Proteinuria

Summary

Proteinuria (MONDO:0003634) is a disease with 18 cohort genes and 137 clinical trials. The dominant Reactome pathway is Anchoring fibril formation (4 cohort genes). Top therapeutic interventions include losartan, enalapril, and aliskiren.

At a glance

• Cohort genes: 18
• ClinVar variants: 32
• Clinical trials: 137

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	proteinuria
Mondo ID	MONDO:0003634
MeSH	D011507
DOID	DOID:576
ICD-10-CM	R80
ICD-11	930895737
UMLS	C0033687
MedGen	10976
Is cancer (heuristic)	no

Data availability: 32 ClinVar variants.

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 › proteinuria

Related subtypes (56): renal hypertension, kidney failure, nephritis, impaired renal function disease, nephrocalcinosis, atheroembolism of kidney, renal artery disease, nephrosis, cystic kidney disease, anuria, stricture or kinking of ureter, renal infectious disease, diabetes insipidus, orthostatic proteinuria, kidney hypertrophy, chronic kidney disease, hydronephrosis, renal tubular transport disease, kidney cortex necrosis, kidney papillary necrosis, perinephritis, renal aminoaciduria, autosomal dominant progressive nephropathy with hypertension, nephrolithiasis, X-linked diffuse leiomyomatosis-Alport syndrome, tubulointerstitial nephritis and uveitis syndrome, distal renal tubular acidosis, oligomeganephronia, duplication of urethra, renal tubular dysgenesis, exstrophy-epispadias complex, fetal lower urinary tract obstruction, IgG4-related kidney disease, congenital primary megaureter, renal nutcracker syndrome, renal hypoplasia, renal dysplasia, congenital megacalycosis, glomerular disorder, congenital renal artery stenosis, kidney neoplasm, renal tubule disorder, pyonephrosis, Arnold stickler bourne syndrome, C1q nephropathy, hypertensive nephropathy, atypical Fanconi syndrome-neonatal hyperinsulinism syndrome, idiopathic non-lupus full-house nephropathy, lachiewicz sibley syndrome, crush syndrome, obstructive nephropathy, inherited kidney disorder, acute tubulointerstitial nephritis, kidney cortex disease, non-syndromic supernumerary kidneys, neonatal renal venous thrombosis

Subtypes (2): hemoglobinuria, proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis

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

32 retrieved; paginated sample, class counts are floors:

