NPHS2

Summary

NPHS2 (NPHS2 stomatin family member, podocin, HGNC:13394) is a protein-coding gene on chromosome 1q25.2, encoding Podocin (Q9NP85). Plays a role in the regulation of glomerular permeability, acting probably as a linker between the plasma membrane and the cytoskeleton.

This gene encodes a protein that plays a role in the regulation of glomerular permeability. Mutations in this gene cause steroid-resistant nephrotic syndrome. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 7827 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nephrotic syndrome, type 2 (Definitive, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 444 total — 39 pathogenic, 54 likely-pathogenic
• Phenotypes (HPO): 23
• MANE Select transcript: NM_014625

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13394
Approved symbol	NPHS2
Name	NPHS2 stomatin family member, podocin
Location	1q25.2
Locus type	gene with protein product
Status	Approved
Aliases	SRN1, PDCN
Ensembl gene	ENSG00000116218
Ensembl biotype	protein_coding
OMIM	604766
Entrez	7827

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000367615, ENST00000367616, ENST00000902256

RefSeq mRNA: 2 — MANE Select: NM_014625 NM_001297575, NM_014625

CCDS: CCDS1331, CCDS72988

Canonical transcript exons

ENST00000367615 — 8 exons

Exon	Start	End
ENSE00000790110	179552603	179552681
ENSE00000790111	179554476	179554531
ENSE00000790112	179557027	179557230
ENSE00000790114	179561289	179561361
ENSE00000790115	179564690	179564793
ENSE00000959326	179559679	179559761
ENSE00001445165	179550539	179551451
ENSE00001926480	179575591	179575948

Expression profiles

Bgee: expression breadth broad, 47 present calls, max score 99.70.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1774 / max 188.1572, expressed in 5 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
16082	0.1774	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
renal glomerulus	UBERON:0000074	99.70	gold quality
metanephric glomerulus	UBERON:0004736	99.64	gold quality
kidney epithelium	UBERON:0004819	95.29	gold quality
adult mammalian kidney	UBERON:0000082	94.03	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.54	gold quality
kidney	UBERON:0002113	89.91	gold quality
nephron tubule	UBERON:0001231	88.33	gold quality
sperm	CL:0000019	87.84	gold quality
male germ cell	CL:0000015	86.52	gold quality
metanephros	UBERON:0000081	85.88	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.25	gold quality
adult organism	UBERON:0007023	81.87	gold quality
cortex of kidney	UBERON:0001225	80.54	gold quality
renal medulla	UBERON:0000362	73.04	gold quality
olfactory bulb	UBERON:0002264	71.77	gold quality
type B pancreatic cell	CL:0000169	71.67	gold quality
metanephros cortex	UBERON:0010533	68.80	gold quality
cervix squamous epithelium	UBERON:0006922	64.97	gold quality
cervix epithelium	UBERON:0004801	61.47	gold quality
oocyte	CL:0000023	61.06	gold quality
left ventricle myocardium	UBERON:0006566	60.87	gold quality
choroid plexus epithelium	UBERON:0003911	59.82	gold quality
cardiac muscle of right atrium	UBERON:0003379	59.22	gold quality
diaphragm	UBERON:0001103	59.14	gold quality
thymus	UBERON:0002370	56.31	gold quality
nasal cavity epithelium	UBERON:0005384	55.76	gold quality
myocardium	UBERON:0002349	55.35	gold quality
oviduct epithelium	UBERON:0004804	55.22	gold quality
quadriceps femoris	UBERON:0001377	55.06	gold quality
vastus lateralis	UBERON:0001379	54.92	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-114530	yes	3236.72
E-GEOD-124472	yes	1355.84
E-CURD-119	yes	34.11
E-HCAD-10	yes	23.20
E-ANND-3	yes	2.78

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): LMX1B, MAFB, USF1

miRNA regulators (miRDB)

