Nephrotic syndrome 14

Summary

Nephrotic syndrome 14 (MONDO:0033203) is a disease caused by SGPL1 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Causal gene: SGPL1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 34
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	nephrotic syndrome 14
Mondo ID	MONDO:0033203
OMIM	617575
Orphanet	506334
DOID	DOID:0080265
UMLS	C4540559
MedGen	1617660
GARD	0013818
Is cancer (heuristic)	no

Also known as: familial steroid-resistant nephrotic syndrome with adrenal insufficiency · nephrotic syndrome 14 · nephrotic syndrome, type 14 · NPHS14 · primary adrenal insufficiency-steroid-resistant nephrotic syndrome due to SGPL1 deficiency · renal, endocrine, neurologic and immune syndrome · RENI syndrome · SGPL1 deficiency, steroid-resistant nephrotic syndrome type 14 · sphingosine phosphate lyase insufficiency syndrome · SPLIS

Data availability: 34 ClinVar variants · 4 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 14

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 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

34 retrieved; paginated sample, class counts are floors:

13 uncertain significance, 10 pathogenic, 5 benign, 3 likely pathogenic, 1 conflicting classifications of pathogenicity, 1 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1173092	NM_003901.4(SGPL1):c.1483C>T (p.Arg495Ter)	SGPL1	Pathogenic	criteria provided, multiple submitters, no conflicts
2577413	NM_003901.4(SGPL1):c.1298+6T>C	SGPL1	Pathogenic	no assertion criteria provided
3254596	NM_003901.4(SGPL1):c.423del (p.Glu142fs)	SGPL1	Pathogenic	criteria provided, single submitter
430861	NM_003901.4(SGPL1):c.665G>A (p.Arg222Gln)	SGPL1	Pathogenic	criteria provided, multiple submitters, no conflicts
430862	NM_003901.4(SGPL1):c.1632CTT[1] (p.Phe545del)	SGPL1	Pathogenic	no assertion criteria provided
430863	NM_003901.4(SGPL1):c.261+1G>A	SGPL1	Pathogenic	no assertion criteria provided
430864	NM_003901.4(SGPL1):c.7dup (p.Ser3fs)	SGPL1	Pathogenic	no assertion criteria provided
430865	NM_003901.4(SGPL1):c.664C>T (p.Arg222Trp)	SGPL1	Pathogenic	no assertion criteria provided
430866	NM_003901.4(SGPL1):c.1037G>T (p.Ser346Ile)	SGPL1	Pathogenic/Likely pathogenic	no assertion criteria provided
430867	NM_003901.4(SGPL1):c.1513C>T (p.Arg505Ter)	SGPL1	Pathogenic	criteria provided, multiple submitters, no conflicts
430868	NM_003901.4(SGPL1):c.934del (p.Leu312fs)	SGPL1	Pathogenic	no assertion criteria provided
3064759	NM_003901.4(SGPL1):c.1588dup (p.Gln530fs)	SGPL1	Likely pathogenic	criteria provided, single submitter
3780599	NM_003901.4(SGPL1):c.991_1001del (p.Tyr331fs)	SGPL1	Likely pathogenic	criteria provided, single submitter
599179	NM_003901.4(SGPL1):c.87del (p.Asn28_Tyr29insTer)	SGPL1	Likely pathogenic	no assertion criteria provided
1408318	NM_003901.4(SGPL1):c.1204G>A (p.Ala402Thr)	SGPL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028170	NM_003901.4(SGPL1):c.1469T>C (p.Leu490Pro)	SGPL1	Uncertain significance	criteria provided, single submitter
1031367	NM_003901.4(SGPL1):c.1132G>A (p.Val378Ile)	SGPL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1310455	NM_003901.4(SGPL1):c.1067A>G (p.Tyr356Cys)	SGPL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2136875	NM_003901.4(SGPL1):c.946G>A (p.Ala316Thr)	SGPL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2262967	NM_003901.4(SGPL1):c.1333A>G (p.Asn445Asp)	SGPL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2365724	NM_003901.4(SGPL1):c.205A>G (p.Arg69Gly)	SGPL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2428320	NM_003901.4(SGPL1):c.1019G>A (p.Arg340Gln)	SGPL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2435916	NM_003901.4(SGPL1):c.452G>A (p.Ser151Asn)	SGPL1	Uncertain significance	criteria provided, single submitter
2582445	NM_003901.4(SGPL1):c.1014T>G (p.Asp338Glu)	SGPL1	Uncertain significance	criteria provided, single submitter
3064890	NM_003901.4(SGPL1):c.1073del (p.Pro358fs)	SGPL1	Uncertain significance	criteria provided, single submitter
3066335	NM_003901.4(SGPL1):c.1061A>G (p.Tyr354Cys)	SGPL1	Uncertain significance	criteria provided, single submitter
3362888	NM_003901.4(SGPL1):c.1018C>T (p.Arg340Trp)	SGPL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4080044	NM_003901.4(SGPL1):c.1306A>T (p.Asn436Tyr)	SGPL1	Uncertain significance	criteria provided, single submitter
1226535	NM_003901.4(SGPL1):c.1299-10_1299-9del	SGPL1	Benign	criteria provided, multiple submitters, no conflicts
1230615	NM_003901.4(SGPL1):c.262-44T>C	SGPL1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
SGPL1	Definitive	Autosomal recessive	nephrotic syndrome 14	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SGPL1	Orphanet:506334	Familial steroid-resistant nephrotic syndrome with adrenal insufficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SGPL1	HGNC:10817	ENSG00000166224	O95470	Sphingosine-1-phosphate lyase 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SGPL1	Sphingosine-1-phosphate lyase 1	Cleaves phosphorylated sphingoid bases (PSBs), such as sphingosine-1-phosphate, into fatty aldehydes and phosphoethanolamine.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SGPL1	Enzyme (other)	yes	4.1.2.27	PyrdxlP-dep_de-COase, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase_small

