
CFHR1	HGNC:4888	ENSG00000244414	Q03591	Complement factor H-related protein 1	clinvar
CFHR2	HGNC:4890	ENSG00000080910	P36980	Complement factor H-related protein 2	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…
CFHR5	Complement factor H-related protein 5	Involved in complement regulation.
CFH	Complement factor H	Glycoprotein that plays an essential role in maintaining a well-balanced immune response by modulating complement activation.
CFI	Complement factor I	Trypsin-like serine protease that plays an essential role in regulating the immune response by controlling all complement pathways.
CFHR1	Complement factor H-related protein 1	Involved in complement regulation.
CFHR2	Complement factor H-related protein 2	Involved in complement regulation.

Protein-family classification

Druggable: 6 · 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	5	223.3×	8e-12
Protease	1	6.1×	0.153

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
C3	Complement	yes	3.4.21.47	Anaphylatoxin/fibulin, Netrin_domain, Macroglobln_a2
CFHR5	Complement	yes		Sushi_SCR_CCP_dom, Sushi/SCR/CCP_sf, ComplSys_Reg/VirEntry_Med
CFH	Complement	yes		Sushi_SCR_CCP_dom, Sushi/SCR/CCP_sf, ComplSys_Reg/VirEntry_Med
CFI	Protease	yes	3.4.21.45	SRCR, Trypsin_dom, Peptidase_S1A
CFHR1	Complement	yes		Sushi_SCR_CCP_dom, Sushi/SCR/CCP_sf, ComplSys_Reg/VirEntry_Med
CFHR2	Complement	yes		Sushi_SCR_CCP_dom, Sushi/SCR/CCP_sf, ComplSys_Reg/VirEntry_Med

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	5
parietal pleura	3
liver	3
male germ line stem cell (sensu Vertebrata) in testis	2
palpebral conjunctiva	1
calcaneal tendon	1
right coronary artery	1
urethra	1
germinal epithelium of ovary	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
CFHR5	15	tissue_specific	marker	right lobe of liver, liver, male germ line stem cell (sensu Vertebrata) in testis
CFH	267	ubiquitous	marker	urethra, calcaneal tendon, right coronary artery
CFI	240	broad	marker	germinal epithelium of ovary, parietal pleura, right lobe of liver
CFHR1	125		marker	right lobe of liver, liver, male germ line stem cell (sensu Vertebrata) in testis
CFHR2	139		marker	right lobe of liver, liver, parietal pleura

Protein interactions among cohort

Intra-cohort edges: 10.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
C3	3,199
CFH	1,844
CFI	1,120
CFHR5	768
CFHR1	599
CFHR2	396

Intra-cohort edges

A	B	Sources
C3	CFH	biogrid_interaction, intact, string_interaction
C3	CFHR1	string_interaction
C3	CFHR2	intact, string_interaction
C3	CFHR5	string_interaction
C3	CFI	biogrid_interaction, intact, string_interaction
CFH	CFHR1	intact
CFH	CFI	intact, string_interaction
CFHR1	CFHR2	biogrid_interaction, intact
CFHR1	CFHR5	intact
CFHR1	CFI	intact, string_interaction

Structural data

PDB: 5 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
C3	P01024	75
CFH	P08603	51
CFHR2	P36980	4
CFI	P05156	2
CFHR1	Q03591	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CFHR5	Q9BXR6	83.76

