Focal segmental glomerulosclerosis

Summary

Focal segmental glomerulosclerosis (MONDO:0100313) is a disease with 67 cohort genes (15 GWAS associations across 2 studies) and 76 clinical trials. The dominant Reactome pathway is Laminin interactions (6 cohort genes). Top therapeutic interventions include sparsentan, corticotropin, and irbesartan.

At a glance

• Cohort genes: 67
• GWAS associations: 15
• ClinVar variants: 280
• Clinical trials: 76

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	focal segmental glomerulosclerosis
Mondo ID	MONDO:0100313
EFO	EFO:0004236
MeSH	D005923
DOID	DOID:1312
NCIT	C37308
SNOMED CT	236403004
UMLS	C0017668
MedGen	4904
GARD	0006517
Is cancer (heuristic)	no

Also known as: FGS (focal glomerular sclerosis) · FSGS · FSGS - focal segmental glomerulosclerosis

Data availability: 280 ClinVar variants · 15 GWAS associations (2 studies) · 2 GenCC gene-disease records · 45 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › urinary system disorder › kidney disorder › glomerular disorder › glomerulosclerosis › focal segmental glomerulosclerosis

Related subtypes (1): renal fibrosis

Subtypes (2): inherited focal segmental glomerulosclerosis, primary focal segmental glomerulosclerosis

Genetics & variants

GWAS landscape

15 GWAS associations across 2 studies. Top hits map to 15 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs2239785	5e-13	APOL1	G
rs5732	7e-08	SCNN1G	G	10.8
rs28730852	1e-07	ALMS1	C	8.05
rs13377246	3e-07	OR4X2 - OR4X1	A	9.8
rs11595844	4e-07	CCDC7	C	6.29
rs73885319	9e-07	APOL1	G	3.25
rs78195097	1e-06	OR6R1P	T	3.99
rs4832089	2e-06	DNAH6	G	8.55
rs138243974	2e-06	GPATCH1	G	8.79
rs148306592	2e-06	PPCS, CCDC30	T	8.62
rs540401032	3e-06	GRB2	G	6.6
rs1966265	4e-06	FGFR4	A	3.21
rs76086051	7e-06	KCNK6	G	3.47
rs10941934	8e-06	CDH12	T	2.41
rs114924943	8e-06	REC8, IPO4	G	7.72

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST000741	Genovese G	2010	56	1,759	A risk allele for focal segmental glomerulosclerosis in African Americans is located within a region containing APOL1 and MYH9.
GCST90134617	Durand A	2022	31	0	Identification of Novel Genetic Risk Factors for Focal Segmental Glomerulosclerosis in Children: Results From the Chronic Kidney Disease in Children (CKiD) Cohort.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	6
Tier 2: splice/UTR	2
Tier 3: regulatory	0
Tier 4: intronic/intergenic	7

MAF distribution

Bucket	Variants
common (>=0.05)	4
low_freq (0.01-0.05)	2
rare (<0.01)	9
unknown	0

Functional consequences

Consequence	Count
missense_variant	6
intron_variant	5
5_prime_UTR_variant	1
intergenic_variant	1
non_coding_transcript_exon_variant	1
3_prime_UTR_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs2239785	22	36265284	G>A,C	0.36	missense_variant	APOL1	5e-13	Tier 1: coding
rs5732	16	23186241	A>G	0	5_prime_UTR_variant	SCNN1G	7e-08	Tier 2: splice/UTR
rs28730852	2	73449720	T>C,G	0	missense_variant	ALMS1	1e-07	Tier 1: coding
rs13377246	11	48247599	T>A	0	intergenic_variant	OR4X2 - OR4X1	3e-07	Tier 4: intronic/intergenic
rs11595844	10	32685527	T>C	0	intron_variant	CCDC7	4e-07	Tier 4: intronic/intergenic
rs73885319	22	36265860	A>G	0.029	missense_variant	APOL1	9e-07	Tier 1: coding
rs78195097	1	247834216	C>T	0.04	non_coding_transcript_exon_variant	OR6R1P	1e-06	Tier 4: intronic/intergenic
rs4832089	2	84528925	G>A,C,T	0	missense_variant	DNAH6	2e-06	Tier 1: coding
rs138243974	19	33121580	A>G	0.01	intron_variant	GPATCH1	2e-06	Tier 4: intronic/intergenic
rs148306592	1	42465563	C>T	0	intron_variant	PPCS, CCDC30	2e-06	Tier 4: intronic/intergenic
rs540401032	17	75319464	T>G	0.009	3_prime_UTR_variant	GRB2	3e-06	Tier 2: splice/UTR
rs1966265	5	177089630	G>A,C,T	0.121	missense_variant	FGFR4	4e-06	Tier 1: coding
rs76086051	19	38320822	T>G	0.118	intron_variant	KCNK6	7e-06	Tier 4: intronic/intergenic
rs10941934	5	22119867	C>T	0.209	intron_variant	CDH12	8e-06	Tier 4: intronic/intergenic
rs114924943	14	24180740	C>G,T	0	missense_variant	REC8, IPO4	8e-06	Tier 1: coding

ClinVar germline variants

280 retrieved; paginated sample, class counts are floors:

68 benign/likely benign, 61 conflicting classifications of pathogenicity, 54 uncertain significance, 37 benign, 19 likely pathogenic, 19 pathogenic, 14 pathogenic/likely pathogenic, 5 likely benign, 3 conflicting classifications of pathogenicity; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
1210364	NM_031885.5(BBS2):c.1725del (p.Phe575fs)	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1449282	NM_000091.5(COL4A3):c.1671dup (p.Leu558fs)	COL4A3	Pathogenic	criteria provided, multiple submitters, no conflicts
397514	NM_000091.5(COL4A3):c.2371C>T (p.Arg791Ter)	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4819378	NM_000092.5(COL4A4):c.2590G>C (p.Gly864Arg)	COL4A4	Pathogenic	criteria provided, single submitter
562421	NM_000092.5(COL4A4):c.3109_3110del (p.Leu1037fs)	COL4A4	Pathogenic	criteria provided, multiple submitters, no conflicts
945738	NM_000092.5(COL4A4):c.1220del (p.Pro407fs)	COL4A4	Pathogenic	criteria provided, multiple submitters, no conflicts
964465	NM_000092.5(COL4A4):c.3704del (p.Pro1235fs)	COL4A4	Pathogenic	criteria provided, multiple submitters, no conflicts
844422	NM_033380.3(COL4A5):c.1815del (p.Asn607fs)	COL4A5	Pathogenic	criteria provided, multiple submitters, no conflicts
217590	NM_001384732.1(CPLANE1):c.1819del (p.Tyr607fs)	CPLANE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
567531	NM_001384732.1(CPLANE1):c.8425del (p.Thr2809fs)	CPLANE1	Pathogenic	criteria provided, multiple submitters, no conflicts
1344641	NM_022489.4(INF2):c.542T>G (p.Val181Gly)	INF2	Pathogenic	no assertion criteria provided
523533	NM_022489.4(INF2):c.658G>A (p.Glu220Lys)	INF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2444244	NM_000214.3(JAG1):c.1713del (p.Cys572fs)	JAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1339205	NM_004646.4(NPHS1):c.2600G>A (p.Gly867Asp)	NPHS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188761	NM_004646.4(NPHS1):c.2928G>T (p.Arg976Ser)	NPHS1	Pathogenic	criteria provided, multiple submitters, no conflicts
56421	NM_004646.4(NPHS1):c.1099C>T (p.Arg367Cys)	NPHS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188823	NM_014625.4(NPHS2):c.855_856del (p.Arg286fs)	NPHS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4819379	NM_014625.4(NPHS2):c.102del (p.Gly35fs)	NPHS2	Pathogenic	criteria provided, single submitter
5361	NM_014625.4(NPHS2):c.412C>T (p.Arg138Ter)	NPHS2	Pathogenic	criteria provided, multiple submitters, no conflicts
556556	NM_014625.4(NPHS2):c.714G>T (p.Arg238Ser)	NPHS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
156297	NM_000278.5(PAX2):c.76dup (p.Val26fs)	PAX2	Pathogenic	criteria provided, multiple submitters, no conflicts
635085	NM_016341.4(PLCE1):c.4978_4981del (p.Gln1660fs)	PLCE1-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7706	NM_000303.3(PMM2):c.422G>A (p.Arg141His)	PMM2	Pathogenic	criteria provided, multiple submitters, no conflicts
374208	NM_014140.4(SMARCAL1):c.723C>A (p.Cys241Ter)	SMARCAL1	Pathogenic	criteria provided, multiple submitters, no conflicts
4171	NM_014140.4(SMARCAL1):c.2542G>T (p.Glu848Ter)	SMARCAL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1189048	NM_030912.3(TRIM8):c.1380T>A (p.Tyr460Ter)	TRIM8	Pathogenic/Likely pathogenic	no assertion criteria provided
1189050	NM_030912.3(TRIM8):c.1163del (p.Phe388fs)	TRIM8	Pathogenic/Likely pathogenic	no assertion criteria provided
1189052	NM_030912.3(TRIM8):c.1231C>T (p.Gln411Ter)	TRIM8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1189054	NM_030912.3(TRIM8):c.1333C>T (p.Gln445Ter)	TRIM8	Pathogenic/Likely pathogenic	no assertion criteria provided
1344829	NM_030912.3(TRIM8):c.1240C>T (p.Gln414Ter)	TRIM8	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 133 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 2

Dual-evidence genes (GWAS + Mendelian — highest-confidence targets)

Gene	HGNC	Evidence routes
APOL1	APOL1	GWAS, Orphanet
MYH9	MYH9	GWAS, Orphanet

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
RCAN1	Moderate	Autosomal dominant	focal segmental glomerulosclerosis
SYNPO	Limited	Autosomal dominant	focal segmental glomerulosclerosis

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
APOL1	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
MYH9	Orphanet:182050	MYH9-related syndromic thrombocytopenia
MYH9	Orphanet:477742	Nodular fasciitis
MYH9	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
CFB	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality
SDCCAG8	Orphanet:110	Bardet-Biedl syndrome
SDCCAG8	Orphanet:3156	Senior-Loken syndrome
SLC17A5	Orphanet:309324	Free sialic acid storage disease, infantile form
SLC17A5	Orphanet:309331	Intermediate severe Salla disease
SLC17A5	Orphanet:309334	Salla disease
SMARCAL1	Orphanet:1830	Schimke immuno-osseous dysplasia
TRPC6	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
C2	Orphanet:169147	Immunodeficiency due to a classical component pathway complement deficiency
WT1	Orphanet:220	Denys-Drash syndrome
WT1	Orphanet:242	46,XY complete gonadal dysgenesis
WT1	Orphanet:251510	46,XY partial gonadal dysgenesis
WT1	Orphanet:3097	Meacham syndrome
WT1	Orphanet:347	Frasier syndrome
WT1	Orphanet:654	Nephroblastoma
WT1	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
WT1	Orphanet:83469	Desmoplastic small round cell tumor
WT1	Orphanet:893	WAGR syndrome
C3	Orphanet:280133	Complement component 3 deficiency
C3	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality
NPHS2	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
CD2AP	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
TRIM8	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
NLRP3	Orphanet:1451	CINCA syndrome
NLRP3	Orphanet:47045	Familial cold urticaria
NLRP3	Orphanet:575	Muckle-Wells syndrome
NLRP3	Orphanet:647815	Keratitis fugax hereditaria
ACTN4	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
SCARB2	Orphanet:163696	Action myoclonus-renal failure syndrome
SCARB2	Orphanet:308	Progressive myoclonic epilepsy type 1
SCARB2	Orphanet:77259	Gaucher disease type 1
PLCE1	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
PMPCA	Orphanet:1170	Autosomal recessive cerebelloparenchymal disorder type 3
CRB2	Orphanet:443988	Ventriculomegaly-cystic kidney disease
CRB2	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
BBS7	Orphanet:110	Bardet-Biedl syndrome
COQ8B	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
COQ8B	Orphanet:791	Retinitis pigmentosa
NPHP4	Orphanet:3156	Senior-Loken syndrome
NPHP4	Orphanet:93592	Juvenile nephronophthisis
INPP5E	Orphanet:1454	Joubert syndrome with hepatic defect
INPP5E	Orphanet:220493	Joubert syndrome with ocular defect
INPP5E	Orphanet:475	Isolated Joubert syndrome
INPP5E	Orphanet:75858	MORM syndrome
COL4A3	Orphanet:653722	Digenic Alport syndrome
COL4A3	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome

Cohort genes → proteins

67 cohort genes, 64 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_and_clinvar	2
multi_evidence	65