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
epithelium of esophagus	1
esophagus squamous epithelium	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SGPL1	286	ubiquitous	marker	esophagus squamous epithelium, epithelium of esophagus, upper leg skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SGPL1	2,899

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SGPL1	O95470	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 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
Sphingolipid catabolism	1	878.5×	0.005	SGPL1
Sphingolipid metabolism	1	167.9×	0.012	SGPL1
Metabolism of lipids	1	31.6×	0.042	SGPL1
Metabolism	1	11.6×	0.086	SGPL1

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
luteinization	1	1872.4×	0.003	SGPL1
Leydig cell differentiation	1	1203.7×	0.003	SGPL1
sphingolipid catabolic process	1	1123.5×	0.003	SGPL1
androgen metabolic process	1	887.0×	0.003	SGPL1
fibroblast migration	1	842.6×	0.003	SGPL1
ceramide metabolic process	1	802.5×	0.003	SGPL1
regulation of multicellular organism growth	1	648.1×	0.003	SGPL1
estrogen metabolic process	1	624.1×	0.003	SGPL1
platelet-derived growth factor receptor signaling pathway	1	561.7×	0.003	SGPL1
skeletal system morphogenesis	1	495.6×	0.003	SGPL1
face morphogenesis	1	495.6×	0.003	SGPL1
hemopoiesis	1	267.5×	0.005	SGPL1
vasculogenesis	1	255.3×	0.005	SGPL1
roof of mouth development	1	247.8×	0.005	SGPL1
apoptotic signaling pathway	1	224.7×	0.006	SGPL1
post-embryonic development	1	205.5×	0.006	SGPL1
fatty acid metabolic process	1	193.7×	0.006	SGPL1
kidney development	1	140.4×	0.008	SGPL1
spermatogenesis	1	35.2×	0.028	SGPL1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SGPL1	FINGOLIMOD

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SGPL1	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FINGOLIMOD	4	SGPL1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SGPL1	19	Binding:19

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SGPL1	4.1.2.27	sphinganine-1-phosphate aldolase

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
FINGOLIMOD	4	SGPL1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SGPL1
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06669949	Not specified	RECRUITING	Natural History of Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)