39 targeting NPHS2, 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-574-5P	100.00	66.01	989
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-4658	99.77	64.94	514
HSA-MIR-6790-5P	99.77	65.24	505
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-3122	99.50	66.33	821
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-1224-5P	99.48	65.59	803
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-196A-3P	99.19	67.34	1204
HSA-MIR-146A-3P	99.13	68.99	1881
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-3164	99.02	68.39	1071
HSA-MIR-6820-3P	99.02	68.50	1035
HSA-MIR-3124-3P	98.87	68.95	2123
HSA-MIR-302F	98.44	69.02	1776
HSA-MIR-5691	98.23	67.02	1335
HSA-MIR-6805-3P	98.23	67.02	1334
HSA-MIR-6757-5P	98.08	65.50	724

Literature-anchored findings (GeneRIF, showing 40)

• First evidence of podocin mutations in sporadic steroid-resistant nephrotic syndrome. (PMID:11729243)
• Mutations interact with nephrin to produce either nephrotic syndrome or focal glomerosclerosis, depending on alleles. (PMID:11854170)
• Ten NPHS2 autosomal recessive mutations have been identified in corticosteroid resistant familial nephrotic syndrome. Podocin plays a major role in glomerular filtration and podocyte physiology. (PMID:11908478)
• Serum glomerular permeability activity in patients with podocin mutations (NPHS2) and steroid-resistant nephrotic syndrome. (PMID:12089392)
• co-localization of nephrin, this protein and the actin cytoskeleton: evidence for a role in podocyte foot process formation. (PMID:12368218)
• Mutated in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele (PMID:12464671)
• Mutations in alpha-actinin 4 (ACTN4) and podocin genes were reported in patients with such familial FSGS. (PMID:12617336)
• results reveal defective cellular processing of the mutant podocin, and provide evidence for pharmacological correction of the processing defect (PMID:12649741)
• NPHS2 gene mutations are not a major cause of chronic renal insufficiency caused by sporadic SRNS or heavy proteinuria in Japanese children. (PMID:12687458)
• mutation is associated with early onset of proteinuria and variable renal lesions (PMID:12707396)
• Dramatic decrease of podocin expression was found in children with nephrotic syndrome. (PMID:12961083)
• Mutations of NPHS1 or NPHS2, the genes encoding for nephrin and podocin, lead to early onset of heavy proteinuria, and rapid progression to end-stage renal disease, suggesting that both proteins are essential for the integrity of the glomerular filter. (PMID:14570703)
• Data show that brefeldin A and most of the NPHS2/podocin mutations lead to retention of podocin in the endoplasmic reticulum. (PMID:14675423)
• A strong association was found between the 229Q allele and microalbuminuria (P= 0.008). (PMID:14871423)
• Heterozygous NPHS2 variants may play a role in atypical cases with mild, late-onset course, and recurrence after transplantation. (PMID:15253708)
• We identified a novel mutation of NPHS2 gene(467_468insT and 503G>A) in a Chinese family with autosomal recessive steroid-resistent nephrotic syndrome by mutational analysis. (PMID:15322893)
• NPHS2 mutations result in profound alteration of podocin expression and/or distribution. (PMID:15327385)
• In steroid-resistant nephrotic syndrome some missense mutations in NPHS2 lead to misfolding and mislocalization of mutated podocin and interfere with slit diaphragm structure and function by altering proper trafficking of nephrin to plasma membrane. (PMID:15496146)
• 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)
• Mutation of NPHS2 can be responsible for congenital nephrotic syndrome in Japanese patients. (PMID:15780077)
• Clinical spectrum and fine mechanisms of NPHS2 (Podocin) mutations in nephrotic syndrome [review] (PMID:15817495)
• serum and plasma factors from focal segmental glomerulosclerosis patients may directly affect nephrin and podocin in human podocytes (PMID:15942677)
• uncommon variants of the NPHS2 gene may play a role in the development of nondiabetic end stage renal disease in African Americans (PMID:15954915)
• Gene mutations for podocin cause the damage of filtration barrier of glomerulus and proteinuria in consequence. (PMID:16898497)
• 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)
• Post kidney transplantation recurrence of podocin in patients carrying homozygous and/or heterozygous posttransplantation recurrence of FSGS in patients originally carrying homozygous and/or heterozygous focal segmental glomerulosclerosis mutations. (PMID:17175312)
• Mutations may play pathogenetic roles in some patients with sporadic steroid resistant nephrotic syndrome. (PMID:17211152)
• study suggests mutations in NPHS2 & WT1 are not a cause of uncomplicated steroid sensitive nephrotic syndrome or frequently relapsing & steroid-dependent nephrotic syndrome(FRNS/SDNS) (PMID:17216259)
• re-evaluated cclinical fils and echocardiography of 12 patients with NPHS2 mutation and sporadic nephrotic syndrome and failed to confirm association with cardiac defects (PMID:17218332)
• The result did not support the possible role of the NPHS2 gene in susceptibility to Henoch-Schonlein purpura nephritis in the population studied. (PMID:17393177)
• no significant difference in the genotypic and allelic frequencies of the identified 954T > C and 1038A > G polymorphisms between the sporadic IgA nephropathy patients and normal controls was found (PMID:17635752)
• data do not support R229Q as a disease-causing mutation for steroid-resistant focal segmental glomerulosclerosis (PMID:17699384)
• Podocin mutations are responsible for some of both familial and sporadic steroid-resistant nephrotic syndrome cases in Turkey. (PMID:17899208)
• NPHS2 and WT1 are now known to be genes commonly involved in the pathogenesis of sporadic steroid-resistant nephrotic syndrome. However, the incidence of NPHS2 gene mutation shows interethnic difference. (PMID:17934764)
• These results indicate that genetic variation or mutation of NPHS2 may play a role in late-onset sporadic FSGS. (PMID:17942957)
• common variants in LRRC7, KIRREL, NPHS2 and ACTN4 do not appeear to contribute to susceptibility to diabetic nephropathy in Finnish patients with type 1 diabetes (PMID:17968527)
• Late steroid-resistant nephrotic syndrome is not typically associated with mutations in the NPHS2 gene. (PMID:18000687)
• no causative NPHS2 mutations were identified in Japanese pediatric focal segmental glomerulosclerosis patients with or without post-transplant recurrence (PMID:18208440)
• nephrotic syndrome in children with truncating or homozygous R138Q mutations manifests predominantly before 6 yr of life, and the onset of disease is significantly earlier than for any other podocin mutations (PMID:18216321)
• NPHS2 mutations are prevalent in Egyptian children with non-familial steroid-resistant nephrotic syndrome (SRNS) and this may in part explain the less favorable prognosis reported in these patients (PMID:18334793)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nphs2	ENSDARG00000042850
mus_musculus	Nphs2	ENSMUSG00000026602
rattus_norvegicus	Nphs2	ENSRNOG00000004030