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
APOL1	HGNC:618	ENSG00000100342	O14791	Apolipoprotein L1	gwas,clinvar
MYH9	HGNC:7579	ENSG00000100345	P35579	Myosin-9	gwas,clinvar
RCAN1	HGNC:3040	ENSG00000159200	P53805	Calcipressin-1	gencc
SYNPO	HGNC:30672	ENSG00000171992	Q8N3V7	Synaptopodin	gencc
CFB	HGNC:1037	ENSG00000243649	P00751	Complement factor B	clinvar
SDCCAG8	HGNC:10671	ENSG00000054282	Q86SQ7	Serologically defined colon cancer antigen 8	clinvar
SLC17A5	HGNC:10933	ENSG00000119899	Q9NRA2	Sialin	clinvar
SMARCAL1	HGNC:11102	ENSG00000138375	Q9NZC9	SNF2 related chromatin remodeling annealing helicase 1	clinvar
TRPC6	HGNC:12338	ENSG00000137672	Q9Y210	Short transient receptor potential channel 6	clinvar
C2	HGNC:1248	ENSG00000166278	P06681	Complement C2	clinvar
WT1	HGNC:12796	ENSG00000184937	P19544	Wilms tumor protein	clinvar
C3	HGNC:1318	ENSG00000125730	P01024	Complement C3	clinvar
NPHS2	HGNC:13394	ENSG00000116218	Q9NP85	Podocin	clinvar
CD2AP	HGNC:14258	ENSG00000198087	Q9Y5K6	CD2-associated protein	clinvar
TRIM8	HGNC:15579	ENSG00000171206	Q9BZR9	E3 ubiquitin-protein ligase TRIM8	clinvar
NLRP3	HGNC:16400	ENSG00000162711	Q96P20	NACHT, LRR and PYD domains-containing protein 3	clinvar
ACTN4	HGNC:166	ENSG00000130402	O43707	Alpha-actinin-4	clinvar
SCARB2	HGNC:1665	ENSG00000138760	Q14108	Lysosome membrane protein 2	clinvar
PLCE1	HGNC:17175	ENSG00000138193	Q9P212	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1	clinvar
PMPCA	HGNC:18667	ENSG00000165688	Q10713	Mitochondrial-processing peptidase subunit alpha	clinvar
CRB2	HGNC:18688	ENSG00000148204	Q5IJ48	Protein crumbs homolog 2	clinvar
BBS7	HGNC:18758	ENSG00000138686	Q8IWZ6	BBSome complex member BBS7	clinvar
KIRREL2	HGNC:18816	ENSG00000126259	Q6UWL6	Kin of IRRE-like protein 2	clinvar
COQ8B	HGNC:19041	ENSG00000123815	Q96D53	Atypical kinase COQ8B, mitochondrial	clinvar
NPHP4	HGNC:19104	ENSG00000131697	O75161	Nephrocystin-4	clinvar
INPP5E	HGNC:21474	ENSG00000148384	Q9NRR6	Phosphatidylinositol polyphosphate 5-phosphatase type IV	clinvar
COL4A3	HGNC:2204	ENSG00000169031	Q01955	Collagen alpha-3(IV) chain	clinvar
COL4A4	HGNC:2206	ENSG00000081052	P53420	Collagen alpha-4(IV) chain	clinvar
COL4A5	HGNC:2207	ENSG00000188153	P29400	Collagen alpha-5(IV) chain	clinvar
PDSS2	HGNC:23041	ENSG00000164494	Q86YH6	All trans-polyprenyl-diphosphate synthase PDSS2	clinvar
INF2	HGNC:23791	ENSG00000203485	Q27J81	Inverted formin-2	clinvar
NOC3L	HGNC:24034	ENSG00000173145	Q8WTT2	Nucleolar complex protein 3 homolog	clinvar
COQ2	HGNC:25223	ENSG00000173085	Q96H96	4-hydroxybenzoate polyprenyltransferase, mitochondrial	clinvar
ARHGAP24	HGNC:25361	ENSG00000138639	Q8N264	Rho GTPase-activating protein 24	clinvar
CUBN	HGNC:2548	ENSG00000107611	O60494	Cubilin	clinvar
TCTN2	HGNC:25774	ENSG00000168778	Q96GX1	Tectonic-2	clinvar
CPLANE1	HGNC:25801	ENSG00000197603	Q9H799	Ciliogenesis and planar polarity effector 1	clinvar
AXDND1	HGNC:26564	ENSG00000162779	Q5T1B0	Axonemal dynein light chain domain-containing protein 1	clinvar
DGKE	HGNC:2852	ENSG00000153933	P52429	Diacylglycerol kinase epsilon	clinvar
NUP93	HGNC:28958	ENSG00000102900	Q8N1F7	Nuclear pore complex protein Nup93	clinvar
CEP290	HGNC:29021	ENSG00000198707	O15078	Centrosomal protein of 290 kDa	clinvar
RPGRIP1L	HGNC:29168	ENSG00000103494	Q68CZ1	Protein fantom	clinvar
ALG13	HGNC:30881	ENSG00000101901	Q9NP73	UDP-N-acetylglucosamine transferase subunit ALG13	clinvar
EEF2KMT	HGNC:32221	ENSG00000118894	Q96G04	Protein-lysine N-methyltransferase EEF2KMT	clinvar
EYA1	HGNC:3519	ENSG00000104313	Q99502	Protein phosphatase EYA1	clinvar
MFF-DT	HGNC:41067	ENSG00000236432		MFF divergent transcript	clinvar
PLCE1-AS1	HGNC:45193	ENSG00000268894		PLCE1 antisense RNA 1	clinvar
NPHP3-ACAD11	HGNC:48351	ENSG00000274810		NPHP3-ACAD11 readthrough (NMD candidate)	clinvar
CFH	HGNC:4883	ENSG00000000971	P08603	Complement factor H	clinvar
CFI	HGNC:5394	ENSG00000205403	P05156	Complement factor I	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
APOL1	Apolipoprotein L1	May play a role in lipid exchange and transport throughout the body.
MYH9	Myosin-9	Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping.
RCAN1	Calcipressin-1	Inhibits calcineurin-dependent transcriptional responses by binding to the catalytic domain of calcineurin A.
SYNPO	Synaptopodin	Actin-associated protein that may play a role in modulating actin-based shape and motility of dendritic spines and renal podocyte foot processes.
CFB	Complement factor B	Precursor of the catalytic component of the C3 and C5 convertase complexes of the alternative pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the…
SDCCAG8	Serologically defined colon cancer antigen 8	Plays a role in the establishment of cell polarity and epithelial lumen formation.
SLC17A5	Sialin	Multifunctional anion transporter that operates via two distinct transport mechanisms, namely proton-coupled anion cotransport and membrane potential-dependent anion transport.
SMARCAL1	SNF2 related chromatin remodeling annealing helicase 1	ATP-dependent annealing helicase that binds selectively to fork DNA relative to ssDNA or dsDNA and catalyzes the rewinding of the stably unwound DNA.
TRPC6	Short transient receptor potential channel 6	Forms a receptor-activated non-selective calcium permeant cation channel.
C2	Complement C2	Precursor of the catalytic component of the C3 and C5 convertase complexes, which are part of the complement pathway, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive i…
WT1	Wilms tumor protein	Transcription factor that plays an important role in cellular development and cell survival.
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…
NPHS2	Podocin	Plays a role in the regulation of glomerular permeability, acting probably as a linker between the plasma membrane and the cytoskeleton.
CD2AP	CD2-associated protein	Seems to act as an adapter protein between membrane proteins and the actin cytoskeleton.
TRIM8	E3 ubiquitin-protein ligase TRIM8	E3 ubiquitin-protein ligase that participates in multiple biological processes including cell survival, differentiation, apoptosis, and in particular, the innate immune response.
NLRP3	NACHT, LRR and PYD domains-containing protein 3	Sensor component of the NLRP3 inflammasome, which mediates inflammasome activation in response to defects in membrane integrity, leading to secretion of inflammatory cytokines IL1B and IL18 and pyroptosis.
ACTN4	Alpha-actinin-4	F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures.
SCARB2	Lysosome membrane protein 2	Acts as a lysosomal receptor for glucosylceramidase (GBA1) targeting.
PLCE1	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1	The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes.
PMPCA	Mitochondrial-processing peptidase subunit alpha	Substrate recognition and binding subunit of the essential mitochondrial processing protease (MPP), which cleaves the mitochondrial sequence off newly imported precursors proteins.
CRB2	Protein crumbs homolog 2	Apical polarity protein that plays a central role during the epithelial-to-mesenchymal transition (EMT) at gastrulation, when newly specified mesodermal cells move inside the embryo.
BBS7	BBSome complex member BBS7	The BBSome complex is thought to function as a coat complex required for sorting of specific membrane proteins to the primary cilia.
KIRREL2	Kin of IRRE-like protein 2	May regulate basal insulin secretion.
COQ8B	Atypical kinase COQ8B, mitochondrial	Atypical kinase involved in the biosynthesis of coenzyme Q, also named ubiquinone, an essential lipid-soluble electron transporter for aerobic cellular respiration.
NPHP4	Nephrocystin-4	Involved in the organization of apical junctions; the function is proposed to implicate a NPHP1-4-8 module.
INPP5E	Phosphatidylinositol polyphosphate 5-phosphatase type IV	Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3), phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol 3,5-bispho…
COL4A3	Collagen alpha-3(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
COL4A4	Collagen alpha-4(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
COL4A5	Collagen alpha-5(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
PDSS2	All trans-polyprenyl-diphosphate synthase PDSS2	Heterotetrameric enzyme that catalyzes the condensation of farnesyl diphosphate (FPP), which acts as a primer, and isopentenyl diphosphate (IPP) to produce prenyl diphosphates of varying chain lengths and participates in the determination…
INF2	Inverted formin-2	Severs actin filaments and accelerates their polymerization and depolymerization.
NOC3L	Nucleolar complex protein 3 homolog	May be required for adipogenesis.
COQ2	4-hydroxybenzoate polyprenyltransferase, mitochondrial	Mediates the second step in the final reaction sequence of coenzyme Q (CoQ) biosynthesis.
ARHGAP24	Rho GTPase-activating protein 24	Rho GTPase-activating protein involved in cell polarity, cell morphology and cytoskeletal organization.
CUBN	Cubilin	Endocytic receptor which plays a role in lipoprotein, vitamin and iron metabolism by facilitating their uptake.
TCTN2	Tectonic-2	Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes.
CPLANE1	Ciliogenesis and planar polarity effector 1	Involved in ciliogenesis.
AXDND1	Axonemal dynein light chain domain-containing protein 1	May be essential for spermiogenesis and male fertility probably by regulating the manchette dynamics, spermatid head shaping and sperm flagellum assembly.
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.
NUP93	Nuclear pore complex protein Nup93	Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance.
CEP290	Centrosomal protein of 290 kDa	Involved in early and late steps in cilia formation.
RPGRIP1L	Protein fantom	Negatively regulates signaling through the G-protein coupled thromboxane A2 receptor (TBXA2R).
ALG13	UDP-N-acetylglucosamine transferase subunit ALG13	Catalytic subunit of the UDP-N-acetylglucosamine transferase complex that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
EEF2KMT	Protein-lysine N-methyltransferase EEF2KMT	Catalyzes the trimethylation of eukaryotic elongation factor 2 (EEF2) on ‘Lys-525’.
EYA1	Protein phosphatase EYA1	Functions both as protein phosphatase and as transcriptional coactivator for SIX1, and probably also for SIX2, SIX4 and SIX5.
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.
ITGB4	Integrin beta-4	Integrin alpha-6/beta-4 is a receptor for laminin.
JAG1	Protein jagged-1	Ligand for multiple Notch receptors and involved in the mediation of Notch signaling.
LAMA5	Laminin subunit alpha-5	Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.

