NPHS1

Summary

NPHS1 (NPHS1 adhesion molecule, nephrin, HGNC:7908) is a protein-coding gene on chromosome 19q13.12, encoding Nephrin (O60500). Seems to play a role in the development or function of the kidney glomerular filtration barrier.

This gene encodes a member of the immunoglobulin family of cell adhesion molecules that functions in the glomerular filtration barrier in the kidney. The gene is primarily expressed in renal tissues, and the protein is a type-1 transmembrane protein found at the slit diaphragm of glomerular podocytes. The slit diaphragm is thought to function as an ultrafilter to exclude albumin and other plasma macromolecules in the formation of urine. Mutations in this gene result in Finnish-type congenital nephrosis 1, characterized by severe proteinuria and loss of the slit diaphragm and foot processes.

Source: NCBI Gene 4868 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital nephrotic syndrome, Finnish type (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 1,998 total — 141 pathogenic, 241 likely-pathogenic
• Phenotypes (HPO): 40
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_004646

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7908
Approved symbol	NPHS1
Name	NPHS1 adhesion molecule, nephrin
Location	19q13.12
Locus type	gene with protein product
Status	Approved
Aliases	CNF, NPHN
Ensembl gene	ENSG00000161270
Ensembl biotype	protein_coding
OMIM	602716
Entrez	4868

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000353632, ENST00000378910, ENST00000585400, ENST00000591817, ENST00000592132, ENST00000869106, ENST00000869107

RefSeq mRNA: 1 — MANE Select: NM_004646 NM_004646

CCDS: CCDS32996

Canonical transcript exons

ENST00000378910 — 29 exons

Exon	Start	End
ENSE00001057256	35831053	35831146
ENSE00001153484	35830844	35830956
ENSE00001181087	35825372	35826645
ENSE00001364309	35842124	35842280
ENSE00001368371	35839237	35839418
ENSE00001373160	35841715	35841866
ENSE00001384533	35831296	35831371
ENSE00001385699	35839496	35839607
ENSE00001479239	35831476	35831500
ENSE00001479242	35831643	35831762
ENSE00001505335	35835705	35835761
ENSE00001594817	35849236	35849363
ENSE00001616014	35849550	35849653
ENSE00001627782	35846008	35846194
ENSE00001684102	35850961	35851089
ENSE00001684606	35848976	35849147
ENSE00001721234	35844103	35844243
ENSE00001725083	35842379	35842550
ENSE00001740392	35850364	35850445
ENSE00001743515	35851457	35851672
ENSE00001747424	35851262	35851384
ENSE00001747710	35843472	35843593
ENSE00001748915	35848041	35848165
ENSE00001786644	35845368	35845540
ENSE00001788097	35845669	35845798
ENSE00003459273	35844319	35844459
ENSE00003482882	35848253	35848397
ENSE00003631217	35848637	35848794
ENSE00003905278	35851780	35852504

Expression profiles

Bgee: expression breadth ubiquitous, 147 present calls, max score 92.71.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2638 / max 148.8281, expressed in 58 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
180584	0.1243	24
180585	0.1099	26
180583	0.0297	12

Top tissues by expression

232 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	92.71	gold quality
body of pancreas	UBERON:0001150	89.75	gold quality
vena cava	UBERON:0004087	89.56	silver quality
tendon of biceps brachii	UBERON:0008188	89.12	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	88.73	silver quality
renal glomerulus	UBERON:0000074	88.30	gold quality
metanephric glomerulus	UBERON:0004736	88.28	gold quality
adult mammalian kidney	UBERON:0000082	83.65	gold quality
pharyngeal mucosa	UBERON:0000355	82.31	silver quality
nipple	UBERON:0002030	81.91	silver quality
body of tongue	UBERON:0011876	81.77	silver quality
sperm	CL:0000019	81.67	silver quality
renal medulla	UBERON:0000362	80.95	gold quality
pancreas	UBERON:0001264	80.58	gold quality
kidney	UBERON:0002113	79.99	gold quality
cardia of stomach	UBERON:0001162	79.95	silver quality
metanephros	UBERON:0000081	79.77	gold quality
gingival epithelium	UBERON:0001949	79.26	silver quality
kidney epithelium	UBERON:0004819	79.26	gold quality
tongue	UBERON:0001723	79.24	silver quality
male germ cell	CL:0000015	79.03	silver quality
pylorus	UBERON:0001166	78.54	silver quality
superior surface of tongue	UBERON:0007371	78.41	silver quality
ventral tegmental area	UBERON:0002691	77.77	silver quality
saphenous vein	UBERON:0007318	77.76	silver quality
trachea	UBERON:0003126	77.74	silver quality
parotid gland	UBERON:0001831	77.63	gold quality
pericardium	UBERON:0002407	77.48	silver quality
pons	UBERON:0000988	77.46	silver quality
subthalamic nucleus	UBERON:0001906	77.41	silver quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-GEOD-124472	yes	7031.86
E-CURD-135	yes	5040.66
E-GEOD-114530	yes	4201.81
E-HCAD-10	yes	3937.04
E-CURD-119	yes	34.68
E-ANND-3	yes	7.28

