Membranoproliferative glomerulonephritis

Summary

Membranoproliferative glomerulonephritis (MONDO:0002461) is a disease with 3 cohort genes (1 GWAS associations across 1 studies) and 12 clinical trials. Top therapeutic interventions include pegcetacoplan, enalapril, and eculizumab.

At a glance

• Cohort genes: 3
• GWAS associations: 1
• ClinVar variants: 30
• Clinical trials: 12

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	membranoproliferative glomerulonephritis
Mondo ID	MONDO:0002461
MeSH	D015432
DOID	DOID:2920
NCIT	C34644
SNOMED CT	80321008
UMLS	C0017662
MedGen	9033
GARD	0023141
Is cancer (heuristic)	no

Also known as: membranoproliferative glomerulonephritis · membranoproliferative glomerulonephritis (disease)

Data availability: 30 ClinVar variants · 1 GWAS association (1 study) · 1 HPO phenotype.

Disease family

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

Related subtypes (19): acute poststreptococcal glomerulonephritis, exudative glomerulonephritis, proliferative glomerulonephritis, focal embolic glomerulonephritis, anti-basement membrane glomerulonephritis, diffuse glomerulonephritis, subacute glomerulonephritis, mesangial proliferative glomerulonephritis, immune-complex glomerulonephritis, IgA glomerulonephritis, membranous glomerulonephritis, lupus nephritis, minimal change disease, granulomatosis with polyangiitis, rapidly progressive glomerulonephritis, primary membranoproliferative glomerulonephritis, Pauci-immune glomerulonephritis, immunotactoid glomerulopathy, autoimmune glomerulonephritis

Genetics & variants

GWAS landscape

1 GWAS associations across 1 studies. Top hits map to 0 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs35406322	3e-08		CG	1.93

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90627781	Levine AP	2020	146	6,442	Large-Scale Whole-Genome Sequencing Reveals the Genetic Architecture of Primary Membranoproliferative GN and C3 Glomerulopathy.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	1

MAF distribution

Bucket	Variants
common (>=0.05)	1
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
unknown	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs35406322				0.36			3e-08	Tier 4: intronic/intergenic

