Nephrotic syndrome, type 2

Summary

Nephrotic syndrome, type 2 (MONDO:0010974) is a disease caused by NPHS2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: NPHS2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 252

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	nephrotic syndrome, type 2
Mondo ID	MONDO:0010974
OMIM	600995
DOID	DOID:0080379
UMLS	C1868672
MedGen	358380
GARD	0015326
Is cancer (heuristic)	no

Also known as: nephrotic syndrome caused by mutation in NPHS2 · nephrotic syndrome, idiopathic, steroid-resistant · nephrotic syndrome, type 2 · NPHS2 · NPHS2 nephrotic syndrome · SRN1

Data availability: 252 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › nephrotic syndrome › familial nephrotic syndrome › familial idiopathic steroid-resistant nephrotic syndrome › nephrotic syndrome, type 2

Related subtypes (13): focal segmental glomerulosclerosis 1, nephrotic syndrome, type 3, nephrotic syndrome, type 6, familial steroid-resistant nephrotic syndrome with sensorineural deafness, nephrotic syndrome, type 8, nephrotic syndrome, type 9, nephrotic syndrome, type 10, nephrotic syndrome, type 11, nephrotic syndrome, type 12, nephrotic syndrome, type 13, familial idiopathic steroid-resistant nephrotic syndrome with diffuse mesangial proliferation, familial idiopathic steroid-resistant nephrotic syndrome with minimal changes, familial idiopathic steroid-resistant nephrotic syndrome with diffuse mesangial sclerosis

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

252 retrieved; paginated sample, class counts are floors:

75 uncertain significance, 58 likely pathogenic, 39 pathogenic/likely pathogenic, 29 conflicting classifications of pathogenicity, 23 pathogenic, 12 benign, 9 likely benign, 7 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
225143	NM_014625.3(NPHS2):c.[-52C>G(;)-51G>T]		Pathogenic	no assertion criteria provided
1068472	NM_014625.4(NPHS2):c.1032del (p.Phe344fs)	AXDND1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075584	NM_014625.4(NPHS2):c.768G>A (p.Trp256Ter)	AXDND1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
126418	NM_014625.4(NPHS2):c.868G>A (p.Val290Met)	AXDND1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1409729	NM_014625.4(NPHS2):c.873+1G>T	AXDND1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3574208	NM_014625.4(NPHS2):c.988_989del (p.Leu330fs)	AXDND1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370718	NM_014625.4(NPHS2):c.890C>T (p.Ala297Val)	AXDND1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371301	NM_014625.4(NPHS2):c.859C>T (p.Gln287Ter)	AXDND1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371673	NM_014625.4(NPHS2):c.964C>T (p.Arg322Ter)	AXDND1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
447882	NM_014625.4(NPHS2):c.779T>A (p.Val260Glu)	AXDND1	Pathogenic	criteria provided, multiple submitters, no conflicts
5369	NM_014625.4(NPHS2):c.871C>T (p.Arg291Trp)	AXDND1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
552884	NM_014625.4(NPHS2):c.873+2T>A	AXDND1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
552959	NM_014625.4(NPHS2):c.874-1G>A	AXDND1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
555445	NM_014625.4(NPHS2):c.873+1G>A	AXDND1	Pathogenic	criteria provided, multiple submitters, no conflicts
635511	NM_014625.4(NPHS2):c.929A>T (p.Glu310Val)	AXDND1	Pathogenic	no assertion criteria provided
801581	NM_014625.4(NPHS2):c.981del (p.Gln328fs)	AXDND1	Pathogenic	criteria provided, single submitter
1073625	NM_014625.4(NPHS2):c.486C>A (p.Tyr162Ter)	NPHS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1344814	NM_014625.4(NPHS2):c.1A>T (p.Met1Leu)	NPHS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1344816	NM_014625.4(NPHS2):c.397del (p.Arg133fs)	NPHS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1439693	NM_014625.4(NPHS2):c.506T>C (p.Leu169Pro)	NPHS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1457049	NM_014625.4(NPHS2):c.378+1_378+2delinsTG	NPHS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1491797	NM_014625.4(NPHS2):c.928G>A (p.Glu310Lys)	NPHS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188730	NM_014625.4(NPHS2):c.503G>A (p.Arg168His)	NPHS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188823	NM_014625.4(NPHS2):c.855_856del (p.Arg286fs)	NPHS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188892	NM_014625.4(NPHS2):c.586C>T (p.Arg196Ter)	NPHS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188952	NM_014625.4(NPHS2):c.502C>T (p.Arg168Cys)	NPHS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188990	NM_014625.4(NPHS2):c.948del (p.Ala317fs)	NPHS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1939980	NM_014625.4(NPHS2):c.370T>C (p.Cys124Arg)	NPHS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2019724	NM_014625.4(NPHS2):c.62_63insG (p.His21fs)	NPHS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2183604	NM_014625.4(NPHS2):c.483del (p.Tyr162fs)	NPHS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
NPHS2	Definitive	Autosomal recessive	nephrotic syndrome, type 2	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NPHS2	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NPHS2	HGNC:13394	ENSG00000116218	Q9NP85	Podocin	gencc,clinvar
AXDND1	HGNC:26564	ENSG00000162779	Q5T1B0	Axonemal dynein light chain domain-containing protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NPHS2	Podocin	Plays a role in the regulation of glomerular permeability, acting probably as a linker between the plasma membrane and the cytoskeleton.
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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NPHS2	Other/Unknown	no		Band_7, Stomatin_HflK_fam, Band_7/stomatin-like_CS
AXDND1	Other/Unknown	no		Axonemal_dynein_light_chain, Axonemal_dynein_LC_domain

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
kidney epithelium	1
metanephric glomerulus	1
renal glomerulus	1
left testis	1
right testis	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NPHS2	47	tissue_specific	marker	renal glomerulus, metanephric glomerulus, kidney epithelium
AXDND1	161	tissue_specific	marker	sperm, left testis, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NPHS2	1,811
AXDND1	263

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NPHS2	Q9NP85	75.00
AXDND1	Q5T1B0	70.90

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Nephrin family interactions	1	475.8×	0.002	NPHS2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
metanephric podocyte development	1	4213.0×	0.001	NPHS2
manchette assembly	1	648.1×	0.004	AXDND1
glomerular filtration	1	468.1×	0.004	NPHS2
gene expression	1	39.9×	0.030	NPHS2
actin cytoskeleton organization	1	39.6×	0.030	NPHS2
spermatogenesis	1	17.6×	0.056	AXDND1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NPHS2	0	0
AXDND1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	NPHS2, AXDND1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NPHS2	0	—
AXDND1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.