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KLF4, NFKB, PAX2, PPARA, SNAI1, SP1, VDR, WT1

miRNA regulators (miRDB)

40 targeting NPHS1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-6839-3P	99.39	68.86	1301
HSA-MIR-155-5P	99.35	70.16	1509
HSA-MIR-501-3P	99.33	66.12	651
HSA-MIR-502-3P	99.33	66.12	651
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-3152-3P	99.10	66.35	678
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-10524-5P	99.05	66.08	963
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-4774-3P	98.90	67.82	737
HSA-MIR-5000-3P	98.79	65.63	1251
HSA-MIR-34B-3P	98.70	67.40	1171
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-532-5P	98.43	67.53	760
HSA-MIR-595	98.25	67.44	699

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• function in the slit diaphragm and glomerular filtration (PMID:11692461)
• Mutations interact with NPHS2 protein to produce either nephrotic syndrome or focal glomerosclerosis, depending on alleles. (PMID:11854170)
• A missense mutation of the nephrin gene (GAC-to-GTC transversion leading to Asp819Val)impairs targeting of the protein to the cell membrane and causes congenital nephrotic syndrome of the Finnish type (CNF). (PMID:12324903)
• co-localization of podocin, this protein and the actin cytoskeleton: evidence for a role in podocyte foot process formation. (PMID:12368218)
• Nephrin protein and mRNA are differentially expressed in acquired proteinuric diseases according to the specific glomerular disease or severity of glomerular damage. (PMID:12407641)
• investigation of the expression of nephrin in human kidney tissue from patients with diabetic nephropathy to elucidate its relationship with proteinuria and the effects of anti-proteinuric therapy with angiotensin converting enzyme inhibition (PMID:12436341)
• The loss of function of the nephrin gene is the main cause of congenital nephrotic syndrome of the Finnish type in Italian patients. (PMID:12495287)
• This study does not support an involvement of the coding region of the nephrin gene in the pathogenesis of diabetic nephropathy in type 1 diabetic patients. (PMID:12631336)
• study indicates that the alteration in nephrin expression is an early event in proteinuric patients with diabetes and suggests that glycated albumin and angiotensin II contribute to nephrin downregulation (PMID:12663475)
• Nephrin is a signaling protein phosphorylated by Src family kinases. (PMID:12846735)
• This study suggests that the NPHS1 G349A polymorphism may be associated with heavy proteinuria and a decline in renal function in patients with IgAN. (PMID:12920248)
• Abnormal distribution of nephrin, podocin, and alpha-actinin were found in children with nephrotic syndrome. (PMID:12961083)
• Nephrin molecules exhibit homophilic interactions that could promote cellular contacts through direct nephrin-nephrin interactions. (PMID:14633607)
• The expression of nephrin mRNA maybe closely linked to the development and progression of proteinuria in diabetic nephropathy. (PMID:14736962)
• an alteration in nephrin expression is not a feature of acquired forms of nephrotic syndrome in childhood. (PMID:14747939)
• heterozygous allelic variants leading to nonconservative amino acid substitutions not previously reported in minimal change nephrotic syndrome (PMID:15086927)
• Extracellular nephrin mRNA and protein were markedly reduced in diabetic patients. (PMID:15149332)
• Interaction of vascular endothelial growth factor with nephrin in cultured human podocytes reduced apoptosis. (PMID:15339792)
• Recombinant WT1 protein can bind and activate the 186-bp NPHS1 fragment in a sequence-specific manner. WT1 may be required for regulation of the NPHS1 gene in vivo. (PMID:15504938)
• NPHN contributes to a porous slit diaphragm scaffold, the molecular filter in renal glomerular capillaries. (PMID:15545998)
• To characterize the structural properties and protein-protein interactions of the nephrin intracellular domain, we produced a series of recombinant nephrin proteins which all bound previously identified ligands (PMID:15634346)
• exposure to normal and non-nephrotic human plasma leads to a concentration of nephrin, podocin, CD2AP, and actin at the cell surface in podocytes (PMID:15659563)
• Mutations are not a major cause of congenital nephrotic syndrome in Japanese patients. (PMID:15780077)
• serum and plasma factors from focal segmental glomerulosclerosis patients may directly affect nephrin and podocin in human podocytes (PMID:15942677)
• Nephrin is expressed at protein and mRNA levels in islet microvascular endothelium. (PMID:16010520)
• data show that PPARalpha activation causes an increased nephrin expression by a dual action, on the one hand by stimulating nephrin promoter activity and on the other hand by reducing nephrin mRNA degradation (PMID:16288986)
• nephrin selectively binds the Src homology 2 (SH2)/SH3 domain-containing Nck adaptor proteins, which in turn control the podocyte cytoskeleton in vivo (PMID:16525419)
• nephrin phosphorylation results in Src kinase activation, recruitment of Nck, and assembly of actin filaments in an Nck-dependent fashion (PMID:16543952)
• Association of single 3 nucleotide polymorphisms with type 2 diabetes. (PMID:16644649)
• A striking finding in this study is the lack of contribution of NPHS1, NPHS2, and NEPH1 genes in 15 Asian families with steroid-resistant nephrotic syndrome. (PMID:16968734)
• Results suggest that nephrin Y1193 serves as a molecular switch that determines the integrity of the slit diaphragm by functional competition between beta-arrestin2 and podocin. (PMID:16968782)
• Mutations may play pathogenetic roles in some patients with sporadic steroid resistant nephrotic syndrome. (PMID:17211152)
• We conclude that down-regulation of nephrin and synaptopodin is associated with proteinuria in women with preeclampsia. (PMID:17255128)
• Mutated in nephrotic syndrome in an 11-year old boy. (PMID:17290294)
• Knocking nephrin down with siRNA in wild-type podocytes abrogated the insulin response, and stable nephrin transfection of nephrin-deficient podocytes rescued their insulin response. (PMID:17395751)
• 3 novel mutations: c.1138C>T (p.Gln380X), c.2160_ 2161insC (p.Cys721fs) and c.1707C>G (p.Ser569Arg)were identified in a highly inbred community; patients were either homozygous for one mutation or compound heterozygotes; they differed in their phenotype (PMID:17413422)
• Nephrin-Neph1 complex transduces phosphorylation-mediated signals that assemble an actin polymerization complex at the podocyte intercellular junction. (PMID:17923684)
• Any one of three phosphorylated (p)YDXV motifs on nephrin is sufficient to recruit Nck through its Src homology 2 (SH2) domain and induce localized actin polymerization at these clusters. (PMID:18212058)
• Neph1 but not nephrin specifically binds to adaptor protein Grb2 and tyrosine kinase Csk in a phosphorylation-dependent manner. (PMID:18258597)
• Reduction of endogenous nephrin expression by application of siRNA to differentiated cells of an immortalized podocyte cell line markedly reduced steady-state surface expression of Slo1. (PMID:18480178)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nphs1	ENSDARG00000060758
mus_musculus	Nphs1	ENSMUSG00000006649
rattus_norvegicus	Nphs1	ENSRNOG00000020873
drosophila_melanogaster	sns	FBGN0024189
drosophila_melanogaster	hbs	FBGN0287864