16 conflicting classifications of pathogenicity, 7 uncertain significance, 5 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity; risk factor, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
523321	NM_000085.5(CLCNKB):c.937_940dup (p.Arg314delinsLysTer)	CLCNKB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
438655	NM_000091.5(COL4A3):c.3546_3548dup (p.Gly1183dup)	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523544	NM_033380.2(COL4A5):c.1424-2_1430delAGGTGACAA	COL4A5	Pathogenic	criteria provided, single submitter
189227	NM_001081.4(CUBN):c.6928_6934del (p.Glu2310fs)	CUBN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523533	NM_022489.4(INF2):c.658G>A (p.Glu220Lys)	INF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
222762	NM_014625.4(NPHS2):c.353C>T (p.Pro118Leu)	NPHS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523548	NM_033380.3(COL4A5):c.4906dup (p.Ile1636fs)	COL4A5	Likely pathogenic	criteria provided, single submitter
127198	NM_003661.4(APOL1):c.1152T>G (p.Ile384Met)	APOL1	Conflicting classifications of pathogenicity; risk factor	criteria provided, conflicting classifications
277678	NM_003661.4(APOL1):c.1024A>G (p.Ser342Gly)	APOL1	Conflicting classifications of pathogenicity; risk factor	criteria provided, conflicting classifications
195951	NM_001845.6(COL4A1):c.1897+7C>G	COL4A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242442	NM_000092.5(COL4A4):c.2320G>C (p.Gly774Arg)	COL4A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
523324	NM_000092.5(COL4A4):c.4394G>A (p.Gly1465Asp)	COL4A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1318858	NM_001081.4(CUBN):c.7968_7969delinsTGTTATACCTTATATAA (p.Leu2656_Pro2657delinsPheValIleProTyrIleThr)	CUBN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3591884	NM_001081.4(CUBN):c.9236+5G>C	CUBN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
523320	NM_000085.5(CLCNKB):c.700T>C (p.Trp234Arg)	LOC106501713	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
903427	NM_002473.6(MYH9):c.4817C>T (p.Ser1606Leu)	MYH9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180461	NM_004646.4(NPHS1):c.1339G>A (p.Glu447Lys)	NPHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180462	NM_004646.4(NPHS1):c.1610C>T (p.Thr537Met)	NPHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180464	NM_004646.4(NPHS1):c.1802G>C (p.Gly601Ala)	NPHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180465	NM_004646.4(NPHS1):c.2873G>A (p.Gly958Glu)	NPHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
5370	NM_014625.4(NPHS2):c.686G>A (p.Arg229Gln)	NPHS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1210225	NM_016341.4(PLCE1):c.3595G>A (p.Gly1199Ser)	PLCE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
879356	NM_016341.4(PLCE1):c.3281G>T (p.Gly1094Val)	PLCE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
213840	NM_003238.6(TGFB2):c.356C>T (p.Pro119Leu)	TGFB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180586	NM_024426.6(WT1):c.764T>A (p.Met255Lys)	WT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180468	NM_014625.4(NPHS2):c.817G>T (p.Gly273Trp)	AXDND1	Uncertain significance	no assertion criteria provided
523549	NM_033380.3(COL4A5):c.808G>A (p.Gly270Arg)	COL4A5	Uncertain significance	criteria provided, single submitter
180374	NM_022489.4(INF2):c.149A>C (p.Tyr50Ser)	INF2	Uncertain significance	criteria provided, single submitter
3769599	NM_002473.6(MYH9):c.3160G>A (p.Glu1054Lys)	MYH9	Uncertain significance	criteria provided, single submitter
180460	NM_004646.4(NPHS1):c.1297C>T (p.Leu433Phe)	NPHS1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 46 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TGFB2	Orphanet:60030	Loeys-Dietz syndrome
TGFB2	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
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
NPHS2	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
PLCE1	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
CLCNKB	Orphanet:358	Gitelman syndrome
CLCNKB	Orphanet:89938	Bartter syndrome type 4
CLCNKB	Orphanet:93605	Bartter syndrome type 3
COL4A1	Orphanet:36383	COL4A1/2-related familial vascular leukoencephalopathy
COL4A1	Orphanet:477749	Pontine autosomal dominant microangiopathy with leukoencephalopathy
COL4A1	Orphanet:481986	Familial schizencephaly
COL4A1	Orphanet:73229	HANAC syndrome
COL4A1	Orphanet:75326	Familial isolated retinal arteriolar tortuosity
COL4A1	Orphanet:899	Walker-Warburg syndrome
COL4A1	Orphanet:99810	Familial porencephaly
COL4A3	Orphanet:653722	Digenic Alport syndrome
COL4A3	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
COL4A3	Orphanet:88918	Autosomal dominant Alport syndrome
COL4A3	Orphanet:88919	Autosomal recessive Alport syndrome
COL4A4	Orphanet:653722	Digenic Alport syndrome
COL4A4	Orphanet:88918	Autosomal dominant Alport syndrome
COL4A4	Orphanet:88919	Autosomal recessive Alport syndrome
COL4A5	Orphanet:1018	X-linked Alport syndrome-diffuse leiomyomatosis
COL4A5	Orphanet:653722	Digenic Alport syndrome
COL4A5	Orphanet:88917	X-linked Alport syndrome
INF2	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
INF2	Orphanet:93114	Autosomal dominant intermediate Charcot-Marie-Tooth disease type E
CUBN	Orphanet:35858	Imerslund-Gräsbeck syndrome
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
NPHS1	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
NPHS1	Orphanet:839	Congenital nephrotic syndrome, Finnish type
PKD1	Orphanet:730	Autosomal dominant polycystic kidney disease
PKD1	Orphanet:88924	Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis
PRKD1	Orphanet:276145	Malignant epithelial tumor of salivary glands
PRKD1	Orphanet:708019	Congenital heart defect-ectodermal dysplasia- brachydactyly-telangiectasia syndrome

