Focal segmental glomerulosclerosis 9

Summary

Focal segmental glomerulosclerosis 9 (MONDO:0014539) is a disease caused by CRB2 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: CRB2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 58

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	focal segmental glomerulosclerosis 9
Mondo ID	MONDO:0014539
OMIM	616220
DOID	DOID:0111134
UMLS	C4015555
MedGen	863992
GARD	0016070
Is cancer (heuristic)	no

Also known as: CRB2 focal segmental glomerulosclerosis · focal segmental glomerulosclerosis 9 · focal segmental glomerulosclerosis caused by mutation in CRB2 · focal segmental glomerulosclerosis type 9 · FSGS9

Data availability: 58 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inherited kidney disorder › inherited focal segmental glomerulosclerosis › focal segmental glomerulosclerosis 9

Related subtypes (7): HIV-associated nephropathy, focal segmental glomerulosclerosis 1, focal segmental glomerulosclerosis 2, focal segmental glomerulosclerosis 5, focal segmental glomerulosclerosis 6, focal segmental glomerulosclerosis 7, focal segmental glomerulosclerosis 8

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

58 retrieved; paginated sample, class counts are floors:

24 uncertain significance, 9 conflicting classifications of pathogenicity, 8 likely pathogenic, 7 benign/likely benign, 6 pathogenic, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1457188	NM_173689.7(CRB2):c.315C>A (p.Cys105Ter)	CRB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
180700	NM_173689.7(CRB2):c.1882C>T (p.Arg628Cys)	CRB2	Pathogenic/Likely pathogenic	no assertion criteria provided
180701	NM_173689.7(CRB2):c.3089_3104dup (p.Gly1036fs)	CRB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
180702	NM_173689.7(CRB2):c.1886G>C (p.Cys629Ser)	CRB2	Pathogenic	no assertion criteria provided
3902743	NM_173689.7(CRB2):c.1006C>T (p.Gln336Ter)	CRB2	Pathogenic	criteria provided, single submitter
4292766	NM_173689.7(CRB2):c.445G>T (p.Glu149Ter)	CRB2	Pathogenic	criteria provided, single submitter
817964	NM_173689.7(CRB2):c.592dup (p.Thr198fs)	CRB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
829899	NM_173689.7(CRB2):c.3613G>A (p.Gly1205Ser)	CRB2	Pathogenic	criteria provided, single submitter
974481	NM_173689.7(CRB2):c.1827C>A (p.Cys609Ter)	CRB2	Pathogenic	criteria provided, single submitter
1327658	NM_016222.4(DDX41):c.931C>T (p.Arg311Ter)	DDX41	Pathogenic	criteria provided, multiple submitters, no conflicts
1679728	NM_173689.7(CRB2):c.1054+2T>G	CRB2	Likely pathogenic	criteria provided, single submitter
2506114	NC_000009.11:g.(126129637_126129851)_(126136200_126136857)del	CRB2	Likely pathogenic	criteria provided, single submitter
3220913	NM_173689.7(CRB2):c.3262G>A (p.Gly1088Ser)	CRB2	Likely pathogenic	criteria provided, single submitter
3779172	NM_173689.7(CRB2):c.2660_2661insTT (p.Ser888fs)	CRB2	Likely pathogenic	criteria provided, single submitter
3779173	NM_173689.7(CRB2):c.2661_2662insC (p.Ser888fs)	CRB2	Likely pathogenic	criteria provided, single submitter
4537205	NC_000009.11:g.(126129966_126132386)_126133028del	CRB2	Likely pathogenic	criteria provided, single submitter
829963	NM_173689.7(CRB2):c.47_53dup (p.Leu19fs)	CRB2	Likely pathogenic	no assertion criteria provided
974518	NM_173689.7(CRB2):c.3214C>T (p.Arg1072Cys)	CRB2	Likely pathogenic	criteria provided, single submitter
1027873	NM_173689.7(CRB2):c.38C>T (p.Ala13Val)	CRB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1411224	NM_173689.7(CRB2):c.952G>A (p.Gly318Ser)	CRB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1576581	NM_173689.7(CRB2):c.966C>T (p.Asp322=)	CRB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1584306	NM_173689.7(CRB2):c.2380G>A (p.Gly794Ser)	CRB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1642786	NM_173689.7(CRB2):c.3373G>T (p.Gly1125Trp)	CRB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180703	NM_173689.7(CRB2):c.3746G>A (p.Arg1249Gln)	CRB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3836225	NM_173689.7(CRB2):c.3679G>A (p.Val1227Ile)	CRB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
721393	NM_173689.7(CRB2):c.3754C>T (p.Arg1252Cys)	CRB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2217867	NM_019074.4(DLL4):c.1102G>A (p.Asp368Asn)	DLL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1024752	NM_173689.7(CRB2):c.1433A>G (p.Asn478Ser)	CRB2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1027871	NM_173689.7(CRB2):c.2314C>G (p.Leu772Val)	CRB2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1027872	NM_173689.7(CRB2):c.2914C>T (p.Arg972Cys)	CRB2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 5 · 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
CRB2	Definitive	Autosomal recessive	focal segmental glomerulosclerosis 9	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CRB2	Orphanet:443988	Ventriculomegaly-cystic kidney disease
CRB2	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
DDX41	Orphanet:488647	DDX41-related hematologic malignancy predisposition syndrome
DLL4	Orphanet:1114	Aplasia cutis congenita
DLL4	Orphanet:974	Adams-Oliver syndrome