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 6 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of Complement cascade	6	233.1×	5e-14	C3, CFHR5, CFH, CFI, CFHR1, CFHR2
Alternative complement activation	1	380.7×	0.013	C3
Activation of C3 and C5	1	211.5×	0.016	C3
Purinergic signaling in leishmaniasis infection	1	70.5×	0.035	C3
Post-translational protein phosphorylation	1	16.7×	0.096	C3
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	14.5×	0.096	C3
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	14.4×	0.096	C3
Peptide ligand-binding receptors	1	12.4×	0.098	C3
G alpha (i) signalling events	1	6.5×	0.160	C3
Neutrophil degranulation	1	3.9×	0.234	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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
complement activation	5	520.1×	2e-12	C3, CFHR5, CFH, CFHR1, CFHR2
obsolete cytolysis by host of symbiont cells	3	1053.2×	3e-08	CFHR5, CFHR1, CFHR2
complement activation, alternative pathway	3	495.6×	2e-07	C3, CFHR5, CFH
negative regulation of protein binding	3	312.1×	7e-07	CFHR5, CFHR1, CFHR2
complement activation, classical pathway	2	181.2×	4e-04	C3, CFI
regulation of triglyceride biosynthetic process	1	1404.3×	0.003	C3
regulation of complement activation, alternative pathway	1	1404.3×	0.003	CFH
complement-dependent cytotoxicity	1	1404.3×	0.003	C3
positive regulation of type IIa hypersensitivity	1	936.2×	0.003	C3
positive regulation of activation of membrane attack complex	1	936.2×	0.003	C3
oviduct epithelium development	1	936.2×	0.003	C3
vertebrate eye-specific patterning	1	936.2×	0.003	C3
complement-mediated synapse pruning	1	702.2×	0.004	C3
regulation of complement-dependent cytotoxicity	1	561.7×	0.005	CFH
positive regulation of apoptotic cell clearance	1	401.2×	0.006	C3
positive regulation of D-glucose transmembrane transport	1	351.1×	0.006	C3
regulation of complement activation	1	351.1×	0.006	CFH
positive regulation of lipid storage	1	234.1×	0.009	C3
positive regulation of phagocytosis, engulfment	1	216.1×	0.009	C3
complement activation, GZMK pathway	1	216.1×	0.009	C3
neuron remodeling	1	200.6×	0.009	C3
complement receptor mediated signaling pathway	1	187.2×	0.009	C3
positive regulation of G protein-coupled receptor signaling pathway	1	175.5×	0.009	C3
central nervous system myelination	1	165.2×	0.010	CFH
amyloid-beta clearance	1	156.0×	0.010	C3
positive regulation of receptor-mediated endocytosis	1	133.8×	0.011	C3
inflammatory response	2	12.6×	0.014	C3, CFH
positive regulation of vascular endothelial growth factor production	1	82.6×	0.016	C3
proteolysis	2	11.4×	0.016	CFH, CFI
B cell activation	1	75.9×	0.017	C3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 2 of 6 evidence-associated genes (33%) 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
CFHR5	0	0
CFH	0	0
CFI	0	0
CFHR1	0	0
CFHR2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
C3	15	Binding:15
CFH	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
C3	3.4.21.47	alternative-complement-pathway C3/C5 convertase
CFI	3.4.21.45	complement factor I

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	5	C3, CFH, CFI, CFHR1, CFHR2
D	Druggable family + AlphaFold only, no drug	1	CFHR5
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
C3	15	—
CFHR5	0	—
CFH	1	—
CFI	0	—
CFHR1	0	—
CFHR2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 11.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	6
PHASE3	2
Not specified	2
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05809531	PHASE3	ACTIVE_NOT_RECRUITING	An Open-Label, Nonrandomized, Multicenter Extension Study to Evaluate the Long-term Safety and Efficacy of Pegcetacoplan in Participants With C3 Glomerulopathy or Immune-Complex Membranoproliferative Glomerulonephritis
NCT05067127	PHASE3	COMPLETED	Phase III Study Assessing the Efficacy and Safety of Pegcetacoplan in Patients With C3 Glomerulopathy or Immune-Complex Membranoproliferative Glomerulonephritis
NCT04183101	PHASE2	RECRUITING	Evaluation of a Renin Inhibitor, Aliskiren, Compared to Enalapril, in C3 Glomerulopathy
NCT03124368	PHASE2	COMPLETED	A Proof-of-Mechanism Study to Determine the Effect of Danicopan on C3 Levels in Participants With C3G or IC-MPGN
NCT03369236	PHASE2	COMPLETED	A Proof-of-Concept Study of Danicopan for 6 Months of Treatment in Participants With C3 Glomerulopathy (C3G)
NCT03453619	PHASE2	COMPLETED	Phase II Study Assessing Safety and Efficacy of APL-2 in Glomerulopathies
NCT03459443	PHASE2	TERMINATED	A Proof of Concept Study for a 12 Month Treatment in Patients With C3G or IC-MPGN Treated With ACH-0144471
NCT04572854	PHASE2	COMPLETED	Study Assessing the Safety and Efficacy of Pegcetacoplan in Post-Transplant Recurrence of C3G or IC-MPGN
NCT01791686	PHASE1	TERMINATED	Clinical Trial of CDX-1135 in Pediatric and Adult Patients With Dense Deposit Disease
NCT03723512	Not specified	COMPLETED	Non-contrast Enhanced MRI in Patients With C3 Glomerulopathy (C3G) or Immune-complex Membranoproliferative Glomerulonephritis (IC-MPGN) Enrolled in the ACH471-205 Study
NCT04729062	Not specified	APPROVED_FOR_MARKETING	C3G/Primary IC-MPGN EAP

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PEGCETACOPLAN	4	5
DANICOPAN	4	3
ENALAPRIL	4	3
ALISKIREN	4	1
CDX-1135	1	1