Paralogs (3): KIRREL2 (ENSG00000126259), KIRREL3 (ENSG00000149571), KIRREL1 (ENSG00000183853)

Protein

Protein identifiers

Nephrin — O60500 (reviewed: O60500)

Alternative names: Renal glomerulus-specific cell adhesion receptor

All UniProt accessions (1): O60500

UniProt curated annotations — full annotation on UniProt →

Function. Seems to play a role in the development or function of the kidney glomerular filtration barrier. Regulates glomerular vascular permeability. May anchor the podocyte slit diaphragm to the actin cytoskeleton. Plays a role in skeletal muscle formation through regulation of myoblast fusion.

Subunit / interactions. Self-associates (via the Ig-like domains). Interacts with CD2AP (via C-terminal domain). Interacts with NPHS2. Interacts with MAGI1 (via PDZ 2 and 3 domains) forming a tripartite complex with IGSF5/JAM4. Interacts with DDN; the interaction is direct. Also interacts (via the Ig-like domains) with KIRREL1/NEPH1 and KIRREL2; the interaction with KIRREL1 is dependent on KIRREL1 glycosylation. Interacts with KIRREL3. Forms a complex with ACTN4, CASK, IQGAP1, MAGI2, SPTAN1 and SPTBN1. Interacts with phosphatidylinositol 3-kinase regulatory subunit PIK3R1; the interaction is reduced by high glucose levels. Interacts (via N-terminus) with GAPVD1 (via Ras-GAP or VPS9 domains).

Subcellular location. Cell membrane.

Tissue specificity. Specifically expressed in podocytes of kidney glomeruli.

Post-translational modifications. Phosphorylated at Tyr-1193 by FYN, leading to the recruitment and activation of phospholipase C-gamma-1/PLCG1. Tyrosine phosphorylation is reduced by high glucose levels. Dephosphorylated by tensin TNS2 which leads to reduced binding of NPHN1 to PIK3R1.