Paralogs (4): STOML1 (ENSG00000067221), STOML3 (ENSG00000133115), STOM (ENSG00000148175), STOML2 (ENSG00000165283)

Protein

Protein identifiers

Podocin — Q9NP85 (reviewed: Q9NP85)

All UniProt accessions (1): Q9NP85

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in the regulation of glomerular permeability, acting probably as a linker between the plasma membrane and the cytoskeleton.

Subunit / interactions. Interacts with nephrin/NPHS1 and KIRREL1. Interacts directly with CD2AP. Interacts with DDN.

Subcellular location. Cell membrane Endoplasmic reticulum.

Tissue specificity. Almost exclusively expressed in the podocytes of fetal and mature kidney glomeruli.

Post-translational modifications. Glycosylated.

Disease relevance. Nephrotic syndrome 2 (NPHS2) [MIM:600995] 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. The disorder is resistant to steroid treatment and progresses to end-stage renal failure in the first or second decades. Some patients show later onset of the disorder. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the band 7/mec-2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NP85-1	1	yes
Q9NP85-2	2, Pod-short

RefSeq proteins (2): NP_001284504, NP_055440* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001107	Band_7	Domain
IPR001972	Stomatin_HflK_fam	Family
IPR018080	Band_7/stomatin-like_CS	Conserved_site
IPR036013	Band_7/SPFH_dom_sf	Homologous_superfamily
IPR043202	Band-7_stomatin-like	Family

Pfam: PF01145

UniProt features (85 total): sequence variant 74, topological domain 2, region of interest 2, compositionally biased region 2, chain 1, intramembrane region 1, lipid moiety-binding region 1, glycosylation site 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NP85-F1	75.00	0.41

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 (1): 101

Glycosylation sites (1): 287

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-373753	Nephrin family interactions

