Complement 3 glomerulopathy

Summary

Complement 3 glomerulopathy (MONDO:0018013) is a disease with 2 cohort genes and 29 clinical trials. Top therapeutic interventions include iptacopan, pegcetacoplan, and danicopan.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 2
• Phenotypes (HPO): 23
• Clinical trials: 29

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.15	Europe	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0000790	Hematuria	Very frequent (80-99%)
HP:0000093	Proteinuria	Frequent (30-79%)
HP:0000793	Membranoproliferative glomerulonephritis	Frequent (30-79%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0003259	Elevated circulating creatinine concentration	Frequent (30-79%)
HP:0003774	Stage 5 chronic kidney disease	Frequent (30-79%)
HP:0005421	Decreased circulating complement C3 concentration	Frequent (30-79%)
HP:0012574	Mesangial hypercellularity	Frequent (30-79%)
HP:0012622	Chronic kidney disease	Frequent (30-79%)
HP:0025364	Extracapillary hypercellularity	Frequent (30-79%)
HP:0030888	C3 nephritic factor positivity	Frequent (30-79%)
HP:0031047	Paraproteinemia	Frequent (30-79%)
HP:0000100	Nephrotic syndrome	Occasional (5-29%)
HP:0000572	Visual loss	Occasional (5-29%)
HP:0001919	Acute kidney injury	Occasional (5-29%)
HP:0002719	Recurrent infections	Occasional (5-29%)
HP:0002960	Autoimmunity	Occasional (5-29%)
HP:0009125	Lipodystrophy	Occasional (5-29%)
HP:0011510	Drusen	Occasional (5-29%)
HP:0025567	Central serous chorioretinopathy	Occasional (5-29%)
HP:0030469	Abnormal dark-adapted electroretinogram	Occasional (5-29%)
HP:0030506	Yellow/white lesions of the retina	Occasional (5-29%)
HP:0045042	Decreased circulating complement C4 concentration	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	complement 3 glomerulopathy
Mondo ID	MONDO:0018013
Orphanet	329918
UMLS	C4087273
MedGen	1672497
GARD	0017507
Is cancer (heuristic)	no

Also known as: C3 glomerulopathy · C3G · non-Ig-mediated membranoproliferative glomerulonephritis · non-Ig-mediated MPGN · non-immunoglobulin-mediated membranoproliferative glomerulonephritis · non-immunoglobulin-mediated MPGN

Data availability: 2 ClinVar variants.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › urinary system disorder › kidney disorder › nephritis › glomerulonephritis › primary membranoproliferative glomerulonephritis › complement 3 glomerulopathy

Related subtypes (2): membranoproliferative glomerulonephritis, X-linked, immunoglobulin-mediated membranoproliferative glomerulonephritis

Subtypes (3): complement factor H deficiency, C3 glomerulonephritis, dense deposit disease

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

2 retrieved; paginated sample, class counts are floors:

1 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
294511	NM_000186.4(CFH):c.2867C>T (p.Thr956Met)	CFH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
773118	NM_005666.4(CFHR2):c.595G>T (p.Glu199Ter)	CFHR2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
CFHR2	Orphanet:329931	C3 glomerulonephritis

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CFH	HGNC:4883	ENSG00000000971	P08603	Complement factor H	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)
CFH	Complement factor H	Glycoprotein that plays an essential role in maintaining a well-balanced immune response by modulating complement activation.
CFHR2	Complement factor H-related protein 2	Involved in complement regulation.

Protein-family classification

Druggable: 2 · 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	2	268.0×	1e-05

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CFH	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.

2 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)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
right coronary artery	1
urethra	1
liver	1
parietal pleura	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CFH	267	ubiquitous	marker	urethra, calcaneal tendon, right coronary artery
CFHR2	139		marker	right lobe of liver, liver, parietal pleura

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CFH	1,844
CFHR2	396

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CFH	P08603	51
CFHR2	P36980	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 evidence-associated genes (2 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 2 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	2	233.1×	2e-05	CFH, CFHR2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 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	2	624.1×	2e-05	CFH, CFHR2
regulation of complement activation, alternative pathway	1	4213.0×	0.001	CFH
regulation of complement-dependent cytotoxicity	1	1685.2×	0.002	CFH
regulation of complement activation	1	1053.2×	0.002	CFH
obsolete cytolysis by host of symbiont cells	1	1053.2×	0.002	CFHR2
complement activation, alternative pathway	1	495.6×	0.003	CFH
central nervous system myelination	1	495.6×	0.003	CFH
negative regulation of protein binding	1	312.1×	0.004	CFHR2
inflammatory response	1	18.9×	0.058	CFH
proteolysis	1	17.1×	0.058	CFH