Protein-family classification

Druggable: 20 · Difficult: 11 · Unknown: 36 · Druggable fraction: 0.3

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	8.0×	0.286
Protease	4	2.2×	0.405
Scaffold/PPI	7	1.8×	0.405
Phosphatase	2	2.5×	0.523
Ion channel	1	1.7×	0.771
Antibody/Immunoglobulin	3	1.3×	0.771
Transporter	1	1.2×	0.771
Other/Unknown	36	1.0×	0.771
Enzyme (other)	5	0.9×	0.771
Kinase	2	0.8×	0.771
Transcription factor	4	0.5×	0.969

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
APOL1	Other/Unknown	no		ApoL
MYH9	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail
RCAN1	Other/Unknown	no		Calcipressin, Nucleotide-bd_a/b_plait_sf, RCAN1_RRM
SYNPO	Other/Unknown	no		Synaptopodin_domain
CFB	Protease	yes	3.4.21.47	Sushi_SCR_CCP_dom, Trypsin_dom, Peptidase_S1A
SDCCAG8	Other/Unknown	no		SDCCAG8
SLC17A5	Transporter	yes		MFS, MFS_dom, MFS_trans_sf
SMARCAL1	Other/Unknown	no		SNF2_N, Helicase_C-like, HARP_dom
TRPC6	Ion channel	yes		Ankyrin_rpt, TRPC_channel, TRPC6_channel
C2	Protease	yes		Sushi_SCR_CCP_dom, Trypsin_dom, Peptidase_S1A
WT1	Transcription factor	no		Wilms_tumour_N, Znf_C2H2_type, Znf_C2H2_sf
C3	Complement	yes	3.4.21.47	Anaphylatoxin/fibulin, Netrin_domain, Macroglobln_a2
NPHS2	Other/Unknown	no		Band_7, Stomatin_HflK_fam, Band_7/stomatin-like_CS
CD2AP	Scaffold/PPI	no		SH3_domain, CD2AP_SH3_1, CD2AP_SH_2
TRIM8	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_CS
NLRP3	Other/Unknown	no		Leu-rich_rpt, DAPIN, NACHT_NTPase
ACTN4	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
SCARB2	Other/Unknown	no		CD36_fam, LimpII
PLCE1	Enzyme (other)	yes	3.1.4.11	C2_dom, RA_dom, PLipase_C_PInositol-sp_X_dom
PMPCA	Protease	yes	3.4.24.64	Pept_M16_Zn_BS, Peptidase_M16_C, Metalloenz_LuxS/M16
CRB2	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Laminin_G
BBS7	Scaffold/PPI	no		WD40/YVTN_repeat-like_dom_sf, Bardet-Biedl_syndrome_7_prot, WD40_repeat_dom_sf
KIRREL2	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
COQ8B	Kinase	yes		ABC1_dom, Kinase-like_dom_sf, ADCK3_dom
NPHP4	Other/Unknown	no		NPHP4, Ig_NPHP4_4th, Ig_NPHP4_3rd
INPP5E	Enzyme (other)	yes	3.1.3.36	IPPc, Endo/exonu/phosph_ase_sf, INPP5E
COL4A3	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
COL4A4	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
COL4A5	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
PDSS2	Enzyme (other)	yes	2.5.1.91	Polyprenyl_synt, Isoprenoid_synthase_dom_sf
INF2	Other/Unknown	no		WH2_dom, FH3_dom, GTPase-bd
NOC3L	Other/Unknown	no		CCAAT-binding_factor, Noc3_N, ARM-type_fold
COQ2	Enzyme (other)	yes	2.5.1.39	UbiA_prenyltransferase, HB_polyprenyltransferase-like, UbiA_prenylTrfase_CS
ARHGAP24	Scaffold/PPI	no		RhoGAP_dom, PH_domain, Rho_GTPase_activation_prot
CUBN	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, CUB_dom
TCTN2	Other/Unknown	no		TCTN1-3_dom, TCTN1-3, TCTN1-3_N
CPLANE1	Scaffold/PPI	no		CPLANE1, WD40_repeat_dom_sf
AXDND1	Other/Unknown	no		Axonemal_dynein_light_chain, Axonemal_dynein_LC_domain
DGKE	Kinase	yes	2.7.1.107	Diacylglycerol_kin_accessory, Diacylglycerol_kinase_cat_dom, PKC_DAG/PE
NUP93	Other/Unknown	no		Nucleoporin_int_Nup93/Nic96
CEP290	Other/Unknown	no		Cep290, Cep209_CC5
RPGRIP1L	Other/Unknown	no		C2_dom, C2-C2_1, RPGRIP1_fam
ALG13	Other/Unknown	no		Tudor, OTU_dom, Glyco_trans_28_C
EEF2KMT	Other/Unknown	no		Methyltransf_16, SAM-dependent_MTases_sf, FAM86_N
EYA1	Other/Unknown	no		EYA_dom, EYA, EYA_dom_sf
MFF-DT	Other/Unknown	no
PLCE1-AS1	Other/Unknown	no
NPHP3-ACAD11	Other/Unknown	no
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

Expression context

Cohort genes with no expression data: 0.