MSigDB gene sets: 143 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_METANEPHROS_DEVELOPMENT, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_METANEPHRIC_EPITHELIUM_DEVELOPMENT, GOBP_KIDNEY_EPITHELIUM_DEVELOPMENT, GOBP_CELL_DIFFERENTIATION_INVOLVED_IN_METANEPHROS_DEVELOPMENT, GOBP_CELL_DIFFERENTIATION_INVOLVED_IN_KIDNEY_DEVELOPMENT, GOBP_NEPHRON_EPITHELIUM_DEVELOPMENT, GOBP_GLOMERULUS_DEVELOPMENT, GOBP_METANEPHRIC_NEPHRON_DEVELOPMENT, GOBP_GLOMERULAR_EPITHELIUM_DEVELOPMENT, GOBP_EPITHELIAL_CELL_DIFFERENTIATION_INVOLVED_IN_KIDNEY_DEVELOPMENT, CUI_TCF21_TARGETS_2_DN, GOCC_CELL_CELL_JUNCTION, GOBP_NEPHRON_DEVELOPMENT

GO Biological Process (4): glomerular filtration (GO:0003094), gene expression (GO:0010467), actin cytoskeleton organization (GO:0030036), metanephric podocyte development (GO:0072249)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (10): endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), cytoplasmic side of plasma membrane (GO:0009898), protein-containing complex (GO:0032991), slit diaphragm (GO:0036057), membrane raft (GO:0045121), 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	2
renal filtration	1
macromolecule biosynthetic process	1
cytoskeleton organization	1
actin filament-based process	1
podocyte development	1
metanephric podocyte differentiation	1
metanephric glomerular epithelial cell development	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
anchoring junction	1
plasma membrane	1
cytoplasmic side of membrane	1
cellular_component	1
filtration diaphragm	1
membrane microdomain	1
extracellular vesicle	1

Protein interactions and networks

STRING

1792 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NPHS2	KIRREL1	Q96J84	999
NPHS2	CD2AP	Q9Y5K6	999
NPHS2	NPHS1	O60500	999
NPHS2	TRPC6	Q9Y210	998
NPHS2	TJP1	Q07157	987
NPHS2	ACTN4	O43707	971
NPHS2	CDH3	P22223	961
NPHS2	PLCE1	Q9P212	943
NPHS2	KIRREL3	Q8IZU9	937
NPHS2	FAT1	Q14517	926
NPHS2	SYNPO	Q8N3V7	926
NPHS2	KIRREL2	Q6UWL6	922
NPHS2	INF2	Q27J81	921
NPHS2	WT1	P19544	918
NPHS2	PODXL	O00592	870

IntAct

5 interactions, top by confidence:

A	B	Type	Score
NPHS2	IQGAP1	psi-mi:“MI:0403”(colocalization)	0.520
IQGAP1	NPHS2	psi-mi:“MI:0915”(physical association)	0.520
NPHS2	IQGAP1	psi-mi:“MI:0915”(physical association)	0.520
IQGAP1	NPHS2	psi-mi:“MI:2364”(proximity)	0.520

BioGRID (14): Nphs1 (Affinity Capture-Western), Nphs2 (Affinity Capture-Western), NPHS1 (Affinity Capture-Western), CD2AP (Affinity Capture-Western), CD2AP (Reconstituted Complex), NPHS1 (Reconstituted Complex), NPHS2 (Reconstituted Complex), NPHS2 (Reconstituted Complex), NPHS2 (Reconstituted Complex), NPHS2 (Cross-Linking-MS (XL-MS)), NPHS2 (Affinity Capture-MS), SH3KBP1 (Affinity Capture-Western), NPHS2 (Affinity Capture-Western), CD2AP (Affinity Capture-Western)

ESM2 similar proteins: A2RAF6, A9UMS3, B8BDV1, H1VAN0, H2FLJ1, O04979, O26788, O60121, O61492, O83151, O83152, P27105, P50085, P50093, P54116, P63694, P72655, P93647, P9WPR8, P9WPR9, Q0E3C8, Q0J032, Q16TM5, Q19200, Q19958, Q20657, Q21190, Q22165, Q27433, Q2TAF8, Q32LL2, Q3MIB4, Q3SX23, Q4FZT0, Q4WVD9, Q5R6M5, Q5UP73, Q6PE84, Q7PPU9, Q86WA8