Cohort genes → proteins

18 cohort genes, 18 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	18

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TBX18	HGNC:11595	ENSG00000112837	O95935	T-box transcription factor TBX18	clinvar
TGFB2	HGNC:11768	ENSG00000092969	P61812	Transforming growth factor beta-2 proprotein	clinvar
WT1	HGNC:12796	ENSG00000184937	P19544	Wilms tumor protein	clinvar
NPHS2	HGNC:13394	ENSG00000116218	Q9NP85	Podocin	clinvar
PLCE1	HGNC:17175	ENSG00000138193	Q9P212	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1	clinvar
CLCNKB	HGNC:2027	ENSG00000184908	P51801	Chloride channel protein ClC-Kb	clinvar
COL4A1	HGNC:2202	ENSG00000187498	P02462	Collagen alpha-1(IV) chain	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
INF2	HGNC:23791	ENSG00000203485	Q27J81	Inverted formin-2	clinvar
CUBN	HGNC:2548	ENSG00000107611	O60494	Cubilin	clinvar
AXDND1	HGNC:26564	ENSG00000162779	Q5T1B0	Axonemal dynein light chain domain-containing protein 1	clinvar
APOL1	HGNC:618	ENSG00000100342	O14791	Apolipoprotein L1	clinvar
MYH9	HGNC:7579	ENSG00000100345	P35579	Myosin-9	clinvar
NPHS1	HGNC:7908	ENSG00000161270	O60500	Nephrin	clinvar
PKD1	HGNC:9008	ENSG00000008710	P98161	Polycystin-1	clinvar
PRKD1	HGNC:9407	ENSG00000184304	Q15139	Serine/threonine-protein kinase D1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBX18	T-box transcription factor TBX18	Acts as a transcriptional repressor involved in developmental processes of a variety of tissues and organs, including the heart and coronary vessels, the ureter and the vertebral column.
TGFB2	Transforming growth factor beta-2 proprotein	Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-2 (TGF-beta-2) chains, which constitute the regulatory and active subunit of TGF-beta-2, respectively.
WT1	Wilms tumor protein	Transcription factor that plays an important role in cellular development and cell survival.
NPHS2	Podocin	Plays a role in the regulation of glomerular permeability, acting probably as a linker between the plasma membrane and the cytoskeleton.
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.
CLCNKB	Chloride channel protein ClC-Kb	Anion-selective channel permeable to small monovalent anions with ion selectivity for chloride > bromide > nitrate > iodide.
COL4A1	Collagen alpha-1(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.
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.
INF2	Inverted formin-2	Severs actin filaments and accelerates their polymerization and depolymerization.
CUBN	Cubilin	Endocytic receptor which plays a role in lipoprotein, vitamin and iron metabolism by facilitating their uptake.
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.
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.
NPHS1	Nephrin	Seems to play a role in the development or function of the kidney glomerular filtration barrier.
PKD1	Polycystin-1	Component of a heteromeric calcium-permeable ion channel formed by PKD1 and PKD2 that is activated by interaction between PKD1 and a Wnt family member, such as WNT3A and WNT9B.
PRKD1	Serine/threonine-protein kinase D1	Serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of MAPK8/JNK1 and Ras signaling, Golgi membrane integrity and tr…

Protein-family classification

Druggable: 4 · Difficult: 3 · Unknown: 11 · Druggable fraction: 0.22

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
Antibody/Immunoglobulin	2	3.2×	0.750
Kinase	1	1.5×	0.791
Other/Unknown	11	1.1×	0.791
Scaffold/PPI	1	1.0×	0.791
Transcription factor	2	0.9×	0.791
Enzyme (other)	1	0.7×	0.792

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBX18	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
TGFB2	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGFb2
WT1	Transcription factor	no		Wilms_tumour_N, Znf_C2H2_type, Znf_C2H2_sf
NPHS2	Other/Unknown	no		Band_7, Stomatin_HflK_fam, Band_7/stomatin-like_CS
PLCE1	Enzyme (other)	yes	3.1.4.11	C2_dom, RA_dom, PLipase_C_PInositol-sp_X_dom
CLCNKB	Other/Unknown	no		CBS_dom, ClC, Cl_channel-K
COL4A1	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
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
INF2	Other/Unknown	no		WH2_dom, FH3_dom, GTPase-bd
CUBN	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, CUB_dom
AXDND1	Other/Unknown	no		Axonemal_dynein_light_chain, Axonemal_dynein_LC_domain
APOL1	Other/Unknown	no		ApoL
MYH9	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail
NPHS1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
PKD1	Antibody/Immunoglobulin	yes		GPS, LRRNT, PC1
PRKD1	Kinase	yes	2.7.11.13	Prot_kinase_dom, PH_domain, PKC_DAG/PE

Expression context

Cohort genes with no expression data: 0.