Disease relevance. Nephrotic syndrome 1 (NPHS1) [MIM:256300] A form of nephrotic syndrome, a renal disease clinically characterized by severe proteinuria, resulting in complications such as hypoalbuminemia, hyperlipidemia and edema. Kidney biopsies show non-specific histologic changes such as focal segmental glomerulosclerosis and diffuse mesangial proliferation. Some affected individuals have an inherited steroid-resistant form and progress to end-stage renal failure. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the immunoglobulin superfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
O60500-1	1	yes
O60500-2	2, Alpha

RefSeq proteins (1): NP_004637* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR003961	FN3_dom	Domain
IPR007110	Ig-like_dom	Domain
IPR013098	Ig_I-set	Domain
IPR013106	Ig_V-set	Domain
IPR013162	CD80_C2-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR051275	Cell_adhesion_signaling	Family

Pfam: PF00041, PF07679, PF07686, PF08205, PF13927

UniProt features (124 total): sequence variant 80, glycosylation site 10, domain 9, disulfide bond 8, modified residue 5, region of interest 4, topological domain 2, signal peptide 1, chain 1, mutagenesis site 1, compositionally biased region 1, transmembrane region 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4ZRT	X-RAY DIFFRACTION	1.74

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60500-F1	77.23	0.34

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (5): 432, 1098, 1101, 1105, 1193

Disulfide bonds (8): 53–111, 160–217, 265–317, 361–417, 465–528, 567–623, 761–816, 863–920

Glycosylation sites (10): 40, 356, 401, 547, 553, 564, 577, 680, 708, 908

Mutagenesis-validated functional residues (1):

Position	Phenotype
1138	increased mtorc1 complex activation.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-373753	Nephrin family interactions

MSigDB gene sets: 223 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_KIDNEY_EPITHELIUM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS, GOBP_CELL_CELL_ADHESION, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_CELL_JUNCTION_ORGANIZATION, MODULE_205, GOBP_CELL_DIFFERENTIATION_INVOLVED_IN_KIDNEY_DEVELOPMENT

GO Biological Process (13): JNK cascade (GO:0007254), skeletal muscle tissue development (GO:0007519), myoblast fusion (GO:0007520), gene expression (GO:0010467), positive regulation of actin filament polymerization (GO:0030838), glomerular basement membrane development (GO:0032836), protein localization to synapse (GO:0035418), slit diaphragm assembly (GO:0036060), podocyte development (GO:0072015), cell-cell adhesion (GO:0098609), MAPK cascade (GO:0000165), cell adhesion (GO:0007155), muscle organ development (GO:0007517)

GO Molecular Function (3): myosin binding (GO:0017022), cell adhesion molecule binding (GO:0050839), protein binding (GO:0005515)

GO Cellular Component (8): plasma membrane (GO:0005886), cell-cell junction (GO:0005911), focal adhesion (GO:0005925), slit diaphragm (GO:0036057), cell projection (GO:0042995), extracellular exosome (GO:0070062), membrane (GO:0016020), cell periphery (GO:0071944)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cell-Cell communication	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
MAPK cascade	1
striated muscle tissue development	1
skeletal muscle organ development	1
syncytium formation by cell-cell fusion	1
myotube differentiation	1
macromolecule biosynthetic process	1
actin filament polymerization	1
regulation of actin filament polymerization	1
positive regulation of protein polymerization	1
positive regulation of cytoskeleton organization	1
positive regulation of supramolecular fiber organization	1
extracellular matrix organization	1
glomerulus development	1
anatomical structure development	1
protein localization to cell junction	1
filtration diaphragm assembly	1
podocyte differentiation	1
glomerular epithelial cell development	1
cell adhesion	1
intracellular signaling cassette	1
cellular process	1
animal organ development	1
muscle structure development	1
cytoskeletal protein binding	1
protein binding	1
binding	1
membrane	1
cell periphery	1
anchoring junction	1
cell-substrate junction	1
filtration diaphragm	1
extracellular vesicle	1

Protein interactions and networks

STRING

1636 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NPHS1	CD2AP	Q9Y5K6	999
NPHS1	NPHS2	Q9NP85	999
NPHS1	TJP1	Q07157	994
NPHS1	NCK1	P16333	994
NPHS1	KIRREL1	Q96J84	991
NPHS1	TRPC6	Q9Y210	990
NPHS1	ACTN4	O43707	988
NPHS1	WASL	O00401	987
NPHS1	CDH3	P22223	985
NPHS1	SYNPO	Q8N3V7	967
NPHS1	PLCE1	Q9P212	948
NPHS1	KIRREL3	Q8IZU9	943
NPHS1	WT1	P19544	934
NPHS1	FAT1	Q14517	928
NPHS1	INF2	Q27J81	928

IntAct

17 interactions, top by confidence:

A	B	Type	Score
NPHS1	IQGAP1	psi-mi:“MI:0403”(colocalization)	0.520
NPHS1	IQGAP1	psi-mi:“MI:0915”(physical association)	0.520
IQGAP1	NPHS1	psi-mi:“MI:0915”(physical association)	0.520
NPHS1	IQGAP1	psi-mi:“MI:2364”(proximity)	0.520
IQGAP1	NPHS1	psi-mi:“MI:0403”(colocalization)	0.520
NCK1	NPHS1	psi-mi:“MI:0915”(physical association)	0.520
NPHS1	NCK2	psi-mi:“MI:0915”(physical association)	0.460
NPHS1	NCK2	psi-mi:“MI:0403”(colocalization)	0.460
NPHS1	Was	psi-mi:“MI:0915”(physical association)	0.400
ALB	CNOT1	psi-mi:“MI:0914”(association)	0.350
KIAA1191	NPHS1	psi-mi:“MI:0914”(association)	0.350
NPHS1	SLC25A16	psi-mi:“MI:0914”(association)	0.350
tenA	NPHS1	psi-mi:“MI:0915”(physical association)	0.000
NPHS1	eno	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (37): IQGAP1 (Affinity Capture-Western), NPHS1 (Affinity Capture-Western), FYN (Affinity Capture-Western), YES1 (Affinity Capture-Western), FYN (Affinity Capture-Western), NPHS1 (Reconstituted Complex), NPHS1 (Affinity Capture-Western), NPHS1 (Biochemical Activity), NPHS1 (Affinity Capture-Western), NPHS1 (Affinity Capture-Western), NPHS1 (Affinity Capture-Western), NPHS1 (Reconstituted Complex), SLC25A16 (Affinity Capture-MS), ATP12A (Affinity Capture-MS), TMEM57 (Affinity Capture-MS)

ESM2 similar proteins: A0A140LHF2, A0JPB1, A2AJ76, A7LCJ3, A8E0Y8, E7FF10, O00241, O60500, P01874, P03988, P04221, P0DOX2, P0DOX3, P0DOX4, P0DOX6, P0DP72, P32507, P35590, P43121, P50895, Q06805, Q06806, Q148M6, Q15109, Q5TFQ8, Q5U5A3, Q5XI43, Q62230, Q62786, Q8HW98, Q8NDA2, Q8R2Y2, Q92154, Q923P0, Q93033, Q95KI3, Q96MS0, Q9BRK3, Q9BZZ2, Q9DBV4

Diamond homologs: O60500, O97394, P04937, P07589, P11276, Q28749, Q64604, Q9N3X8, Q9QZS7, Q9R044, B0BNK7, B4MR28, D2HFT7, D4A1J9, D4ABX8, O60229, P0C5E3, P56974, Q08E66, Q14982, Q149C3, Q1RMS4, Q3UH53, Q3UQ28, Q3URE9, Q460M5, Q58EX2, Q5IS61, Q5STE3, Q60ZN5, Q62718, Q63HQ2, Q68FQ2, Q696W0, Q6NUX0, Q6PGX3, Q6PJG9, Q6UY18, Q6V4S5, Q7Z5N4

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
PRKCA	“up-regulates activity”	NPHS1	phosphorylation
FYN	“up-regulates activity”	NPHS1	phosphorylation
SRC	“up-regulates activity”	NPHS1	phosphorylation
WT1	“up-regulates quantity by expression”	NPHS1	“transcriptional regulation”
AGTR1	“down-regulates activity”	NPHS1

Disease & clinical

Clinical variants and AI predictions

ClinVar

1998 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	141
Likely pathogenic	241
Uncertain significance	449
Likely benign	891
Benign	46

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071713	NC_000019.9:g.(?36317274)(36326673_?)del	Pathogenic
1071839	NM_004646.4(NPHS1):c.3128_3132del (p.Gly1043fs)	Pathogenic
1071951	NM_004646.4(NPHS1):c.2289del (p.Asp764fs)	Pathogenic
1074718	NM_004646.4(NPHS1):c.3213del (p.Leu1072fs)	Pathogenic
1357218	NM_004646.4(NPHS1):c.2335-2A>G	Pathogenic
1361511	NM_004646.4(NPHS1):c.1768_1772del (p.Val590fs)	Pathogenic
1369825	NM_004646.4(NPHS1):c.649del (p.Cys217fs)	Pathogenic
1377212	NM_004646.4(NPHS1):c.1279G>T (p.Glu427Ter)	Pathogenic
1381042	NM_004646.4(NPHS1):c.298del (p.Ala100fs)	Pathogenic
1384606	NM_004646.4(NPHS1):c.1121G>A (p.Trp374Ter)	Pathogenic
1423988	NM_004646.4(NPHS1):c.322G>T (p.Glu108Ter)	Pathogenic
1432288	NM_004646.4(NPHS1):c.1908_1909insGAGAGGAGGTCGCGGCGCCGGAGGCCCCAGAAGGGTCGACGGCGCCGCGGGCTGGGGTCGGTGGCTTAGGGAGCCCNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAGAAACCGTGAGCTCC (p.Phe637delinsGluArgArgSerArgArgArgArgProGlnLysGlyArgArgArgArgGlyLeuGlySerValAlaTer)	Pathogenic
1440426	NM_004646.4(NPHS1):c.459del (p.Gln154fs)	Pathogenic
1442289	NM_004646.4(NPHS1):c.1753del (p.Glu585fs)	Pathogenic
1454548	NM_004646.4(NPHS1):c.479G>A (p.Cys160Tyr)	Pathogenic
1455449	NM_004646.4(NPHS1):c.3258del (p.Trp1086fs)	Pathogenic
1459984	NC_000019.9:g.(?36330129)(36335371_?)del	Pathogenic
1526163	NM_004646.4(NPHS1):c.869del (p.Gly290fs)	Pathogenic
1722406	NM_004646.4(NPHS1):c.2587T>C (p.Cys863Arg)	Pathogenic
180463	NM_004646.4(NPHS1):c.1756A>G (p.Arg586Gly)	Pathogenic
1809715	NM_004646.4(NPHS1):c.2931T>G (p.Tyr977Ter)	Pathogenic
1809716	NM_004646.4(NPHS1):c.1745_1749del (p.Lys582fs)	Pathogenic
188734	NM_004646.4(NPHS1):c.2335-1G>A	Pathogenic
188761	NM_004646.4(NPHS1):c.2928G>T (p.Arg976Ser)	Pathogenic
188816	NM_004646.4(NPHS1):c.565G>T (p.Glu189Ter)	Pathogenic
189074	NM_004646.4(NPHS1):c.3442C>T (p.Gln1148Ter)	Pathogenic
1986199	NM_004646.4(NPHS1):c.3135_3136del (p.Glu1046fs)	Pathogenic
2004649	NM_004646.4(NPHS1):c.2840del (p.Gly946_Leu947insTer)	Pathogenic
2008297	NM_004646.4(NPHS1):c.2443C>T (p.Gln815Ter)	Pathogenic
2011690	NM_004646.4(NPHS1):c.3259C>T (p.Gln1087Ter)	Pathogenic