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
CRB2	HGNC:18688	ENSG00000148204	Q5IJ48	Protein crumbs homolog 2	gencc,clinvar
DDX41	HGNC:18674	ENSG00000183258	Q9UJV9	Probable ATP-dependent RNA helicase DDX41	clinvar
DLL4	HGNC:2910	ENSG00000128917	Q9NR61	Delta-like protein 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CRB2	Protein crumbs homolog 2	Apical polarity protein that plays a central role during the epithelial-to-mesenchymal transition (EMT) at gastrulation, when newly specified mesodermal cells move inside the embryo.
DDX41	Probable ATP-dependent RNA helicase DDX41	Multifunctional protein that participates in many aspects of cellular RNA metabolism.
DLL4	Delta-like protein 4	Involved in the Notch signaling pathway as Notch ligand.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CRB2	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Laminin_G
DDX41	Other/Unknown	no		Helicase_C-like, DEAD/DEAH_box_helicase_dom, Helicase_ATP-bd
DLL4	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, DSL

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
ganglionic eminence	1
male germ line stem cell (sensu Vertebrata) in testis	1
ventricular zone	1
granulocyte	1
lower esophagus mucosa	1
right frontal lobe	1
apex of heart	1
body of tongue	1
vena cava	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CRB2	99	broad	marker	ventricular zone, ganglionic eminence, male germ line stem cell (sensu Vertebrata) in testis
DDX41	274	ubiquitous	marker	granulocyte, right frontal lobe, lower esophagus mucosa
DLL4	188	broad	marker	vena cava, apex of heart, body of tongue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DLL4	2,749
DDX41	2,388
CRB2	1,640

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DDX41	Q9UJV9	5
CRB2	Q5IJ48	1
DLL4	Q9NR61	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	815.7×	0.005	DLL4
STING mediated induction of host immune responses	1	519.1×	0.005	DDX41
NOTCH4 Activation and Transmission of Signal to the Nucleus	1	519.1×	0.005	DLL4
IRF3-mediated induction of type I IFN	1	407.9×	0.005	DDX41
Constitutive Signaling by NOTCH1 HD Domain Mutants	1	380.7×	0.005	DLL4
Regulation of innate immune responses to cytosolic DNA	1	380.7×	0.005	DDX41
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	237.9×	0.007	DLL4
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	219.6×	0.007	DLL4
Activated NOTCH1 Transmits Signal to the Nucleus	1	178.4×	0.007	DLL4
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	98.5×	0.011	DLL4
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	98.5×	0.011	DLL4
mRNA Splicing - Major Pathway	1	27.3×	0.036	DDX41

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
ingression involved in gastrulation with mouth forming second	1	5617.3×	0.005	CRB2
blood vessel lumenization	1	2808.7×	0.005	DLL4
notochord formation	1	1872.4×	0.005	CRB2
ventral spinal cord interneuron fate commitment	1	1872.4×	0.005	DLL4
regulation of neural retina development	1	1872.4×	0.005	DLL4
visual perception	2	53.0×	0.005	CRB2, DLL4
cGAS/STING signaling pathway	1	1123.5×	0.006	DDX41
cardiac atrium morphogenesis	1	936.2×	0.006	DLL4
regulation of gastrulation	1	936.2×	0.006	CRB2
maintenance of epithelial cell apical/basal polarity	1	802.5×	0.006	CRB2
pericardium morphogenesis	1	702.2×	0.006	DLL4
dorsal aorta morphogenesis	1	702.2×	0.006	DLL4
negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis	1	702.2×	0.006	DLL4
cardiac ventricle morphogenesis	1	624.1×	0.006	DLL4
negative regulation of endopeptidase activity	1	561.7×	0.006	CRB2
retinal cone cell development	1	468.1×	0.007	CRB2
circulatory system development	1	468.1×	0.007	CRB2
retina homeostasis	1	374.5×	0.008	CRB2
ventricular trabecula myocardium morphogenesis	1	351.1×	0.008	DLL4
negative regulation of cell migration involved in sprouting angiogenesis	1	330.4×	0.008	DLL4
negative regulation of endothelial cell migration	1	255.3×	0.009	DLL4
positive regulation of neural precursor cell proliferation	1	255.3×	0.009	DLL4
establishment or maintenance of epithelial cell apical/basal polarity	1	193.7×	0.011	CRB2
cellular response to vascular endothelial growth factor stimulus	1	187.2×	0.011	DLL4
cellular response to fibroblast growth factor stimulus	1	181.2×	0.011	DLL4
branching involved in blood vessel morphogenesis	1	175.5×	0.011	DLL4
cellular response to interferon-beta	1	175.5×	0.011	DDX41
mesoderm formation	1	165.2×	0.011	CRB2
positive regulation of BMP signaling pathway	1	151.8×	0.012	CRB2
aortic valve morphogenesis	1	144.0×	0.012	DLL4

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DDX41	1	2
CRB2	0	0
DLL4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	DDX41

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
DDX41	7	Binding:7

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

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)
MOLIBRESIB	2	DDX41

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	1	DDX41
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	CRB2, DLL4

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)
CRB2	0	—
DLL4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.