18 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)	18
unknown	0

Top tissues across cohort

Tissue	Cohort genes
metanephric glomerulus	3
renal glomerulus	3
ventricular zone	3
right coronary artery	2
kidney epithelium	2
metanephros cortex	2
renal medulla	2
pigmented layer of retina	2
thoracic aorta	2
popliteal artery	1
tibial artery	1
calcaneal tendon	1
cartilage tissue	1
tendon	1
germinal epithelium of ovary	1
adult mammalian kidney	1
placenta	1
visceral pleura	1
retina	1
skeletal muscle tissue of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBX18	162	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
TGFB2	206	ubiquitous	marker	calcaneal tendon, tendon, cartilage tissue
WT1	168	broad	marker	germinal epithelium of ovary, renal glomerulus, metanephric glomerulus
NPHS2	47	tissue_specific	marker	renal glomerulus, metanephric glomerulus, kidney epithelium
PLCE1	271	broad	marker	renal glomerulus, metanephric glomerulus, ventricular zone
CLCNKB	165	broad	marker	renal medulla, adult mammalian kidney, metanephros cortex
COL4A1	283	ubiquitous	marker	visceral pleura, placenta, right coronary artery
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
INF2	260	ubiquitous	marker	sural nerve, nerve, tibial nerve
CUBN	188	broad	marker	adult organism, nephron tubule, kidney epithelium
AXDND1	161	tissue_specific	marker	sperm, left testis, right testis
APOL1	252	ubiquitous	marker	gall bladder, right lobe of liver, liver
MYH9	279	ubiquitous	marker	stromal cell of endometrium, ascending aorta, thoracic aorta
NPHS1	147	tissue_specific	marker	buccal mucosa cell, body of pancreas, vena cava
PKD1	290		marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
PRKD1	239	ubiquitous	marker	ventricular zone, seminal vesicle, thoracic aorta

Protein interactions among cohort

Intra-cohort edges: 30.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYH9	5,533
WT1	3,938
COL4A1	2,909
PRKD1	2,131
INF2	2,070
NPHS2	1,811
COL4A5	1,738
NPHS1	1,690
COL4A3	1,671
PLCE1	1,560

Intra-cohort edges

A	B	Sources
APOL1	INF2	string_interaction
APOL1	MYH9	string_interaction
APOL1	NPHS1	string_interaction
APOL1	NPHS2	string_interaction
APOL1	PLCE1	string_interaction
COL4A3	COL4A4	string_interaction
COL4A3	MYH9	string_interaction
COL4A3	NPHS1	string_interaction
COL4A3	NPHS2	string_interaction
COL4A4	COL4A5	string_interaction
COL4A4	INF2	string_interaction
COL4A4	MYH9	string_interaction
COL4A4	NPHS1	string_interaction
COL4A4	NPHS2	string_interaction
COL4A5	NPHS1	string_interaction
COL4A5	NPHS2	string_interaction
INF2	MYH9	intact, string_interaction
INF2	NPHS1	string_interaction
INF2	NPHS2	string_interaction
INF2	PLCE1	string_interaction
INF2	WT1	string_interaction
MYH9	NPHS1	string_interaction
NPHS1	NPHS2	biogrid_interaction, string_interaction
NPHS1	PLCE1	string_interaction
NPHS1	WT1	string_interaction
NPHS2	PLCE1	string_interaction
NPHS2	WT1	string_interaction
PKD1	PRKD1	string_interaction
PLCE1	WT1	string_interaction
TBX18	WT1	string_interaction