SpliceAI

6612 predictions. Top by Δscore:

Variant	Effect	Δscore
19:35830843:CCAT:C	donor_gain	1.0000
19:35831291:CTTA:C	donor_loss	1.0000
19:35831292:TTA:T	donor_loss	1.0000
19:35831293:TA:T	donor_loss	1.0000
19:35831295:C:CT	donor_loss	1.0000
19:35831376:CAGGA:C	acceptor_gain	1.0000
19:35831380:A:AC	acceptor_gain	1.0000
19:35839262:C:A	donor_gain	1.0000
19:35839298:A:AC	donor_gain	1.0000
19:35839299:C:CC	donor_gain	1.0000
19:35839322:T:C	donor_gain	1.0000
19:35839492:CCAC:C	donor_loss	1.0000
19:35839494:ACC:A	donor_loss	1.0000
19:35839495:C:CG	donor_loss	1.0000
19:35839604:CGGC:C	acceptor_gain	1.0000
19:35839605:GGC:G	acceptor_gain	1.0000
19:35839606:GCC:G	acceptor_loss	1.0000
19:35839607:CCTAT:C	acceptor_loss	1.0000
19:35839608:C:CC	acceptor_gain	1.0000
19:35839609:T:C	acceptor_loss	1.0000
19:35841713:A:AC	donor_gain	1.0000
19:35841714:C:CC	donor_gain	1.0000
19:35842378:CAT:C	donor_gain	1.0000
19:35844312:C:A	donor_gain	1.0000
19:35844313:CCTCA:C	donor_loss	1.0000
19:35844314:CTCA:C	donor_loss	1.0000
19:35844315:TCAC:T	donor_loss	1.0000
19:35844316:CACC:C	donor_loss	1.0000
19:35844472:C:CT	acceptor_gain	1.0000
19:35844475:C:CT	acceptor_gain	1.0000

AlphaMissense

7955 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:35839542:A:G	W961R	0.998
19:35839542:A:T	W961R	0.998
19:35842162:C:A	W875C	0.998
19:35842162:C:G	W875C	0.998
19:35842164:A:G	W875R	0.998
19:35842164:A:T	W875R	0.998
19:35841758:G:C	N924K	0.997
19:35841758:G:T	N924K	0.997
19:35841777:A:G	F918S	0.997
19:35841819:A:G	L904P	0.997
19:35848687:A:G	W374R	0.997
19:35848687:A:T	W374R	0.997
19:35841765:G:T	A922D	0.996
19:35844146:G:C	N723K	0.996
19:35844146:G:T	N723K	0.996
19:35848047:C:A	W478C	0.996
19:35848047:C:G	W478C	0.996
19:35848049:A:G	W478R	0.996
19:35848049:A:T	W478R	0.996
19:35848685:C:A	W374C	0.996
19:35848685:C:G	W374C	0.996
19:35841770:A:C	C920W	0.995
19:35841772:A:G	C920R	0.994
19:35851539:C:A	W64C	0.994
19:35851539:C:G	W64C	0.994
19:35851541:A:G	W64R	0.994
19:35851541:A:T	W64R	0.994
19:35839540:C:A	W961C	0.993
19:35839540:C:G	W961C	0.993
19:35839601:G:T	P941H	0.993

dbSNP variants (sampled 300 via entrez): RS1000080131 (19:35844296 C>G,T), RS1000115851 (19:35834705 C>T), RS1000278889 (19:35850748 C>T), RS1000370933 (19:35849726 G>T), RS1000478122 (19:35832653 G>A), RS1000517160 (19:35838197 C>G,T), RS1000624410 (19:35844569 T>A), RS1000712587 (19:35851040 G>A,C), RS1000716762 (19:35833665 C>T), RS1000905929 (19:35827004 C>T), RS1001024410 (19:35832096 T>A), RS1001055464 (19:35832436 C>G,T), RS1001095277 (19:35826410 G>A,C), RS1001290941 (19:35828268 CTTTTTCTTTTTT>C), RS1001316458 (19:35849852 G>T)