Diamond homologs: H2FLJ1, O26788, O28852, O59180, O60121, P0AA53, P0AA54, P0AA55, P0AA56, P0DKS0, P27105, P54116, P63694, P72655, P9WPR8, P9WPR9, Q16TM5, Q19200, Q19958, Q20657, Q21190, Q22165, Q27433, Q32LL2, Q4FZT0, Q58237, Q5UP73, Q6PE84, Q7PPU9, Q8CI66, Q8K4G9, Q8K914, Q8TAV4, Q91X05, Q99JB2, Q9NP85, Q9UBI4, Q9UJZ1, Q9V0Y1, Q9VZA4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	39
Likely pathogenic	54
Uncertain significance	111
Likely benign	156
Benign	20

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1073153	NM_014625.4(NPHS2):c.522dup (p.Pro175fs)	Pathogenic
1073625	NM_014625.4(NPHS2):c.486C>A (p.Tyr162Ter)	Pathogenic
1075133	NM_014625.4(NPHS2):c.360del (p.Ile121fs)	Pathogenic
1344814	NM_014625.4(NPHS2):c.1A>T (p.Met1Leu)	Pathogenic
1344816	NM_014625.4(NPHS2):c.397del (p.Arg133fs)	Pathogenic
1439693	NM_014625.4(NPHS2):c.506T>C (p.Leu169Pro)	Pathogenic
188990	NM_014625.4(NPHS2):c.948del (p.Ala317fs)	Pathogenic
2023790	NM_014625.4(NPHS2):c.388G>T (p.Glu130Ter)	Pathogenic
2025352	NM_014625.4(NPHS2):c.676del (p.Leu225_Leu226insTer)	Pathogenic
2029307	NM_014625.4(NPHS2):c.586del (p.Arg196fs)	Pathogenic
2030308	NM_014625.4(NPHS2):c.738+1G>C	Pathogenic
2091205	NM_014625.4(NPHS2):c.48_156del (p.Gly17fs)	Pathogenic
2202889	NM_014625.4(NPHS2):c.555del (p.Phe185fs)	Pathogenic
2734049	NM_014625.4(NPHS2):c.562G>T (p.Glu188Ter)	Pathogenic
2742914	NM_014625.4(NPHS2):c.736A>T (p.Lys246Ter)	Pathogenic
2771430	NM_014625.4(NPHS2):c.3G>T (p.Met1Ile)	Pathogenic
2836227	NM_014625.4(NPHS2):c.205G>T (p.Glu69Ter)	Pathogenic
3024013	NM_014625.4(NPHS2):c.130G>T (p.Glu44Ter)	Pathogenic
3239972	NM_014625.4(NPHS2):c.104_126dup (p.Pro43fs)	Pathogenic
3247988	NC_000001.10:g.(?179533805)(179533948_?)del	Pathogenic
3247989	NC_000001.10:g.(?179530415)(179537345_?)del	Pathogenic
3574492	NM_014625.4(NPHS2):c.2T>C (p.Met1Thr)	Pathogenic
397592	NM_014625.4(NPHS2):c.452-1G>A	Pathogenic
4059073	NM_014625.4(NPHS2):c.377del (p.Lys126fs)	Pathogenic
447876	NM_014625.4(NPHS2):c.104dup (p.Arg36fs)	Pathogenic
4711235	NM_014625.4(NPHS2):c.126_166del (p.Pro43fs)	Pathogenic
4815732	NM_014625.4(NPHS2):c.378+1G>T	Pathogenic
4819379	NM_014625.4(NPHS2):c.102del (p.Gly35fs)	Pathogenic
5361	NM_014625.4(NPHS2):c.412C>T (p.Arg138Ter)	Pathogenic
5366	NM_014625.4(NPHS2):c.274G>T (p.Gly92Cys)	Pathogenic

SpliceAI

1179 predictions. Top by Δscore:

Variant	Effect	Δscore
1:179559673:GCTTA:G	donor_loss	1.0000
1:179559674:CTTA:C	donor_loss	1.0000
1:179559675:TTAC:T	donor_loss	1.0000
1:179559676:TA:T	donor_loss	1.0000
1:179559760:ACCTA:A	acceptor_loss	1.0000
1:179559761:CCTA:C	acceptor_loss	1.0000
1:179559762:C:T	acceptor_loss	1.0000
1:179575588:TA:T	donor_loss	1.0000
1:179575589:ACCTT:A	donor_gain	1.0000
1:179575590:CCT:C	donor_loss	1.0000
1:179575590:CCTTC:C	donor_gain	1.0000
1:179575593:T:TA	donor_gain	1.0000
1:179552677:CTTTA:C	acceptor_gain	0.9900
1:179552682:C:CC	acceptor_gain	0.9900
1:179559678:CCT:C	donor_gain	0.9900
1:179559762:C:CC	acceptor_gain	0.9900
1:179575624:C:CT	donor_gain	0.9900
1:179575625:C:CT	donor_gain	0.9900
1:179552678:TTTA:T	acceptor_gain	0.9800
1:179552679:TTA:T	acceptor_gain	0.9800
1:179552680:TA:T	acceptor_gain	0.9800
1:179554435:T:A	donor_gain	0.9800
1:179559677:A:AC	donor_gain	0.9800
1:179559678:C:CC	donor_gain	0.9800
1:179575589:A:AC	donor_gain	0.9800
1:179575590:C:CC	donor_gain	0.9800
1:179575590:CCTT:C	donor_gain	0.9800
1:179551452:C:CC	acceptor_gain	0.9700
1:179554495:T:TA	acceptor_gain	0.9700
1:179559759:GAC:G	acceptor_gain	0.9700

AlphaMissense

2461 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:179554501:C:G	G257R	0.993
1:179554501:C:T	G257R	0.993
1:179554500:C:T	G257E	0.992
1:179561327:C:G	R138P	0.990
1:179554500:C:A	G257V	0.989
1:179557188:A:G	C193R	0.989
1:179561321:C:T	G140E	0.989
1:179559710:C:G	R168P	0.988
1:179554504:A:G	W256R	0.987
1:179554504:A:T	W256R	0.987
1:179561321:C:A	G140V	0.986
1:179559735:C:G	D160H	0.984
1:179559761:C:T	G151D	0.984
1:179559734:T:A	D160V	0.982
1:179561328:G:C	R138G	0.982
1:179557178:C:G	R196P	0.978
1:179557218:C:G	D183H	0.978
1:179559734:T:G	D160A	0.978
1:179559711:G:T	R168S	0.977
1:179551436:C:G	A297P	0.975
1:179564698:A:G	C124R	0.975
1:179557223:G:A	T181I	0.974
1:179559735:C:A	D160Y	0.973
1:179561295:C:G	G149R	0.973
1:179561322:C:G	G140R	0.972
1:179561322:C:T	G140R	0.972
1:179561341:T:A	R133S	0.972
1:179561341:T:G	R133S	0.972
1:179551400:C:G	A309P	0.970
1:179557186:G:C	C193W	0.970

dbSNP variants (sampled 300 via entrez): RS1000064232 (1:179552867 A>G), RS1000176976 (1:179566028 A>G), RS1000246305 (1:179558845 G>A), RS1000294905 (1:179565086 C>T), RS1000391125 (1:179565274 A>C), RS1000504725 (1:179559389 C>T), RS1000553709 (1:179564573 G>A,T), RS1000569070 (1:179557840 G>A), RS1000648500 (1:179565077 C>A), RS1000725364 (1:179567052 T>C), RS1000791387 (1:179571197 G>A), RS1001021725 (1:179557605 G>A,C,T), RS1001060291 (1:179552881 T>A), RS1001333954 (1:179577784 C>A), RS1001444281 (1:179571641 T>C)

Disease associations

OMIM: gene MIM:604766 | disease phenotypes: MIM:600995, MIM:256300

GenCC curated gene-disease

Disease	Classification	Inheritance
nephrotic syndrome, type 2	Definitive	Autosomal recessive
familial idiopathic steroid-resistant nephrotic syndrome	Supportive	Autosomal dominant