Structural data

PDB: 13 · AlphaFold-only: 5 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
WT1	P19544	28
PKD1	P98161	13
TGFB2	P61812	11
INF2	Q27J81	10
MYH9	P35579	8
APOL1	O14791	5
COL4A1	P02462	4
PLCE1	Q9P212	3
COL4A3	Q01955	2
COL4A4	P53420	2
COL4A5	P29400	2
CUBN	O60494	2
NPHS1	O60500	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLCNKB	P51801	87.16
NPHS2	Q9NP85	75.00
AXDND1	Q5T1B0	70.90
PRKD1	Q15139	68.99
TBX18	O95935	61.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 90. Enrichment computed across 18 evidence-associated genes (15 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 15 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Anchoring fibril formation	4	203.0×	2e-07	COL4A1, COL4A3, COL4A4, COL4A5
Fibronectin matrix formation	4	152.3×	3e-07	COL4A1, COL4A3, COL4A4, COL4A5
Crosslinking of collagen fibrils	4	152.3×	3e-07	COL4A1, COL4A3, COL4A4, COL4A5
Attachment of bacteria to epithelial cells	4	132.4×	4e-07	COL4A1, COL4A3, COL4A4, COL4A5
ECM proteoglycans	5	50.1×	6e-07	TGFB2, COL4A1, COL4A3, COL4A4, COL4A5
Laminin interactions	4	101.5×	8e-07	COL4A1, COL4A3, COL4A4, COL4A5
Collagen chain trimerization	4	69.2×	3e-06	COL4A1, COL4A3, COL4A4, COL4A5
Signaling by PDGF	4	67.7×	3e-06	COL4A1, COL4A3, COL4A4, COL4A5
NCAM1 interactions	4	66.2×	3e-06	COL4A1, COL4A3, COL4A4, COL4A5
Assembly of collagen fibrils and other multimeric structures	4	53.4×	7e-06	COL4A1, COL4A3, COL4A4, COL4A5
Collagen degradation	4	46.9×	1e-05	COL4A1, COL4A3, COL4A4, COL4A5
Collagen biosynthesis and modifying enzymes	4	45.5×	1e-05	COL4A1, COL4A3, COL4A4, COL4A5
Non-integrin membrane-ECM interactions	4	41.1×	1e-05	COL4A1, COL4A3, COL4A4, COL4A5
Integrin cell surface interactions	4	35.8×	2e-05	COL4A1, COL4A3, COL4A4, COL4A5
Nephrin family interactions	2	63.4×	0.003	NPHS2, NPHS1
Defective AMN causes MGA1	1	253.8×	0.021	CUBN
Defective CUBN causes MGA1	1	253.8×	0.021	CUBN
HDL clearance	1	152.3×	0.033	CUBN
TGFBR3 regulates TGF-beta signaling	1	95.2×	0.050	TGFB2
CD163 mediating an anti-inflammatory response	1	76.1×	0.056	MYH9
Uptake of dietary cobalamins into enterocytes	1	76.1×	0.056	CUBN
Vitamin D (calciferol) metabolism	1	58.6×	0.064	CUBN
Scavenging of heme from plasma	1	58.6×	0.064	APOL1
Nephron development	1	58.6×	0.064	WT1
Transcriptional regulation of testis differentiation	1	47.6×	0.075	WT1
Sema4D in semaphorin signaling	1	44.8×	0.077	MYH9
Scavenging by Class A Receptors	1	40.1×	0.077	COL4A1
RHO GTPases activate CIT	1	40.1×	0.077	MYH9
RHO GTPases Activate ROCKs	1	40.1×	0.077	MYH9
Sema4D induced cell migration and growth-cone collapse	1	38.1×	0.077	MYH9

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 18 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	340.4×	1e-07	WT1, COL4A3, COL4A4, NPHS1
collagen fibril organization	5	62.4×	2e-06	TGFB2, COL4A1, COL4A3, COL4A4, COL4A5
collagen-activated tyrosine kinase receptor signaling pathway	3	216.1×	3e-05	COL4A1, COL4A3, COL4A5
glomerulus development	2	144.0×	0.007	WT1, PLCE1
epithelial cell differentiation	3	29.3×	0.009	TGFB2, WT1, COL4A1
cartilage condensation	2	85.1×	0.012	TGFB2, PKD1
kidney development	3	23.4×	0.012	TGFB2, WT1, PKD1
myoblast fusion	2	66.9×	0.016	MYH9, NPHS1
neuromuscular junction development	2	58.5×	0.019	COL4A1, COL4A5
regulation of timing of catagen	1	936.2×	0.020	TGFB2
sinoatrial node cell fate commitment	1	936.2×	0.020	TBX18
positive regulation of activation-induced cell death of T cells	1	936.2×	0.020	TGFB2
metanephric distal tubule morphogenesis	1	936.2×	0.020	PKD1
negative regulation of metanephric glomerular mesangial cell proliferation	1	936.2×	0.020	WT1
regulation of apoptotic process involved in outflow tract morphogenesis	1	936.2×	0.020	TGFB2
negative regulation of epithelial to mesenchymal transition involved in endocardial cushion formation	1	936.2×	0.020	TGFB2
regulation of animal organ formation	1	468.1×	0.020	WT1
cardioblast differentiation	1	468.1×	0.020	TGFB2
regulation of skeletal muscle contraction by modulation of calcium ion sensitivity of myofibril	1	468.1×	0.020	PRKD1
uropod organization	1	468.1×	0.020	MYH9
adrenal cortex formation	1	468.1×	0.020	WT1
slit diaphragm assembly	1	468.1×	0.020	NPHS1
uterine wall breakdown	1	468.1×	0.020	TGFB2
cortical granule exocytosis	1	468.1×	0.020	MYH9
visceral serous pericardium development	1	468.1×	0.020	WT1
nitrogen cycle metabolic process	1	468.1×	0.020	PKD1
mesonephric tubule development	1	468.1×	0.020	PKD1
posterior mesonephric tubule development	1	468.1×	0.020	WT1
metanephric podocyte development	1	468.1×	0.020	NPHS2
substantia propria of cornea development	1	468.1×	0.020	TGFB2

