Familial nephrotic syndrome

Summary

Familial nephrotic syndrome (MONDO:0002350) is a disease (an umbrella term covering 18 Mondo subtypes) with 3 cohort genes.

At a glance

• Umbrella term: 18 Mondo subtypes
• Cohort genes: 3
• ClinVar variants: 140

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial nephrotic syndrome
Mondo ID	MONDO:0002350
OMIM	256300
DOID	DOID:2590
ICD-11	1524476844
NCIT	C35337
SNOMED CT	48796009
UMLS	C3501848
MedGen	502251
GARD	0027602
Is cancer (heuristic)	no

Also known as: congenital nephrotic syndrome · hereditary nephrotic syndrome

Data availability: 140 ClinVar variants · 1 cell line.

Disease family

An umbrella term covering 18 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › nephrotic syndrome › familial nephrotic syndrome

Related subtypes (3): idiopathic nephrotic syndrome, nephrotic syndrome ocular anomalies, steroid-resistant nephrotic syndrome

Subtypes (18): congenital nephrotic syndrome, Finnish type, nephrotic syndrome, type 4, LAMB2-related infantile-onset nephrotic syndrome, immunoglobulin-mediated membranoproliferative glomerulonephritis, familial idiopathic steroid-resistant nephrotic syndrome, nephrotic syndrome, type 20, nephrotic syndrome, type 22, nephrotic syndrome, type 23, nephrotic syndrome, type 24, nephrotic syndrome, IIa 26, nephrotic syndrome, type 17, nephrotic syndrome, type 18, nephrotic syndrome, type 19, nephrotic syndrome, type 21, nephrotic syndrome 14, nephrotic syndrome 15, nephrotic syndrome 16, idiopathic multidrug-resistant nephrotic syndrome

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

140 retrieved; paginated sample, class counts are floors:

58 conflicting classifications of pathogenicity, 55 uncertain significance, 11 benign, 9 benign/likely benign, 3 likely benign, 2 pathogenic/likely pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
56456	NM_004646.4(NPHS1):c.1928T>C (p.Leu643Pro)	NPHS1	Pathogenic/Likely pathogenic	no assertion criteria provided
812905	NM_004646.4(NPHS1):c.2663+2T>A	NPHS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56507	NM_004646.4(NPHS1):c.500C>T (p.Pro167Leu)	NPHS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
812957	NC_000019.10:g.35823999_35838548del	NPHS1	Likely pathogenic	no assertion criteria provided
259483	NM_004646.4(NPHS1):c.128T>C (p.Val43Ala)	KIRREL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
259502	NM_004646.4(NPHS1):c.43G>C (p.Gly15Arg)	KIRREL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
259504	NM_004646.4(NPHS1):c.59-5C>G	KIRREL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328882	NM_004646.4(NPHS1):c.151C>T (p.Leu51=)	KIRREL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328883	NM_004646.4(NPHS1):c.115G>A (p.Glu39Lys)	KIRREL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328885	NM_004646.4(NPHS1):c.-57G>T	KIRREL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
732252	NM_004646.4(NPHS1):c.14C>T (p.Thr5Met)	KIRREL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
737074	NM_004646.4(NPHS1):c.126G>T (p.Thr42=)	KIRREL2	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
180466	NM_004646.4(NPHS1):c.3173C>T (p.Ser1058Leu)	NPHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225423	NM_004646.4(NPHS1):c.2869G>C (p.Val957Leu)	NPHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
259480	NM_004646.4(NPHS1):c.1170+8G>A	NPHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
259485	NM_004646.4(NPHS1):c.1930+10C>T	NPHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
259491	NM_004646.4(NPHS1):c.2746G>T (p.Ala916Ser)	NPHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
259505	NM_004646.4(NPHS1):c.597G>A (p.Glu199=)	NPHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
282372	NM_004646.4(NPHS1):c.563A>T (p.Asn188Ile)	NPHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
290122	NM_004646.4(NPHS1):c.658T>G (p.Ser220Ala)	NPHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328853	NM_004646.4(NPHS1):c.3419G>A (p.Arg1140His)	NPHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328854	NM_004646.4(NPHS1):c.3388-14C>T	NPHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328856	NM_004646.4(NPHS1):c.3311+14T>C	NPHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328859	NM_004646.4(NPHS1):c.2961T>C (p.Tyr987=)	NPHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328863	NM_004646.4(NPHS1):c.2469G>A (p.Ala823=)	NPHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328865	NM_004646.4(NPHS1):c.1926A>G (p.Val642=)	NPHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328867	NM_004646.4(NPHS1):c.1799A>G (p.Lys600Arg)	NPHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NPHS1	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
NPHS1	Orphanet:839	Congenital nephrotic syndrome, Finnish type