62 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)	67
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	11
calcaneal tendon	9
right uterine tube	7
right lobe of liver	6
ventricular zone	6
primordial germ cell in gonad	5
metanephric glomerulus	5
renal glomerulus	5
stromal cell of endometrium	4
sural nerve	4
germinal epithelium of ovary	4
body of pancreas	4
metanephros cortex	4
buccal mucosa cell	4
liver	3
apex of heart	3
adrenal tissue	3
secondary oocyte	3
renal medulla	3
sperm	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
APOL1	252	ubiquitous	marker	gall bladder, right lobe of liver, liver
MYH9	279	ubiquitous	marker	stromal cell of endometrium, ascending aorta, thoracic aorta
RCAN1	300	ubiquitous	marker	cortical plate, cranial nerve II, cartilage tissue
SYNPO	291	ubiquitous	marker	hindlimb stylopod muscle, apex of heart, descending thoracic aorta
CFB	134	broad	marker	right lobe of liver, liver, gall bladder
SDCCAG8	134	ubiquitous	marker	corpus callosum, calcaneal tendon, thyroid gland
SLC17A5	264	ubiquitous	marker	corpus epididymis, stromal cell of endometrium, mucosa of sigmoid colon
SMARCAL1	264	ubiquitous	marker	primordial germ cell in gonad, stromal cell of endometrium, sural nerve
TRPC6	180	broad	marker	right lung, lower esophagus muscularis layer, lower esophagus
C2	138	ubiquitous	marker	liver, right lobe of liver, placenta
WT1	168	broad	marker	germinal epithelium of ovary, renal glomerulus, metanephric glomerulus
C3	289	ubiquitous	marker	parietal pleura, right lobe of liver, palpebral conjunctiva
NPHS2	47	tissue_specific	marker	renal glomerulus, metanephric glomerulus, kidney epithelium
CD2AP	275	ubiquitous	marker	jejunal mucosa, esophagus squamous epithelium, colonic mucosa
TRIM8	292	ubiquitous	marker	endothelial cell, nasal cavity epithelium, medial globus pallidus
NLRP3	172	broad	marker	monocyte, mononuclear cell, leukocyte
ACTN4	145	ubiquitous	marker	popliteal artery, tibial artery, smooth muscle tissue
SCARB2	298	ubiquitous	marker	inferior vagus X ganglion, subthalamic nucleus, germinal epithelium of ovary
PLCE1	271	broad	marker	renal glomerulus, metanephric glomerulus, ventricular zone
PMPCA	276	ubiquitous	marker	right lobe of liver, adrenal tissue, apex of heart
CRB2	99	broad	marker	ventricular zone, ganglionic eminence, male germ line stem cell (sensu Vertebrata) in testis
BBS7	262	ubiquitous	marker	endothelial cell, calcaneal tendon, lateral nuclear group of thalamus
KIRREL2	97	tissue_specific	marker	body of pancreas, pancreas, left ventricle myocardium
COQ8B	227	ubiquitous	marker	right uterine tube, adenohypophysis, pituitary gland
NPHP4	165	ubiquitous	marker	right uterine tube, adenohypophysis, right lobe of thyroid gland
INPP5E	279	ubiquitous	yes	right uterine tube, secondary oocyte, oocyte
COL4A3	233	broad	marker	skeletal muscle tissue of biceps brachii, pigmented layer of retina, retina
COL4A4	187	broad	marker	renal medulla, metanephros cortex, pigmented layer of retina
COL4A5	267	ubiquitous	marker	mucosa of stomach, ventricular zone, lower esophagus muscularis layer
PDSS2	256	ubiquitous	marker	buccal mucosa cell, nephron tubule, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 137.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYH9	5,533
SCARB2	5,405
JAG1	4,405
WT1	3,938
NLRP3	3,797
PMPCA	3,679
ACTN4	3,303
C3	3,199
NOC3L	3,036
NUP93	3,031

Intra-cohort edges

A	B	Sources
ACTN4	CD2AP	string_interaction
ACTN4	INF2	string_interaction
ACTN4	MYH9	biogrid_interaction, string_interaction
ACTN4	NPHS1	string_interaction
ACTN4	NPHS2	string_interaction
ACTN4	PLCE1	string_interaction
ACTN4	PODXL	string_interaction
ACTN4	PTPRO	string_interaction
ACTN4	SYNPO	biogrid_interaction, string_interaction
ACTN4	TRPC6	string_interaction
APOL1	CD2AP	string_interaction
APOL1	INF2	string_interaction
APOL1	MYH9	string_interaction
APOL1	NPHS1	string_interaction
APOL1	NPHS2	string_interaction
APOL1	PLCE1	string_interaction
APOL1	TRPC6	string_interaction
ARHGAP24	INF2	string_interaction
ARHGAP24	NPHS1	string_interaction
ARHGAP24	NPHS2	string_interaction
ARHGAP24	NXF5	string_interaction
BBS2	BBS7	biogrid_interaction, intact, string_interaction
BBS2	CEP290	string_interaction
BBS2	PAX2	intact
BBS7	INPP5E	string_interaction
BBS7	PAX2	intact
C2	C3	string_interaction
C2	CFH	string_interaction
C2	CFI	string_interaction
C3	CFB	intact, string_interaction
C3	CFH	biogrid_interaction, intact, string_interaction
C3	CFI	biogrid_interaction, intact, string_interaction
C3	EYA1	biogrid_interaction
CD2AP	INF2	string_interaction
CD2AP	LAMB2	string_interaction
CD2AP	NPHS1	string_interaction
CD2AP	NPHS2	biogrid_interaction, string_interaction
CD2AP	PLCE1	string_interaction
CD2AP	PTPRO	string_interaction
CD2AP	RPGRIP1L	biogrid_interaction
CD2AP	SYNPO	string_interaction
CD2AP	TRPC6	string_interaction
CEP290	INPP5E	string_interaction
CEP290	NPHP1	string_interaction
CEP290	NPHP3	string_interaction
CEP290	NPHP4	string_interaction
CEP290	RPGRIP1L	string_interaction
CEP290	SDCCAG8	string_interaction
CEP290	TCTN2	string_interaction
CFB	CFI	string_interaction