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
Candesartan Cilexetil	Phase 3 (in late-stage trials)
Curcumin	Phase 3 (in late-stage trials)
Dextromethorphan	Phase 3 (in late-stage trials)
Losartan	Phase 3 (in late-stage trials)
Olmesartan Medoxomil	Phase 3 (in late-stage trials)
Paricalcitol	Phase 3 (in late-stage trials)
Rituximab	Phase 3 (in late-stage trials)
Silybin A	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Belatacept, Nifedipine, Pirfenidone, Sitaxentan.

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 3 · Undrugged: 15

Druggability breadth: 11 of 18 evidence-associated genes (61%) 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
PRKD1	INGENOL MEBUTATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKD1	26	4
TGFB2	1	2
MYH9	1	2
TBX18	0	0
WT1	0	0
NPHS2	0	0
PLCE1	0	0
CLCNKB	0	0
COL4A1	0	0
COL4A3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
INGENOL MEBUTATE	4	PRKD1
MIDOSTAURIN	4	PRKD1
TAMOXIFEN	4	PRKD1
NERATINIB	4	PRKD1
BRIGATINIB	4	PRKD1
NINTEDANIB	4	PRKD1
SUNITINIB	4	PRKD1
CRIZOTINIB	4	PRKD1
GEFITINIB	4	PRKD1
SURAMIN	3	PRKD1
FASUDIL	3	PRKD1
ALVOCIDIB	3	PRKD1
LESTAURTINIB	3	PRKD1
GALUNISERTIB	2	TGFB2
MOLIBRESIB	2	MYH9
PHORBOL MYRISTATE ACETATE	2	PRKD1
EDELFOSINE	2	PRKD1
UPROSERTIB	2	PRKD1
UCN-01	2	PRKD1
SU-014813	2	PRKD1
AT-9283	2	PRKD1
BI-2536	2	PRKD1
KW-2449	1	PRKD1
BMS-387032	1	PRKD1
PF-03758309	1	PRKD1
SRA-737	1	PRKD1
GSK-690693	1	PRKD1
AST-487	1	PRKD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PRKD1	660	Binding:650, Functional:10
PKD1	27	Binding:27
MYH9	10	Binding:10
APOL1	4	Binding:4
TGFB2	3	Binding:3
INF2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLCE1	3.1.4.11	phosphoinositide phospholipase C
PRKD1	2.7.11.13	protein kinase C

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PRKD1	660

Pharmacogenomics

Cohort genes with a PharmGKB record: 18; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