Disease associations

OMIM: gene MIM:602716 | disease phenotypes: MIM:256300

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital nephrotic syndrome, Finnish type	Definitive	Autosomal recessive
familial idiopathic steroid-resistant nephrotic syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
congenital nephrotic syndrome, Finnish type	Definitive	AR

Mondo (10): congenital nephrotic syndrome, Finnish type (MONDO:0009732), nephrotic syndrome (MONDO:0005377), focal segmental glomerulosclerosis (MONDO:0100313), kidney disorder (MONDO:0005240), familial nephrotic syndrome (MONDO:0002350), proteinuria (MONDO:0003634), familial idiopathic steroid-resistant nephrotic syndrome (MONDO:0019006), atypical hemolytic-uremic syndrome (MONDO:0016244), steroid-resistant nephrotic syndrome (MONDO:0044765), glomerulonephritis (MONDO:0002462)

Orphanet (3): Congenital nephrotic syndrome, Finnish type (Orphanet:839), Hereditary steroid-resistant nephrotic syndrome (Orphanet:656), Atypical hemolytic uremic syndrome (Orphanet:2134)

HPO phenotypes

40 total (30 of 40 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000091	Abnormal renal tubule morphology
HP:0000092	Renal tubular atrophy
HP:0000093	Proteinuria
HP:0000096	Glomerular sclerosis
HP:0000097	Focal segmental glomerulosclerosis
HP:0000100	Nephrotic syndrome
HP:0000696	Delayed eruption of permanent teeth
HP:0000707	Abnormality of the nervous system
HP:0000737	Irritability
HP:0000821	Hypothyroidism
HP:0000969	Edema
HP:0001510	Growth delay
HP:0001518	Small for gestational age
HP:0001945	Fever
HP:0001967	Diffuse mesangial sclerosis
HP:0002020	Gastroesophageal reflux
HP:0002021	Pyloric stenosis
HP:0002027	Abdominal pain
HP:0002315	Headache
HP:0002586	Peritonitis
HP:0002643	Neonatal respiratory distress
HP:0002719	Recurrent infections
HP:0003073	Hypoalbuminemia
HP:0003075	Hypoproteinemia
HP:0003077	Hyperlipidemia
HP:0003124	Hypercholesterolemia
HP:0003270	Abdominal distention
HP:0003577	Congenital onset

GWAS associations

0 associations (top):

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D065766	Atypical Hemolytic Uremic Syndrome	C12.050.351.968.419.936.463.500; C12.200.777.419.936.463.500; C12.950.419.936.463.500; C15.378.050.141.610.500; C15.378.140.855.925.500.500; C15.378.243.937.925.500.500
D005921	Glomerulonephritis	C12.050.351.968.419.570.363; C12.200.777.419.570.363; C12.950.419.570.363
D005923	Glomerulosclerosis, Focal Segmental	C12.050.351.968.419.570.363.640; C12.200.777.419.570.363.660; C12.950.419.570.363.640
D007674	Kidney Diseases	C12.050.351.968.419; C12.200.777.419; C12.950.419
D009404	Nephrotic Syndrome	C12.050.351.968.419.630.643; C12.200.777.419.630.643; C12.950.419.630.643
D011507	Proteinuria	C12.050.351.968.934.734; C12.200.777.934.734; C12.950.934.734; C23.888.942.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs3814995	Efficacy	3	losartan	Hypertension

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3814995	KIRREL2, NPHS1	3	0.00	1	losartan

CTD chemical–gene interactions

36 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases reaction	2
sodium arsenite	affects methylation, increases expression	2
Tretinoin	decreases reaction, increases expression, increases activity, affects binding	2
aristolochic acid I	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
propionaldehyde	increases expression	1
pirinixic acid	decreases reaction, increases expression, increases reaction, increases stability	1
cobaltous chloride	affects localization, decreases expression	1
butyraldehyde	increases expression	1
bisphenol A diglycidyl ether	increases expression, decreases reaction	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
arachidonyl-2-chloroethylamide	decreases reaction, increases expression	1
BMS 189453	decreases reaction, increases activity	1
abrine	increases expression	1
licochalcone B	increases expression	1
jinfukang	increases expression	1
trametinib	affects cotreatment, decreases expression	1
(+)-JQ1 compound	increases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Pioglitazone	decreases reaction, increases expression, affects binding, increases reaction	1
Aldehydes	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Bezafibrate	increases reaction, increases stability, decreases reaction, increases expression	1
Glucose	affects reaction, decreases expression	1
Puromycin	affects localization	1
Silicon Dioxide	increases expression	1
Tamoxifen	decreases expression, decreases reaction	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1YU	Abcam HeLa NPHS1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