Mondo (10): steroid-resistant nephrotic syndrome (MONDO:0044765), nephrotic syndrome, type 2 (MONDO:0010974), kidney disorder (MONDO:0005240), nephrotic syndrome (MONDO:0005377), idiopathic nephrotic syndrome (MONDO:0018170), congenital nephrotic syndrome, Finnish type (MONDO:0009732), chronic kidney disease (MONDO:0005300), focal segmental glomerulosclerosis (MONDO:0100313), proteinuria (MONDO:0003634), familial idiopathic steroid-resistant nephrotic syndrome (MONDO:0019006)

Orphanet (3): Hereditary steroid-resistant nephrotic syndrome (Orphanet:656), Idiopathic nephrotic syndrome (Orphanet:357502), Congenital nephrotic syndrome, Finnish type (Orphanet:839)

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000097	Focal segmental glomerulosclerosis
HP:0000100	Nephrotic syndrome
HP:0000707	Abnormality of the nervous system
HP:0000737	Irritability
HP:0000969	Edema
HP:0001945	Fever
HP:0001967	Diffuse mesangial sclerosis
HP:0002027	Abdominal pain
HP:0002315	Headache
HP:0002586	Peritonitis
HP:0003073	Hypoalbuminemia
HP:0003077	Hyperlipidemia
HP:0003621	Juvenile onset
HP:0003678	Rapidly progressive
HP:0003774	Stage 5 chronic kidney disease
HP:0011463	Childhood onset
HP:0011947	Respiratory tract infection
HP:0012579	Minimal change glomerulonephritis
HP:0012622	Chronic kidney disease
HP:0031504	Foamy urine
HP:0100539	Periorbital edema

GWAS associations

0 associations (top):

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
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
D007676	Kidney Failure, Chronic	C12.050.351.968.419.780.750.500; C12.200.777.419.780.750.500; C12.950.419.780.750.500; C23.550.291.500.906.500
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)