ClinVar germline variants

30 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 4 benign, 3 pathogenic, 2 conflicting classifications of pathogenicity, 2 pathogenic, low penetrance, 1 pathogenic/likely pathogenic, 1 likely pathogenic, low penetrance, 1 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1322206	NM_003647.3(DGKE):c.1068_1071del (p.Asn356fs)	DGKE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
135641	NM_003647.3(DGKE):c.966G>A (p.Trp322Ter)	DGKE	Pathogenic	criteria provided, multiple submitters, no conflicts
39578	NM_003647.3(DGKE):c.127C>T (p.Gln43Ter)	DGKE	Pathogenic	criteria provided, single submitter
39580	NM_003647.3(DGKE):c.889-2A>G	DGKE	Pathogenic	criteria provided, single submitter
4280373	NM_003647.3(DGKE):c.1282_1284+18del	DGKE	Pathogenic, low penetrance	criteria provided, single submitter
4280375	NM_003647.3(DGKE):c.1303C>T (p.Arg435Ter)	DGKE	Pathogenic, low penetrance	criteria provided, single submitter
813262	Single allele	CFH	Likely pathogenic	no assertion criteria provided
4280358	NM_003647.3(DGKE):c.490C>T (p.His164Tyr)	DGKE	Likely pathogenic, low penetrance	criteria provided, single submitter
289334	NM_003647.3(DGKE):c.1679A>G (p.Gln560Arg)	DGKE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
290120	NM_003647.3(DGKE):c.35C>T (p.Pro12Leu)	DGKE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
812882	NM_000064.4(C3):c.3085G>A (p.Asp1029Asn)	C3	Uncertain significance	criteria provided, single submitter
1297633	NM_003647.3(DGKE):c.851G>A (p.Gly284Glu)	DGKE	Uncertain significance	criteria provided, single submitter
2046511	NM_003647.3(DGKE):c.318C>G (p.Phe106Leu)	DGKE	Uncertain significance	criteria provided, multiple submitters, no conflicts
2376306	NM_003647.3(DGKE):c.562C>A (p.Pro188Thr)	DGKE	Uncertain significance	criteria provided, multiple submitters, no conflicts
4280349	NM_003647.3(DGKE):c.236A>C (p.Gln79Pro)	DGKE	Uncertain significance	criteria provided, single submitter
4280352	NM_003647.3(DGKE):c.323G>A (p.Cys108Tyr)	DGKE	Uncertain significance	criteria provided, single submitter
4280353	NM_003647.3(DGKE):c.325A>G (p.Lys109Glu)	DGKE	Uncertain significance	criteria provided, single submitter
4280359	NM_003647.3(DGKE):c.494A>G (p.Asp165Gly)	DGKE	Uncertain significance	criteria provided, single submitter
4280362	NM_003647.3(DGKE):c.654C>T (p.Thr218=)	DGKE	Uncertain significance	criteria provided, single submitter
4280366	NM_003647.3(DGKE):c.793A>C (p.Thr265Pro)	DGKE	Uncertain significance	criteria provided, single submitter
4280368	NM_003647.3(DGKE):c.889-37T>A	DGKE	Uncertain significance	criteria provided, single submitter
4280370	NM_003647.3(DGKE):c.994G>C (p.Val332Leu)	DGKE	Uncertain significance	criteria provided, single submitter
4280376	NM_003647.3(DGKE):c.1420G>A (p.Asp474Asn)	DGKE	Uncertain significance	criteria provided, single submitter
4280378	NM_003647.3(DGKE):c.1442G>C (p.Gly481Ala)	DGKE	Uncertain significance	criteria provided, single submitter
4280383	NM_003647.3(DGKE):c.1597A>C (p.Thr533Pro)	DGKE	Uncertain significance	criteria provided, single submitter
1235190	NM_003647.3(DGKE):c.183G>A (p.Gly61=)	DGKE	Benign	criteria provided, multiple submitters, no conflicts
1280501	NM_003647.3(DGKE):c.888+55AT[9]	DGKE	Benign	criteria provided, multiple submitters, no conflicts
259116	NM_003647.3(DGKE):c.579A>C (p.Thr193=)	DGKE	Benign	criteria provided, multiple submitters, no conflicts
4280374	NM_003647.3(DGKE):c.1284+151A>G	DGKE	Benign	criteria provided, single submitter
783790	NM_003647.3(DGKE):c.59G>A (p.Gly20Glu)	DGKE	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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
DGKE	Orphanet:329903	Immunoglobulin-mediated membranoproliferative glomerulonephritis
DGKE	Orphanet:357008	Hemolytic uremic syndrome with DGKE deficiency
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

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
C3	HGNC:1318	ENSG00000125730	P01024	Complement C3	clinvar
DGKE	HGNC:2852	ENSG00000153933	P52429	Diacylglycerol kinase epsilon	clinvar
CFH	HGNC:4883	ENSG00000000971	P08603	Complement factor H	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…
DGKE	Diacylglycerol kinase epsilon	Membrane-bound diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids.
CFH	Complement factor H	Glycoprotein that plays an essential role in maintaining a well-balanced immune response by modulating complement activation.

Protein-family classification

Druggable: 3 · 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	178.7×	8e-05
Kinase	1	9.2×	0.104

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
C3	Complement	yes	3.4.21.47	Anaphylatoxin/fibulin, Netrin_domain, Macroglobln_a2
DGKE	Kinase	yes	2.7.1.107	Diacylglycerol_kin_accessory, Diacylglycerol_kinase_cat_dom, PKC_DAG/PE
CFH	Complement	yes		Sushi_SCR_CCP_dom, Sushi/SCR/CCP_sf, ComplSys_Reg/VirEntry_Med

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
palpebral conjunctiva	1
parietal pleura	1
right lobe of liver	1
Brodmann (1909) area 23	1
buccal mucosa cell	1
middle temporal gyrus	1
calcaneal tendon	1
right coronary artery	1
urethra	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
DGKE	250	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, buccal mucosa cell
CFH	267	ubiquitous	marker	urethra, calcaneal tendon, right coronary artery

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
C3	3,199
CFH	1,844
DGKE	1,045

Intra-cohort edges

A	B	Sources
C3	CFH	biogrid_interaction, intact, string_interaction
CFH	DGKE	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
C3	P01024	75
CFH	P08603	51