174 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00308321	PHASE4	UNKNOWN	Long Term Tapering or Standard Steroids for Nephrotic Syndrome
NCT01021540	PHASE4	COMPLETED	Prospective Study Evaluating the Effect of Repository Corticotropin in the Treatment of Various Nephrotic Syndromes
NCT01028287	PHASE4	COMPLETED	Adrenocorticotropic Hormone (ACTH) Treatment of Nephrotic Range Proteinuria in Diabetic Nephropathy (NRDN)
NCT01162005	PHASE4	COMPLETED	Therapeutic Effect of Tacrolimus on Primary Nephrotic Syndrome in Children
NCT01895894	PHASE4	COMPLETED	Mycophenolate Mofetil in Pediatric Steroid Dependent Nephrotic Syndrome
NCT02238418	PHASE4	COMPLETED	Efficacy of Usual Vitamin D Supplementation and Its Impact on Children and Adolescents Calciuria.
NCT02382575	PHASE4	UNKNOWN	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Resistant Nephrotic Syndrome
NCT02427880	PHASE4	COMPLETED	Role of Acetazolamide and Hydrochlorothiazide Followed by Furosemide in Treating Nephrotic Edema
NCT03210688	PHASE4	COMPLETED	Active Vitamin D And Reduced Dose Prednisolone for Treatment in Minimal Change Nephropathy
NCT03347357	PHASE4	COMPLETED	Pharmacokinetics of Tacrolimus in Children
NCT05696977	PHASE4	UNKNOWN	Effect of Obesity on Cyclosporine Blood Trough Level in Nephrotic Syndrome Patients
NCT05966818	PHASE4	UNKNOWN	Effect of Dapagliflozin in Non-Diabetic Patients With Nephrotic Syndrome.
NCT06026787	PHASE4	COMPLETED	Clinical Value of Adding Dapagliflozin in Patients With Nephrotic Syndrome
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
NCT07219121	PHASE4	RECRUITING	Sparsentan in Posttransplant Immunoglobulin A Nephropathy or Focal Segmental Glomerulosclerosis
NCT00354731	PHASE3	COMPLETED	Efficacy of Pentoxifylline on Primary Nephrotic Syndrome
NCT00615667	PHASE3	COMPLETED	Prospective, Multicenter Study of the Efficacy and Tolerance of Tacrolimus on Refractory Nephrotic Syndrome (RNS)
NCT00981838	PHASE3	COMPLETED	Rituximab in Multirelapsing Minimal Change Disease (MCD) or Focal Segmental Glomerulosclerosis (FSGS)
NCT01197040	PHASE3	COMPLETED	Evaluation of Low Dose Corticosteroids Efficiency, Associated With Myfortic ® in the Treatment of Nephrotic Syndrome
NCT01309477	PHASE3	COMPLETED	The Efficacy and Tolerance of Tacrolimus Sustained-release Capsules on Refractory Nephrotic Syndrome (RNS)
NCT02132195	PHASE3	COMPLETED	Adrenocorticotropic Hormone (ACTH) for Frequently Relapsing and Steroid Dependent Nephrotic Syndrome
NCT02257697	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mizoribine in the Treatment of Refractory Nephrotic Syndrome
NCT02438982	PHASE3	COMPLETED	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Dependent Nephrotic Syndrome
NCT03141970	PHASE3	COMPLETED	Prednisolone Trial in Children Younger Than 4 Years
NCT03501459	PHASE3	UNKNOWN	Lymphocyte Markers As Predictors Of Responsiveness To Rituximab Among Patients With Idiopathic Nephrotic Syndrome
NCT05079789	PHASE3	TERMINATED	Amiloride in Nephrotic Syndrome
NCT05716880	PHASE3	RECRUITING	Ketoanalogues for Muscle Mass Loss in Nephrotic Syndrome
NCT06635720	PHASE3	ACTIVE_NOT_RECRUITING	REduced-dose Steroid PrOtocol for Childhood Nephrotic SyndromE (RESPONSE)
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
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)
NCT05183646	PHASE3	RECRUITING	A Study of the Efficacy and Safety of DMX-200 in Patients With FSGS Who Are Receiving an ARB
NCT07220083	PHASE3	RECRUITING	A Study to Find Out if BI 764198 Helps Adults and Adolescents With a Kidney Condition Called Focal Segmental Glomerulosclerosis (FSGS)
NCT00001212	PHASE2	COMPLETED	Drug Therapy in Lupus Nephropathy
NCT00001959	PHASE2	COMPLETED	Pirfenidone to Treat Kidney Disease (Focal Segmental Glomerulosclerosis)
NCT00004466	PHASE2	TERMINATED	Pilot Study of Atorvastatin in Children With Chronic Hyperlipidemia Secondary to Nephrotic Syndrome