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	decreases methylation, increases expression	3
Silicon Dioxide	increases expression	2
pirinixic acid	decreases expression, increases activity, affects binding	1
bisphenol A	decreases expression, decreases reaction	1
ergosta-4,6,8(14),22-tetraen-3-one	decreases expression, decreases reaction	1
tebuconazole	decreases expression	1
CGP 52608	increases reaction, affects binding	1
pachymic acid	decreases expression, decreases reaction	1
ICG 001	decreases reaction, affects cotreatment, decreases expression	1
alisol B 23-acetate	decreases expression, decreases reaction	1
bisphenol S	affects cotreatment, decreases expression	1
Arsenic Trioxide	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Dexamethasone	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Tamoxifen	decreases expression, decreases reaction	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Copper Sulfate	increases expression	1
Losartan	decreases expression, decreases reaction, affects cotreatment	1
Simvastatin	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_ZZ83	IMAGINi007-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03408405	PHASE4	WITHDRAWN	ACTHAR Gel for Drug REsistant Nephrotic Syndrome in Children
NCT00067990	PHASE4	COMPLETED	Angiotensin II Blockade for Chronic Allograft Nephropathy
NCT00117078	PHASE4	COMPLETED	Aranesp® Monthly Preference Study - 2
NCT00117130	PHASE4	COMPLETED	Study to Evaluate Effectiveness of Aranesp®
NCT00132431	PHASE4	COMPLETED	START: Sensipar Treatment Algorithm to Reach K/DOQI Targets in Chronic Kidney Disease Subjects With Secondary Hyperparathyroidism
NCT00140985	PHASE4	COMPLETED	Antiproteinuric Efficacy of Losartan Potassium in Patients With Non-Diabetic Proteinuric Renal Diseases (0954-213)
NCT00246129	PHASE4	COMPLETED	CamTac Trial:Campath-Tacrolimus vs IL2R MoAb/Tacrolimus/MMF in Renal Transplantation
NCT00275535	PHASE4	COMPLETED	The Comparison of Tacrolimus and Sirolimus Immunosuppression Based Drug Regimens in Kidney Transplant Recipients
NCT00282217	PHASE4	COMPLETED	Study Evaluating Sirolimus in the Treatment of Kidney Transplant
NCT00289614	PHASE4	COMPLETED	Patients With Renal Impairment and Diabetes Undergoing Computed Tomography (CT)
NCT00290069	PHASE4	UNKNOWN	Renal Function Optimization With Mycophenolate Mofetil (MMF) Immunosuppressor Regimes (ALHAMBRA)
NCT00338468	PHASE4	TERMINATED	A Study to Assess Disability in Anemic Elderly Patients With Kidney Disease Receiving PROCRIT (Epoetin Alfa)
NCT00368901	PHASE4	COMPLETED	STAAR-2 Clinical Study
NCT00369733	PHASE4	COMPLETED	STAAR-3 Clinical Study
NCT00369772	PHASE4	COMPLETED	STAAR-1 Clinical Study
NCT00379899	PHASE4	COMPLETED	ADVANCE: Study to Evaluate Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Hemodialysis
NCT00443508	PHASE4	UNKNOWN	Reduction or Discontinuation of CNI’s With Conversion to Everolimus-Based Immunosuppresion
NCT00452478	PHASE4	TERMINATED	Conversion From Standard Phosphate Binder Therapy to Fosrenol® (Lanthanum Carbonate) in Chronic Kidney Disease Stage 5
NCT00492518	PHASE4	COMPLETED	Acetylcysteine, Theophylline, and a Combination of Both in the Prophylaxis of Contrast-Induced Nephropathy
NCT00505102	PHASE4	UNKNOWN	Safe Renal Function In Long Term Heart Transplanted Patients
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00688480	PHASE4	COMPLETED	Do Xanthine Oxidase Inhibitors Reduce Both Left Ventricular Hypertrophy and Endothelial Dysfunction in Cardiovascular Patients With Renal Dysfunction?
NCT00863707	PHASE4	COMPLETED	A Study of the Safety and Tolerance of Regadenoson in Subjects With Renal Impairment
NCT01101698	PHASE4	UNKNOWN	Vitamin K2 and Vessel Calcification in Chronic Kidney Disease Patients
NCT01150201	PHASE4	COMPLETED	Aliskiren Combined With Losartan in Proteinuric, Non-diabetic Chronic Kidney Disease
NCT01155141	PHASE4	COMPLETED	Idiopathic Focal Segmental Glomerulosclerosis (FSGS) and Treatment With ACTH
NCT01228279	PHASE4	COMPLETED	Sympathetic Activity in Patients With End-stage Renal Disease on Peritoneal Dialysis
NCT01334333	PHASE4	COMPLETED	Comparison of Medication Adherence Between Once and Twice Daily Tacrolimus in Stable Renal Transplant Recipients
NCT01437943	PHASE4	TERMINATED	Effect of Short Term Aliskiren Treatment in Kidney Transplant Patients
NCT01545479	PHASE4	COMPLETED	Increased Renal Oxygenation and Angiotensin Converting Enzyme Inhibition
NCT01614431	PHASE4	COMPLETED	N Acetyl Cysteine for Cystinosis Patients
NCT01631149	PHASE4	COMPLETED	Effect of Deep BLock on Intraoperative Surgical Conditions
NCT01722513	PHASE4	UNKNOWN	Efficacy and Safety of Alprostadil Prevent Contrast Induced Nephropathy
NCT01985360	PHASE4	COMPLETED	ISCHEMIA-Chronic Kidney Disease Trial
NCT02311010	PHASE4	UNKNOWN	Practical Use of Advagraf de Novo After Kidney Transplantation According to Recipient Genetic Polymorphism
NCT02413073	PHASE4	COMPLETED	Whole Body Vibration in Kidney Disease
NCT02444013	PHASE4	UNKNOWN	Folic Acid for Prevention of Contrast Induced Nephropathy
NCT02663713	PHASE4	COMPLETED	A Randomized, Pharmacodynamic Comparison of Low Dose Ticagrelor to Clopidogrel in Patients With Prior Myocardial Infarction
NCT02707809	PHASE4	COMPLETED	Effects of Dexmedetomidine on Microcirculation of Kidney Transplant Recipient
NCT02761577	PHASE4	COMPLETED	A Prospective Study on Incidence and Prevention of Contrast-induced Nephropathy in Croatia