28 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)
INGENOL MEBUTATE	4	PRKD1
MIDOSTAURIN	4	PRKD1
TAMOXIFEN	4	PRKD1
NERATINIB	4	PRKD1
BRIGATINIB	4	PRKD1
NINTEDANIB	4	PRKD1
SUNITINIB	4	PRKD1
CRIZOTINIB	4	PRKD1
GEFITINIB	4	PRKD1
SURAMIN	3	PRKD1
FASUDIL	3	PRKD1
ALVOCIDIB	3	PRKD1
LESTAURTINIB	3	PRKD1
GALUNISERTIB	2	TGFB2
MOLIBRESIB	2	MYH9
PHORBOL MYRISTATE ACETATE	2	PRKD1
EDELFOSINE	2	PRKD1
UPROSERTIB	2	PRKD1
UCN-01	2	PRKD1
SU-014813	2	PRKD1
AT-9283	2	PRKD1
BI-2536	2	PRKD1
KW-2449	1	PRKD1
BMS-387032	1	PRKD1
PF-03758309	1	PRKD1
SRA-737	1	PRKD1
GSK-690693	1	PRKD1
AST-487	1	PRKD1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PRKD1
B	Phased (≥1) drug, not yet approved	2	TGFB2, MYH9
C	Druggable family + PDB, no drug	3	PLCE1, NPHS1, PKD1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	12	TBX18, WT1, NPHS2, CLCNKB, COL4A1, COL4A3, COL4A4, COL4A5, INF2, CUBN (+2 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
COL4A4	0	MYH9
APOL1	4	MYH9
PKD1	27	PRKD1
TBX18	0	—
WT1	0	—
NPHS2	0	—
PLCE1	0	—
CLCNKB	0	—
COL4A1	0	—
COL4A3	0	—
COL4A5	0	—
INF2	1	—
CUBN	0	—
AXDND1	0	—
NPHS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 137.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	61
PHASE4	33
PHASE3	17
PHASE2	17
PHASE1	5
PHASE2/PHASE3	2
PHASE1/PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07030894	PHASE4	RECRUITING	Nefecon and Ambrisentan in IgA Nephropathy
NCT07219121	PHASE4	RECRUITING	Sparsentan in Posttransplant Immunoglobulin A Nephropathy or Focal Segmental Glomerulosclerosis
NCT07358520	PHASE4	NOT_YET_RECRUITING	Clinical Study on the Use of Huaier Granules for the Treatment of Proteinuria Related to Bevacizumab and Anlotinib in Lung Cancer Patients
NCT00067990	PHASE4	COMPLETED	Angiotensin II Blockade for Chronic Allograft Nephropathy
NCT00234871	PHASE4	COMPLETED	Tarka® vs. Lotrel® in Hypertensive, Diabetic Subjects With Renal Disease (TANDEM)
NCT00241085	PHASE4	COMPLETED	Effect of Valsartan on Proteinuria in Patients With Hypertension and Diabetes Mellitus
NCT00369538	PHASE4	SUSPENDED	Specific Blockage of Angiotensine 2 and Podocyturia in Glomerular Nephropathies With Hypertension and Proteinuria
NCT00508898	PHASE4	WITHDRAWN	The Efficacy and Safety of Calcitriol for the Treatment of Lupus Nephritis and Persistent Proteinuria
NCT00550095	PHASE4	COMPLETED	To Assess the Effects of Valsartan on Albuminuria/Proteinuria in Hypertensive Patients With Type 2 Diabetes Mellitus
NCT00674596	PHASE4	COMPLETED	The Effect of Renin Angiotensin System Blockage (RAS) Blockade On PTX3 Levels In Diabetic Patients With Proteinuria
NCT00858299	PHASE4	UNKNOWN	The Change of Urinary Angiotensinogen Excretion After Valsartan Treatment in Patients With Persistent Proteinuria
NCT00893425	PHASE4	COMPLETED	Effect of Renin Angiotensin System Blockade on the Fas Antigen (CD95) and Asymmetric Dimethylarginine (ADMA) Levels in Type-2 Diabetic Patients With Proteinuria
NCT00921570	PHASE4	COMPLETED	The Effects of Renin Angiotensin System Blockage (RAS), Calcium Channel Blocker and Combined Drugs on TWEAK, PTX3 and FMD Levels in Diabetic Proteinuric Patients With Hypertension
NCT00961207	PHASE4	TERMINATED	Triple Blockade of the Renin Angiotensin Aldosterone System in Diabetic (Type 1&2) Proteinuric Patients
NCT01169857	PHASE4	WITHDRAWN	Velcade for Proliferative Lupus Nephritis
NCT01219413	PHASE4	COMPLETED	Influence of Aliskiren on Proteinuria
NCT01386554	PHASE4	COMPLETED	Acthar for Treatment of Proteinuria in Membranous Nephropathy Patients