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ZNF91	HGNC:13166	ENSG00000167232	Q05481	Zinc finger protein 91	clinvar
KIRREL2	HGNC:18816	ENSG00000126259	Q6UWL6	Kin of IRRE-like protein 2	clinvar
NPHS1	HGNC:7908	ENSG00000161270	O60500	Nephrin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZNF91	Zinc finger protein 91	Transcription factor specifically required to repress SINE-VNTR-Alu (SVA) retrotransposons: recognizes and binds SVA sequences and represses their expression by recruiting a repressive complex containing TRIM28/KAP1.
KIRREL2	Kin of IRRE-like protein 2	May regulate basal insulin secretion.
NPHS1	Nephrin	Seems to play a role in the development or function of the kidney glomerular filtration barrier.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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	19.5×	0.007
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZNF91	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
KIRREL2	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
NPHS1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	2
lateral globus pallidus	1
lateral nuclear group of thalamus	1
type B pancreatic cell	1
left ventricle myocardium	1
pancreas	1
buccal mucosa cell	1
vena cava	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZNF91	296	ubiquitous	marker	type B pancreatic cell, lateral nuclear group of thalamus, lateral globus pallidus
KIRREL2	97	tissue_specific	marker	body of pancreas, pancreas, left ventricle myocardium
NPHS1	147	tissue_specific	marker	buccal mucosa cell, body of pancreas, vena cava

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NPHS1	1,690
KIRREL2	1,077
ZNF91	614

Intra-cohort edges

A	B	Sources
KIRREL2	NPHS1	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NPHS1	O60500	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KIRREL2	Q6UWL6	75.30
ZNF91	Q05481	72.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 3 evidence-associated genes (2 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 2 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	2	475.8×	8e-06	KIRREL2, NPHS1
Cell-Cell communication	1	68.8×	0.014	KIRREL2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
slit diaphragm assembly	1	2808.7×	0.002	NPHS1
cell-cell adhesion	2	67.7×	0.002	KIRREL2, NPHS1
glomerular basement membrane development	1	510.7×	0.006	NPHS1
podocyte development	1	510.7×	0.006	NPHS1
transposable element silencing	1	330.4×	0.008	ZNF91
protein localization to synapse	1	255.3×	0.008	NPHS1
myoblast fusion	1	200.6×	0.009	NPHS1
positive regulation of actin filament polymerization	1	110.1×	0.014	NPHS1
skeletal muscle tissue development	1	96.8×	0.014	NPHS1
JNK cascade	1	90.6×	0.014	NPHS1
gene expression	1	26.6×	0.044	NPHS1
cell adhesion	1	12.5×	0.084	KIRREL2
regulation of transcription by RNA polymerase II	1	3.9×	0.236	ZNF91

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
ZNF91	0	0
KIRREL2	0	0
NPHS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	NPHS1
D	Druggable family + AlphaFold only, no drug	1	KIRREL2
E	Difficult family or no structure, no drug	1	ZNF91

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ZNF91	0	—
KIRREL2	0	—
NPHS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.