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DGKE	P52429	86.18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 3 evidence-associated genes (3 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 3 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	155.4×	6e-04	C3, CFH
Alternative complement activation	1	761.3×	0.007	C3
Activation of C3 and C5	1	423.0×	0.009	C3
Effects of PIP2 hydrolysis	1	152.3×	0.016	DGKE
Purinergic signaling in leishmaniasis infection	1	141.0×	0.016	C3
Post-translational protein phosphorylation	1	33.4×	0.047	C3
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	29.1×	0.047	C3
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	28.8×	0.047	C3
Peptide ligand-binding receptors	1	24.7×	0.049	C3
G alpha (i) signalling events	1	13.0×	0.083	C3
Neutrophil degranulation	1	7.7×	0.124	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 3 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, alternative pathway	2	660.9×	1e-04	C3, CFH
complement activation	2	416.1×	2e-04	C3, CFH
regulation of triglyceride biosynthetic process	1	2808.7×	0.003	C3
regulation of complement activation, alternative pathway	1	2808.7×	0.003	CFH
complement-dependent cytotoxicity	1	2808.7×	0.003	C3
positive regulation of type IIa hypersensitivity	1	1872.4×	0.003	C3
positive regulation of activation of membrane attack complex	1	1872.4×	0.003	C3
oviduct epithelium development	1	1872.4×	0.003	C3
vertebrate eye-specific patterning	1	1872.4×	0.003	C3
complement-mediated synapse pruning	1	1404.3×	0.003	C3
regulation of complement-dependent cytotoxicity	1	1123.5×	0.004	CFH
positive regulation of apoptotic cell clearance	1	802.5×	0.004	C3
positive regulation of D-glucose transmembrane transport	1	702.2×	0.004	C3
regulation of complement activation	1	702.2×	0.004	CFH
glycerolipid metabolic process	1	702.2×	0.004	DGKE
lipid phosphorylation	1	561.7×	0.005	DGKE
positive regulation of lipid storage	1	468.1×	0.005	C3
positive regulation of phagocytosis, engulfment	1	432.1×	0.005	C3
complement activation, GZMK pathway	1	432.1×	0.005	C3
neuron remodeling	1	401.2×	0.005	C3
diacylglycerol metabolic process	1	401.2×	0.005	DGKE
inflammatory response	2	25.1×	0.005	C3, CFH
complement receptor mediated signaling pathway	1	374.5×	0.005	C3
positive regulation of G protein-coupled receptor signaling pathway	1	351.1×	0.005	C3
central nervous system myelination	1	330.4×	0.005	CFH
amyloid-beta clearance	1	312.1×	0.005	C3
positive regulation of receptor-mediated endocytosis	1	267.5×	0.006	C3
complement activation, classical pathway	1	181.2×	0.009	C3
phosphatidic acid biosynthetic process	1	170.2×	0.009	DGKE
positive regulation of vascular endothelial growth factor production	1	165.2×	0.009	C3

Therapeutics

Drugs indicated for this disease

0 approved, 3 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Cyclosporine	Phase 3 (in late-stage trials)
Iptacopan	Phase 3 (in late-stage trials)
Rituximab	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Danicopan, Daratumumab, Eculizumab, Pegcetacoplan.

Drug target analysis

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

Druggability breadth: 3 of 3 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
DGKE	0	0
CFH	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
DGKE	1	Binding:1
CFH	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
C3	3.4.21.47	alternative-complement-pathway C3/C5 convertase
DGKE	2.7.1.107	diacylglycerol kinase (ATP)

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	C3, CFH
D	Druggable family + AlphaFold only, no drug	1	DGKE
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
C3	15	—
DGKE	1	—
CFH	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 12.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	4
Not specified	4
PHASE3	3
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
NCT03180723	PHASE3	UNKNOWN	Effect of Rituximab in Treatment of 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
NCT02093533	PHASE2	COMPLETED	Eculizumab in Primary MPGN
NCT03095118	PHASE2	COMPLETED	Daratumumab in Treatment of PGNMID and C3 GN
NCT04572854	PHASE2	COMPLETED	Study Assessing the Safety and Efficacy of Pegcetacoplan in Post-Transplant Recurrence of C3G or IC-MPGN
NCT01221181	PHASE1	COMPLETED	Eculizumab Therapy for Dense Deposit Disease and C3 Nephropathy
NCT05985122	Not specified	ACTIVE_NOT_RECRUITING	New Analytic Tools for aHUS and C3G Diagnosis
NCT05996731	Not specified	RECRUITING	Developing a Pipeline to Employ RNA-Seq as a Complementary Diagnostic Tool in Rare Diseases
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases
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	4
ENALAPRIL	4	3
ECULIZUMAB	4	2
DARATUMUMAB	4	1
RITUXIMAB	4	1