NCT01512862	PHASE4	UNKNOWN	Anti-proteinuric Effect of Calcitriol in Non-diabetic Kidney Disease Patients
NCT01541267	PHASE4	COMPLETED	The Effect of Various Types of the Renin-angiotensin-aldosterone System Blockade on Proteinuria
NCT01637259	PHASE4	COMPLETED	MARCH Renal Substudy
NCT01703234	PHASE4	COMPLETED	FGF-23 and Endothelial Dysfunction in Diabetic Proteinuric Patients
NCT01820832	PHASE4	UNKNOWN	Oral Calcitriol for Reduction of Mild Proteinuria in Patients With CKD
NCT01827202	PHASE4	COMPLETED	RAS Quantification in Patients With Aliskiren or Candesartan
NCT02057523	PHASE4	TERMINATED	Acthar as Rescue Therapy for Transplant Glomerulopathy in Kidney Transplant Recipients
NCT02063100	PHASE4	UNKNOWN	Efficacy and Safety of Shenyankangfu Tablets for Primary Glomerulonephritis
NCT02382523	PHASE4	WITHDRAWN	Acthar on Proteinuria in IgA Nephropathy Patients
NCT02522650	PHASE4	UNKNOWN	A Crossover Pilot Study of the Effect of Amiloride on Proteinuria
NCT03195023	PHASE4	UNKNOWN	Effect of RAS Blockers on CKD Progression in Elderly Patients With Non Proteinuric Nephropathies (PROERCAN01)
NCT03550859	PHASE4	UNKNOWN	HMG-CoA Reductase add-on in Chronic Kidney Disease Patients With Proteinuria
NCT03983551	PHASE4	COMPLETED	Comparing the Renal Effect of Dipeptidyl-peptidase 4 Inhibitors and Sulfonylureas
NCT04531397	PHASE4	WITHDRAWN	Efficacy and Safety of Dapagliflozin in Children With Proteinuric Chronic Kidney Disease
NCT04534270	PHASE4	COMPLETED	Efficacy and Safety of Dapagliflozin in Children With Proteinuria
NCT06374043	PHASE4	COMPLETED	Decentralized N=1 Study: A Feasible Approach to Evaluate Individual Therapy Response to Dapagliflozin.
NCT05196035	PHASE3	RECRUITING	A Study to Learn More About How Well the Study Treatment Finerenone Works, How Safe it is, How it Moves Into, Through, and Out of the Body, and the Effects it Has on the Body When Taken With an ACE Inhibitor or Angiotensin Receptor Blocker in Children With Chronic Kidney Disease and Proteinuria
NCT05457283	PHASE3	RECRUITING	A Study to Learn More About How Safe the Study Treatment Finerenone is in Long-term Use When Taken With an ACE Inhibitor or Angiotensin Receptor Blocker Over 18 Months of Use in Children and Young Adults From 1 to 18 Years of Age With Chronic Kidney Disease and Proteinuria
NCT07586371	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Proteinuria in Normotensive Diabetic Patients: ARBs Alone or in Combination of SGLT2i
NCT00106561	PHASE2/PHASE3	COMPLETED	Using the Drug Spironolactone to Test If It Reduces Protein Leakage From the Kidney
NCT00141453	PHASE3	COMPLETED	ORIENT: Olmesartan Reducing Incidence of End Stage Renal Disease in Diabetic Nephropathy Trial
NCT00199927	PHASE3	COMPLETED	Statins in Proteinuric Nephropathies
NCT00242346	PHASE3	COMPLETED	High Doses of Candesartan Cilexetil on the Reduction of Proteinuria

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LOSARTAN	4	16
ENALAPRIL	4	6
ALISKIREN	4	4
VALSARTAN	4	4
AMILORIDE	4	3
CALCITRIOL	4	3
CORTICOTROPIN	4	3
NIFEDIPINE	4	3
PARICALCITOL	4	3
PERINDOPRIL	4	3
RAMIPRIL	4	3
AMLODIPINE	4	2
BORTEZOMIB	4	2
DAPAGLIFLOZIN	4	2
LEVAMISOLE	4	2
LISINOPRIL ANHYDROUS	4	2
OLMESARTAN MEDOXOMIL	4	2
ROSUVASTATIN	4	2
SPARSENTAN	4	2
TELMISARTAN	4	2
AMBRISENTAN	4	1
BELATACEPT	4	1
BENAZEPRIL	4	1
BEVACIZUMAB	4	1
CANDESARTAN CILEXETIL	4	1
CHOLECALCIFEROL	4	1
CLONIDINE	4	1
CLONIDINE HYDROCHLORIDE	4	1
DEXTROMETHORPHAN	4	1
DEXTROMETHORPHAN HYDROBROMIDE	4	1