Structural data

PDB: 38 · AlphaFold-only: 26 · No structure: 3

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
C3	P01024	75
CFH	P08603	51
WT1	P19544	28
CFB	P00751	26
NLRP3	Q96P20	24
C2	P06681	14
ITGB4	P16144	13
CD2AP	Q9Y5K6	12
SCARB2	Q14108	10
INF2	Q27J81	10
MYH9	P35579	8
SLC17A5	Q9NRA2	7
NUP93	Q8N1F7	7
JAG1	P78504	7
PMM2	O15305	7
TRPC6	Q9Y210	6
APOL1	O14791	5
ACTN4	O43707	5
NOC3L	Q8WTT2	4
PLCE1	Q9P212	3
COL4A3	Q01955	2
COL4A4	P53420	2
COL4A5	P29400	2
CUBN	O60494	2
CFI	P05156	2
LAMA5	O15230	2
NPHP1	O15259	2
PTPRO	Q16827	2
PTPRU	Q92729	2
REG1A	P05451	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BBS7	Q8IWZ6	92.99
BBS2	Q9BXC9	89.49
PMPCA	Q10713	88.46
DGKE	P52429	86.18
COQ2	Q96H96	85.64
PDSS2	Q86YH6	80.28
SDCCAG8	Q86SQ7	78.67
COQ8B	Q96D53	77.00
NXF5	Q9H1B4	76.63
LAMB2	P55268	75.94
KIRREL2	Q6UWL6	75.30
NPHS2	Q9NP85	75.00
TCTN2	Q96GX1	74.71
NPHP4	O75161	72.44
TRIM8	Q9BZR9	72.26
AXDND1	Q5T1B0	70.90
LMX1B	O60663	70.79
ARHGAP24	Q8N264	66.68
EYA1	Q99502	66.68
PAX2	Q02962	61.52
CEP290	O15078	60.90
MYO9A	B2RTY4	58.07
ALG13	Q9NP73	54.42
PODXL	O00592	53.66
SYNPO	Q8N3V7	50.70
CPLANE1	Q9H799

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 235. Enrichment computed across 67 evidence-associated genes (53 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 53 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Laminin interactions	6	43.1×	1e-06	COL4A3, COL4A4, COL4A5, ITGB4, LAMA5, LAMB2
Attachment of bacteria to epithelial cells	5	46.8×	6e-06	COL4A3, COL4A4, COL4A5, LAMA5, LAMB2
Nephrin family interactions	5	44.9×	6e-06	NPHS2, CD2AP, ACTN4, KIRREL2, NPHS1
Non-integrin membrane-ECM interactions	6	17.5×	6e-05	COL4A3, COL4A4, COL4A5, ITGB4, LAMA5, LAMB2
Regulation of Complement cascade	5	22.0×	1e-04	CFB, C2, C3, CFH, CFI
Activation of C3 and C5	3	71.8×	2e-04	CFB, C2, C3
Anchoring of the basal body to the plasma membrane	6	12.8×	2e-04	SDCCAG8, NPHP4, TCTN2, CEP290, RPGRIP1L, NPHP1
Cilium Assembly	6	12.3×	2e-04	SDCCAG8, BBS7, INPP5E, TCTN2, CEP290, BBS2
Ubiquinol biosynthesis	3	49.7×	6e-04	COQ8B, PDSS2, COQ2
Nephron development	3	49.7×	6e-04	WT1, JAG1, PAX2
ECM proteoglycans	5	14.2×	6e-04	COL4A3, COL4A4, COL4A5, LAMA5, LAMB2
Anchoring fibril formation	3	43.1×	8e-04	COL4A3, COL4A4, COL4A5
Fibronectin matrix formation	3	32.3×	0.002	COL4A3, COL4A4, COL4A5
Crosslinking of collagen fibrils	3	32.3×	0.002	COL4A3, COL4A4, COL4A5
Assembly of collagen fibrils and other multimeric structures	4	15.1×	0.002	COL4A3, COL4A4, COL4A5, ITGB4
Organelle biogenesis and maintenance	6	7.5×	0.002	SDCCAG8, BBS7, INPP5E, TCTN2, CEP290, BBS2
Alternative complement activation	2	86.2×	0.003	CFB, C3
Cell-Cell communication	4	10.4×	0.008	CD2AP, ACTN4, KIRREL2, ITGB4
Collagen chain trimerization	3	14.7×	0.013	COL4A3, COL4A4, COL4A5
Signaling by PDGF	3	14.4×	0.013	COL4A3, COL4A4, COL4A5
NCAM1 interactions	3	14.1×	0.013	COL4A3, COL4A4, COL4A5
Cargo trafficking to the periciliary membrane	3	14.1×	0.013	BBS7, INPP5E, BBS2
MET promotes cell motility	2	22.7×	0.034	LAMA5, LAMB2
Collagen degradation	3	9.9×	0.034	COL4A3, COL4A4, COL4A5
Collagen biosynthesis and modifying enzymes	3	9.7×	0.034	COL4A3, COL4A4, COL4A5
Defective PMM2 causes PMM2-CDG	1	215.5×	0.040	PMM2
Defective SLC17A5 causes Salla disease (SD) and ISSD	1	215.5×	0.040	SLC17A5
BBSome-mediated cargo-targeting to cilium	2	18.7×	0.041	BBS7, BBS2
Formation of the ureteric bud	2	18.7×	0.041	EYA1, PAX2
Effects of PIP2 hydrolysis	2	17.2×	0.046	TRPC6, DGKE

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 64 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glomerular basement membrane development	4	95.8×	4e-05	WT1, COL4A3, COL4A4, NPHS1
complement activation	4	39.0×	5e-04	CFB, C2, C3, CFH
non-motile cilium assembly	5	22.7×	5e-04	BBS7, CEP290, RPGRIP1L, NPHP3, BBS2
cilium assembly	8	9.2×	5e-04	BBS7, INPP5E, TCTN2, CPLANE1, CEP290, LAMA5, NPHP3, BBS2
slit diaphragm assembly	2	263.3×	1e-03	NPHS1, PTPRO
metanephric podocyte development	2	263.3×	1e-03	NPHS2, LAMB2
podocyte development	3	71.8×	1e-03	JAG1, NPHS1, PODXL
podocyte differentiation	3	65.8×	1e-03	WT1, CD2AP, PTPRO
glomerulus development	3	60.8×	1e-03	WT1, PLCE1, PTPRO
response to bacterium	5	15.1×	0.001	CFB, SLC17A5, C2, C3, CUBN
branching involved in ureteric bud morphogenesis	4	22.9×	0.001	WT1, EYA1, LAMA5, PAX2
photoreceptor cell maintenance	4	22.4×	0.001	CRB2, NPHP4, NPHP3, BBS2
complement activation, alternative pathway	3	46.5×	0.002	CFB, C3, CFH
ubiquinone biosynthetic process	3	43.9×	0.002	COQ8B, PDSS2, COQ2
metanephric epithelium development	2	105.3×	0.006	WT1, PAX2
visual perception	6	7.5×	0.006	CRB2, BBS7, LAMB2, MYO9A, PAX2, BBS2
visual behavior	2	87.8×	0.007	NPHP4, NPHP1
ureter development	2	87.8×	0.007	NPHP3, PAX2
complement activation, classical pathway	3	25.5×	0.007	C2, C3, CFI
pronephros development	2	75.2×	0.008	CEP290, PAX2
metanephric mesenchyme development	2	75.2×	0.008	WT1, PAX2
protein localization to ciliary transition zone	2	75.2×	0.008	NPHP4, TCTN2
positive regulation of apoptotic cell clearance	2	75.2×	0.008	C2, C3
mesodermal cell fate specification	2	65.8×	0.010	EYA1, PAX2
cell-cell adhesion	5	7.9×	0.010	KIRREL2, NPHP4, ITGB4, NPHP1, NPHS1
isoprenoid biosynthetic process	2	52.7×	0.014	PDSS2, COQ2
positive regulation of bicellular tight junction assembly	2	52.7×	0.014	NPHP4, NPHP1
mesenchymal to epithelial transition	2	47.9×	0.016	WT1, PAX2
camera-type eye development	3	16.8×	0.016	WT1, CEP290, PAX2
collagen-activated tyrosine kinase receptor signaling pathway	2	40.5×	0.021	COL4A3, COL4A5