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CFH	0	0
CFHR2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CFH	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	CFH, CFHR2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CFH	1	—
CFHR2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 29.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	13
Not specified	9
PHASE3	4
PHASE1/PHASE2	2
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03955445	PHASE3	RECRUITING	Long-term Efficacy, Safety and Tolerability of Iptacopan in C3G or IC-MPGN
NCT04817618	PHASE3	RECRUITING	Study of Efficacy and Safety of Iptacopan in Patients With C3 Glomerulopathy.
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
NCT05647811	PHASE1/PHASE2	NOT_YET_RECRUITING	Study of NM8074 in Adult C3 Glomerulopathy Patients
NCT06209736	PHASE2	RECRUITING	Safety and Efficacy Study of OMS906 in Patients With C3G and ICGN
NCT06786338	PHASE2	NOT_YET_RECRUITING	A Study of SGB-9768 in Patients with Complement-mediated Kidney Diseases
NCT06989359	PHASE2	RECRUITING	Phase 2 Study of ADX-038 in Complement-Mediated Kidney Disease
NCT07522099	PHASE2	RECRUITING	Chinese Adults With Kidney Disease
NCT02682407	PHASE2	TERMINATED	Safety Study of IgAN, LN, MN, & C3 Glomerulopathy Including Dense Deposit Disease Treated With OMS721
NCT03124368	PHASE2	COMPLETED	A Proof-of-Mechanism Study to Determine the Effect of Danicopan on C3 Levels in Participants With C3G or IC-MPGN
NCT03301467	PHASE2	COMPLETED	Controlled Trial Evaluating Avacopan in C3 Glomerulopathy
NCT03369236	PHASE2	COMPLETED	A Proof-of-Concept Study of Danicopan for 6 Months of Treatment in Participants With C3 Glomerulopathy (C3G)
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
NCT05083364	PHASE1/PHASE2	COMPLETED	Study of ARO-C3 in Adult Healthy Volunteers and Patients With Complement Mediated Renal Disease
NCT05162066	PHASE2	TERMINATED	Study to Evaluate the Safety, Tolerability of BCX9930 in Participants With Either Complement 3 Glomerulopathy (C3G), Immunoglobulin A Nephropathy (IgAN), or Primary Membranous Nephropathy (PMN)
NCT06419205	PHASE2	WITHDRAWN	A Phase 2 Study to Evaluate the Safety, PD, PK, and Clinical Activity of ADX-097 in Participants With IgAN, LN or C3G
NCT07483827	PHASE1	RECRUITING	A Clinical Trial to Test the Safety, Tolerability, and How the Body Processes CPV-104 in Healthy People and Patients With C3-Glomerulopathy
NCT05222412	Not specified	AVAILABLE	Managed Access Programs for LNP023, Iptacopan
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases
NCT07029542	Not specified	RECRUITING	Home Reported Outcomes in C3G Study
NCT07156149	Not specified	RECRUITING	Fabhalta Capsules Specified Drug-use Survey
NCT07331259	Not specified	NOT_YET_RECRUITING	CHART-C3G/CLNP023B12011
NCT07416162	Not specified	NOT_YET_RECRUITING	A Study of Iptacopan in Korean Patients With Paroxysmal Nocturnal Hemoglobinuria or C3 Glomerulopathy
NCT07598448	Not specified	NOT_YET_RECRUITING	A Study of Complement 3 Glomerulopathy (C3G) Patients Treated With Iptacopan Through an Early Access Program in Spain
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
IPTACOPAN	4	4
PEGCETACOPLAN	4	4
DANICOPAN	4	3
ENALAPRIL	4	3
ALISKIREN	4	1
AVACOPAN	4	1
NARSOPLIMAB	3	1
TELITACICEPT	3	1
EBRIBAFUSP ALFA	2	1
RUXOPRUBART	2	1