Nephrotic syndrome 15

Summary

Nephrotic syndrome 15 (MONDO:0033262) is a disease caused by MAGI2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: MAGI2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 205

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	nephrotic syndrome 15
Mondo ID	MONDO:0033262
OMIM	617609
DOID	DOID:0080271
UMLS	C4539896
MedGen	1620414
GARD	0027951
Is cancer (heuristic)	no

Also known as: nephrotic syndrome 15 · nephrotic syndrome, type 15 · NPHS15

Data availability: 205 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › nephrotic syndrome › familial nephrotic syndrome › nephrotic syndrome 15

Related subtypes (17): 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 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

205 retrieved; paginated sample, class counts are floors:

179 uncertain significance, 7 conflicting classifications of pathogenicity, 6 likely pathogenic, 4 benign/likely benign, 3 likely benign, 3 benign, 3 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
431755	NM_012301.4(MAGI2):c.3998del (p.Gly1333fs)	MAGI2	Pathogenic	no assertion criteria provided
431756	NM_012301.4(MAGI2):c.64_71del (p.Arg22fs)	MAGI2	Pathogenic	no assertion criteria provided
431757	NM_012301.4(MAGI2):c.3526_3533dup (p.Glu1178fs)	MAGI2	Pathogenic	no assertion criteria provided
1683652	NM_012301.4(MAGI2):c.147del (p.Gly50fs)	MAGI2	Likely pathogenic	criteria provided, single submitter
3594849	NM_012301.4(MAGI2):c.2269+2dup	MAGI2	Likely pathogenic	criteria provided, single submitter
3594897	NM_012301.4(MAGI2):c.712G>T (p.Glu238Ter)	MAGI2	Likely pathogenic	criteria provided, single submitter
3594912	NM_012301.4(MAGI2):c.79C>T (p.Gln27Ter)	MAGI2	Likely pathogenic	criteria provided, single submitter
4081507	NM_012301.4(MAGI2):c.1390del (p.Asp464fs)	MAGI2	Likely pathogenic	criteria provided, single submitter
4847529	NM_012301.4(MAGI2):c.3567+1G>T	MAGI2	Likely pathogenic	criteria provided, single submitter
594574	NM_012301.4(MAGI2):c.4001G>T (p.Gly1334Val)	LOC129998720	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1345986	NM_012301.4(MAGI2):c.1717C>G (p.Pro573Ala)	MAGI2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193699	NM_012301.4(MAGI2):c.1530C>T (p.Tyr510=)	MAGI2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
194647	NM_012301.4(MAGI2):c.2830T>C (p.Ser944Pro)	MAGI2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3122247	NM_012301.4(MAGI2):c.1141C>G (p.Leu381Val)	MAGI2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3594861	NM_012301.4(MAGI2):c.1929C>T (p.Gly643=)	MAGI2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
499736	NM_012301.4(MAGI2):c.411G>A (p.Thr137=)	MAGI2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3594782	NM_012301.4(MAGI2):c.4141G>A (p.Glu1381Lys)	LOC129998720	Uncertain significance	criteria provided, multiple submitters, no conflicts
3594783	NM_012301.4(MAGI2):c.4124C>G (p.Ser1375Cys)	LOC129998720	Uncertain significance	criteria provided, single submitter
3594784	NM_012301.4(MAGI2):c.4121G>T (p.Gly1374Val)	LOC129998720	Uncertain significance	criteria provided, single submitter
3594785	NM_012301.4(MAGI2):c.4118C>T (p.Ala1373Val)	LOC129998720	Uncertain significance	criteria provided, single submitter
3594786	NM_012301.4(MAGI2):c.4109G>A (p.Arg1370His)	LOC129998720	Uncertain significance	criteria provided, multiple submitters, no conflicts
3594787	NM_012301.4(MAGI2):c.4094G>A (p.Gly1365Glu)	LOC129998720	Uncertain significance	criteria provided, multiple submitters, no conflicts
3594788	NM_012301.4(MAGI2):c.4088_4091delinsTGGT (p.Ala1363_Gly1364delinsValVal)	LOC129998720	Uncertain significance	criteria provided, single submitter
3594789	NM_012301.4(MAGI2):c.4066GACGCGGCG[3] (p.Ala1361_Arg1362insAspAlaAla)	LOC129998720	Uncertain significance	criteria provided, single submitter
3594791	NM_012301.4(MAGI2):c.4065_4073del (p.1356DAA[1])	LOC129998720	Uncertain significance	criteria provided, single submitter
3594793	NM_012301.4(MAGI2):c.4064C>G (p.Ala1355Gly)	LOC129998720	Uncertain significance	criteria provided, single submitter
3594794	NM_012301.4(MAGI2):c.4048C>T (p.Pro1350Ser)	LOC129998720	Uncertain significance	criteria provided, multiple submitters, no conflicts
3594795	NM_012301.4(MAGI2):c.4043G>C (p.Arg1348Thr)	LOC129998720	Uncertain significance	criteria provided, single submitter
3594796	NM_012301.4(MAGI2):c.4021_4041dup (p.Ala1347_Arg1348insGlyArgProAlaSerGluAla)	LOC129998720	Uncertain significance	criteria provided, single submitter
3594797	NM_012301.4(MAGI2):c.4021G>A (p.Gly1341Ser)	LOC129998720	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
MAGI2	Strong	Autosomal recessive	nephrotic syndrome 15	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MAGI2	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MAGI2	HGNC:18957	ENSG00000187391	Q86UL8	Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2	gencc,clinvar
MAGI2-AS3	HGNC:40862	ENSG00000234456		MAGI2 antisense RNA 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MAGI2	Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2	Seems to act as a scaffold molecule at synaptic junctions by assembling neurotransmitter receptors and cell adhesion proteins.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MAGI2	Kinase	yes		WW_dom, PDZ, Guanylate_kin-like_dom
MAGI2-AS3	Other/Unknown	no

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
calcaneal tendon	2
Brodmann (1909) area 23	1
corpus callosum	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MAGI2	267	ubiquitous	marker	calcaneal tendon, corpus callosum, Brodmann (1909) area 23
MAGI2-AS3	248	ubiquitous	marker	calcaneal tendon, cerebellar hemisphere, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MAGI2	3,246
MAGI2-AS3	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MAGI2	Q86UL8	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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×	0.004	MAGI2
Cell-Cell communication	1	137.6×	0.007	MAGI2

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
podocyte development	1	1532.0×	0.004	MAGI2
negative regulation of activin receptor signaling pathway	1	1404.3×	0.004	MAGI2
nerve growth factor signaling pathway	1	1296.3×	0.004	MAGI2
SMAD protein signal transduction	1	732.7×	0.004	MAGI2
positive regulation of receptor internalization	1	702.2×	0.004	MAGI2
receptor clustering	1	624.1×	0.004	MAGI2
clathrin-dependent endocytosis	1	581.1×	0.004	MAGI2
cellular response to nerve growth factor stimulus	1	468.1×	0.004	MAGI2
Wnt signaling pathway, planar cell polarity pathway	1	455.5×	0.004	MAGI2
negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	263.3×	0.006	MAGI2
positive regulation of neuron projection development	1	137.0×	0.010	MAGI2
negative regulation of cell migration	1	111.6×	0.011	MAGI2
nervous system development	1	45.9×	0.025	MAGI2
negative regulation of cell population proliferation	1	42.1×	0.025	MAGI2
signal transduction	1	16.1×	0.062	MAGI2

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
MAGI2	0	0
MAGI2-AS3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	MAGI2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MAGI2-AS3

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)
MAGI2	0	—
MAGI2-AS3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.