Therapeutics

Drugs indicated for this disease

0 approved, 8 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Chlorambucil	Phase 3 (in late-stage trials)
Corticotropin	Phase 3 (in late-stage trials)
Cyclosporine	Phase 3 (in late-stage trials)
Dexamethasone	Phase 3 (in late-stage trials)
Irbesartan	Phase 3 (in late-stage trials)
Mycophenolate Mofetil	Phase 3 (in late-stage trials)
Prednisolone	Phase 3 (in late-stage trials)
Sparsentan	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Adalimumab, Atorvastatin, Basiliximab, Galactose, Isotretinoin, Lisinopril Anhydrous, Losartan, Losmapimod, Obinutuzumab, Pirfenidone, Prednisone, Rituximab, Sirolimus, Tacrolimus Anhydrous, Voclosporin.

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 4 · Phased (≥1): 8 · Undrugged: 59

Druggability breadth: 27 of 67 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CFB	IPTACOPAN
NLRP3	CLOMIPHENE
COQ8B	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NLRP3	11	4
COQ8B	9	4
MYH9	1	2
CFB	1	4
TRPC6	1	2
ACTN4	1	2
NUP93	1	2
PMM2	1	3
APOL1	0	0
RCAN1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IPTACOPAN	4	CFB
CLOMIPHENE	4	NLRP3
GLYBURIDE	4	NLRP3
FEDRATINIB	4	COQ8B
VANDETANIB	4	COQ8B
ERLOTINIB	4	COQ8B
CRIZOTINIB	4	COQ8B
CURCUMIN	3	NLRP3
JT-001	3	NLRP3
CANERTINIB	3	COQ8B
EBSELEN	3	PMM2
MOLIBRESIB	2	ACTN4, MYH9, NUP93
CLEMIZOLE	2	TRPC6
TRICLOCARBAN	2	NLRP3
CLIOXANIDE	2	NLRP3
DAPANSUTRILE	2	NLRP3
USNOFLAST	2	NLRP3
TG100-115	2	COQ8B
R-406	2	COQ8B
PELITINIB	2	COQ8B
INZOMELID	1	NLRP3
BMS-986299	1	NLRP3
NT-0796	1	NLRP3
BMS-387032	1	COQ8B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 12.

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

Symbol	Assays	Type breakdown
NLRP3	534	Binding:527, Functional:6, ADMET:1
COQ8B	77	Binding:77
CFB	33	Binding:33
TRPC6	30	Binding:30
C3	15	Binding:15
SLC17A5	14	Binding:14
MYH9	10	Binding:10
ACTN4	7	Binding:7
NUP93	7	Binding:7
PTPRO	7	Binding:7
APOL1	4	Binding:4
C2	4	Binding:4
PMM2	3	Binding:3
ITGB4	2	Binding:2
CD2AP	1	Binding:1
PMPCA	1	Binding:1
INF2	1	Binding:1
DGKE	1	Binding:1
CFH	1	Binding:1
JAG1	1	Binding:1
PAX2	1	Binding:1
PTPRU	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CFB	3.4.21.47	alternative-complement-pathway C3/C5 convertase
C3	3.4.21.47	alternative-complement-pathway C3/C5 convertase
PLCE1	3.1.4.11	phosphoinositide phospholipase C
PMPCA	3.4.24.64	mitochondrial processing peptidase
INPP5E	3.1.3.36	phosphoinositide 5-phosphatase
PDSS2	2.5.1.91	all-trans-decaprenyl-diphosphate synthase
COQ2	2.5.1.39	4-hydroxybenzoate polyprenyltransferase
DGKE	2.7.1.107	diacylglycerol kinase (ATP)
CFI	3.4.21.45	complement factor I
PMM2	5.4.2.8	phosphomannomutase
PTPRO	3.1.3.48	protein-tyrosine-phosphatase
PTPRU	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
NLRP3	534

Pharmacogenomics

Cohort genes with a PharmGKB record: 64; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

24 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.

Compound	Max phase	Cohort target (bioactivity)
IPTACOPAN	4	CFB
CLOMIPHENE	4	NLRP3
GLYBURIDE	4	NLRP3
FEDRATINIB	4	COQ8B
VANDETANIB	4	COQ8B
ERLOTINIB	4	COQ8B
CRIZOTINIB	4	COQ8B
CURCUMIN	3	NLRP3
JT-001	3	NLRP3
CANERTINIB	3	COQ8B
EBSELEN	3	PMM2
MOLIBRESIB	2	ACTN4, MYH9, NUP93
CLEMIZOLE	2	TRPC6
TRICLOCARBAN	2	NLRP3
CLIOXANIDE	2	NLRP3
DAPANSUTRILE	2	NLRP3
USNOFLAST	2	NLRP3
TG100-115	2	COQ8B
R-406	2	COQ8B
PELITINIB	2	COQ8B
INZOMELID	1	NLRP3
BMS-986299	1	NLRP3
NT-0796	1	NLRP3
BMS-387032	1	COQ8B

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	CFB, NLRP3, COQ8B
B	Phased (≥1) drug, not yet approved	5	MYH9, TRPC6, ACTN4, NUP93, PMM2
C	Druggable family + PDB, no drug	11	SLC17A5, C2, C3, PLCE1, INPP5E, CFH, CFI, ITGB4, NPHS1, PTPRO (+1 more)
D	Druggable family + AlphaFold only, no drug	5	PMPCA, KIRREL2, PDSS2, COQ2, DGKE
E	Difficult family or no structure, no drug	43	APOL1, RCAN1, SYNPO, SDCCAG8, SMARCAL1, WT1, NPHS2, CD2AP, TRIM8, SCARB2 (+33 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
APOL1	4	MYH9
SYNPO	0	ACTN4
C3	15	CFB
NPHS2	0	TRPC6
PLCE1	0	TRPC6
COL4A4	0	MYH9
INF2	1	ACTN4
DGKE	1	CFB
CFI	0	CFB
RCAN1	0	—
SDCCAG8	0	—
SLC17A5	14	—
SMARCAL1	0	—
C2	4	—
WT1	0	—
CD2AP	1	—
TRIM8	0	—
SCARB2	0	—
PMPCA	1	—
CRB2	0	—
BBS7	0	—
KIRREL2	0	—
NPHP4	0	—
INPP5E	0	—
COL4A3	0	—
COL4A5	0	—
PDSS2	0	—
NOC3L	0	—
COQ2	0	—
ARHGAP24	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 76.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	28
PHASE2	20
PHASE1	10
PHASE3	6
PHASE4	5
PHASE2/PHASE3	3
PHASE1/PHASE2	3
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07219121	PHASE4	RECRUITING	Sparsentan in Posttransplant Immunoglobulin A Nephropathy or Focal Segmental Glomerulosclerosis
NCT01129557	PHASE4	TERMINATED	Aldosterone Breakthrough During Diovan, Tekturna, and Combination Therapy in Patients With Proteinuric Kidney Disease
NCT02399462	PHASE4	WITHDRAWN	Acthar for Treatment of Post-transplant FSGS
NCT02585804	PHASE4	COMPLETED	Treating to Reduce Albuminuria and Normalize Hemodynamic Function in Focal ScLerosis With dApagliflozin Trial Effects
NCT02633046	PHASE4	COMPLETED	Acthar for Treatment-Resistant or Treatment-Intolerant Proteinuria
NCT05183646	PHASE3	RECRUITING	A Study of the Efficacy and Safety of DMX-200 in Patients With FSGS Who Are Receiving an ARB
NCT07213960	PHASE2/PHASE3	NOT_YET_RECRUITING	A Sequential Phase 2/3 Study of APL2 in Patients With Focal Segmental Glomerulosclerosis
NCT07220083	PHASE3	RECRUITING	A Study to Find Out if BI 764198 Helps Adults and Adolescents With a Kidney Condition Called Focal Segmental Glomerulosclerosis (FSGS)
NCT07499700	PHASE2/PHASE3	RECRUITING	A Clinical Study of BAT4406F Injection in Patients With Minimal Change Disease/Focal Segmental Glomerulosclerosis
NCT01164098	PHASE3	TERMINATED	Rituximab to Prevent Recurrence of Proteinuria
NCT02683889	PHASE3	COMPLETED	Use of Acthar in Patients With FSGS That Will be Undergoing Renal Transplantation
NCT02896270	PHASE2/PHASE3	UNKNOWN	Valproic Acid for Idiopathic Nephrotic Syndrome
NCT03298698	PHASE3	UNKNOWN	Efficacy of Rituximab in Comparison to Continued Corticosteroid Treatment in Idiopathic Nephrotic Syndrome
NCT03493685	PHASE3	COMPLETED	Study of Sparsentan in Patients With Primary Focal Segmental Glomerulosclerosis (FSGS)
NCT04573920	PHASE2	ACTIVE_NOT_RECRUITING	Atrasentan in Patients With Proteinuric Glomerular Diseases
NCT05003986	PHASE2	RECRUITING	Study of Sparsentan Treatment in Pediatrics With Proteinuric Glomerular Diseases
NCT05508009	PHASE1/PHASE2	RECRUITING	Early Trial of Allogeneic Hematopoietic Stem Cell Transplantation for Patients Who Will Receive a Kidney Transplant From the Same Donor
NCT06090227	PHASE1/PHASE2	RECRUITING	AMPK-activation by Metformin in FSGS: AMP-FSGS
NCT06500702	PHASE2	RECRUITING	A Study to Evaluate the Efficacy and Safety of Frexalimab, Brivekimig, or Rilzabrutinib in Participants Aged 16 to 75 Years With Primary Focal Segmental Glomerulosclerosis or Minimal Change Disease
NCT06664814	PHASE2	RECRUITING	An Open-Label Phase 2 Study of N-Acetyl-D-Mannosamine (ManNAc) in Subjects With Primary Focal Segmental Glomerulosclerosis
NCT06983028	PHASE2	RECRUITING	Atacicept in Multiple Glomerular Diseases
NCT07268638	PHASE2	RECRUITING	A Study of Praliciguat in Participants With Focal Segmental Glomerulosclerosis (FSGS)
NCT07614477	PHASE2	RECRUITING	Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of EVER001 in Participants With Selected Proteinuric Glomerular Diseases
NCT00007475	PHASE1/PHASE2	COMPLETED	Permeability Factor in Focal Segmental Glomerulosclerosis
NCT00550342	PHASE2	WITHDRAWN	Rituximab Treatment of Focal Segmental Glomerulosclerosis
NCT00814255	PHASE2	COMPLETED	Novel Therapies for Resistant FSGS (FONTII): Phase II Clinical Trial
NCT01613118	PHASE2	COMPLETED	Randomized, Double-Blind, Safety and Efficacy Study of RE-021 (Sparsentan) in Focal Segmental Glomerulosclerosis
NCT02592798	PHASE2	COMPLETED	Pilot Study to Evaluate the Safety and Efficacy of Abatacept in Adults and Children 6 Years and Older With Excessive Loss of Protein in the Urine Due to Either Focal Segmental Glomerulosclerosis (FSGS) or Minimal Change Disease (MCD)
NCT03366337	PHASE2	COMPLETED	A Phase 2 Trial of the Safety and Efficacy of Bardoxolone Methyl in Patients With Rare Chronic Kidney Diseases - PHOENIX
NCT03448692	PHASE2	TERMINATED	A Study to Evaluate PF-06730512 in Adults With Focal Segmental Glomerulosclerosis (FSGS)
NCT03536754	PHASE2	COMPLETED	A Study of CCX140-B in Subjects With FSGS
NCT03598036	PHASE2	TERMINATED	Dose-Exploration Evaluating the Efficacy and Safety of Voclosporin in Subjects With Focal Segmental Glomerulosclerosis
NCT03649152	PHASE2	COMPLETED	Safety and Effectiveness of Propagermanium in Focal Segmental Glomerulosclerosis Participants Receiving Irbesartan
NCT03703908	PHASE2	TERMINATED	A Study of CCX140-B in Subjects With Primary FSGS and Nephrotic Syndrome
NCT04009668	PHASE2	COMPLETED	Tumor Necrosis Factor Inhibition in Focal Segmental Glomerulosclerosis and Treatment Resistant Minimal Change Disease
NCT05267262	PHASE2	COMPLETED	Study to Evaluate R3R01 in Patients With Alport Syndrome and Patients With Focal Segmental Glomerulosclerosis
NCT05441826	PHASE2	TERMINATED	Efficacy and Safety of VB119 in Subjects With Minimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS)
NCT05942625	PHASE1	RECRUITING	A First in Human Study to Evaluate Safety, Tolerability, Pharmacology of HS-10390 in Healthy Subjects
NCT07267026	PHASE1	RECRUITING	A Study to Evaluate the Safety, Tolerability and PK of SK-09
NCT00464321	PHASE1	COMPLETED	Safety Study of GC1008 in Patients With Focal Segmental Glomerulosclerosis (FSGS) of Single Doses of GC1008 in Patients With Treatment Resistant Idiopathic FSGS

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SPARSENTAN	4	4
CORTICOTROPIN	4	3
IRBESARTAN	4	2
ALISKIREN	4	1
DAPAGLIFLOZIN	4	1
DEXTROSE	4	1
VALPROIC ACID	4	1
VALSARTAN	4	1
VOCLOSPORIN	4	1
GALACTOSE	3	4
ATACICEPT	3	1
ATRASENTAN	3	1
BARDOXOLONE METHYL	3	1
FREXALIMAB	3	1
PAMREVLUMAB	3	1
RILZABRUTINIB	3	1
ILACIRNON	2	2
BRIVEKIMIG	2	1
BUDOPRUTUG	2	1
FRESOLIMUMAB	2	1
INAXAPLIN	2	1
N-ACETYLMANNOSAMINE	2	1
PRALICIGUAT	2	1
PROPAGERMANIUM	2	1
CHEMBL115622	0	1
CHEMBL4281478	0	1
CHEMBL4460360	0	1
CHEMBL5205741	0	1
D-GALACTOSE	0	1