Inherited focal segmental glomerulosclerosis

Summary

Inherited focal segmental glomerulosclerosis (MONDO:0005363) is a disease (an umbrella term covering 8 Mondo subtypes) with 3 cohort genes.

At a glance

• Umbrella term: 8 Mondo subtypes
• Cohort genes: 3
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	inherited focal segmental glomerulosclerosis
Mondo ID	MONDO:0005363
OMIM	603278
GARD	0024175
Is cancer (heuristic)	no

Data availability: 5 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 8 Mondo subtypes.

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

Related subtypes (25): familial juvenile hyperuricemic nephropathy, familial nephrotic syndrome, hereditary renal cell carcinoma, hereditary kidney oncocytoma, hereditary nephritis, prune belly syndrome, neurohypophyseal diabetes insipidus, fibronectin glomerulopathy, Liddle syndrome, familial renal glucosuria, nail-patella-like renal disease, renal tubular dysgenesis of genetic origin, proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis, nephrolithiasis, X-linked recessive, with renal failure, hypophosphatemic nephrolithiasis/osteoporosis 1, hypophosphatemic nephrolithiasis/osteoporosis 2, inherited renal tubular disease, renal agenesis, congenital anomaly of kidney and urinary tract, familial cystic renal disease, Alsing syndrome, inherited pseudohypoaldosteronism, Gitelman-like kidney tubulopathy due to mitochondrial DNA mutation, nephrolithiasis, calcium oxalate, inherited distal renal tubular acidosis

Subtypes (8): 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, focal segmental glomerulosclerosis 9

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

5 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
498798	NM_001174147.2(LMX1B):c.737G>A (p.Arg246Gln)	LMX1B	Pathogenic	criteria provided, multiple submitters, no conflicts
1018891	NM_012120.3(CD2AP):c.1488G>A (p.Met496Ile)	CD2AP	Uncertain significance	criteria provided, multiple submitters, no conflicts
2619433	NM_012120.3(CD2AP):c.1517A>G (p.Asn506Ser)	CD2AP	Uncertain significance	criteria provided, multiple submitters, no conflicts
357176	NM_012120.3(CD2AP):c.1569AGA[2] (p.Glu525del)	CD2AP	Uncertain significance	criteria provided, multiple submitters, no conflicts
3779019	NM_012120.3(CD2AP):c.920G>A (p.Gly307Asp)	CD2AP	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · 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
ARHGAP24	Limited	Autosomal dominant	inherited focal segmental glomerulosclerosis	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ARHGAP24	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
CD2AP	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
LMX1B	Orphanet:2613	Nail-patella-like renal disease
LMX1B	Orphanet:2614	Nail-patella syndrome
LMX1B	Orphanet:495818	9q33.3q34.11 microdeletion 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
ARHGAP24	HGNC:25361	ENSG00000138639	Q8N264	Rho GTPase-activating protein 24	gencc
CD2AP	HGNC:14258	ENSG00000198087	Q9Y5K6	CD2-associated protein	clinvar
LMX1B	HGNC:6654	ENSG00000136944	O60663	LIM homeobox transcription factor 1-beta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARHGAP24	Rho GTPase-activating protein 24	Rho GTPase-activating protein involved in cell polarity, cell morphology and cytoskeletal organization.
CD2AP	CD2-associated protein	Seems to act as an adapter protein between membrane proteins and the actin cytoskeleton.
LMX1B	LIM homeobox transcription factor 1-beta	Transcription factor involved in the regulation of podocyte-expressed genes.

Protein-family classification

Druggable: 0 · Difficult: 3 · Unknown: 0 · 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
Scaffold/PPI	2	11.5×	0.019
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ARHGAP24	Scaffold/PPI	no		RhoGAP_dom, PH_domain, Rho_GTPase_activation_prot
CD2AP	Scaffold/PPI	no		SH3_domain, CD2AP_SH3_1, CD2AP_SH_2
LMX1B	Transcription factor	no		HD, Znf_LIM, Homeodomain-like_sf

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
metanephros cortex	1
pons	1
renal medulla	1
colonic mucosa	1
esophagus squamous epithelium	1
jejunal mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARHGAP24	263	ubiquitous	marker	renal medulla, pons, metanephros cortex
CD2AP	275	ubiquitous	marker	jejunal mucosa, esophagus squamous epithelium, colonic mucosa
LMX1B	74	broad	marker	sural nerve, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CD2AP	2,408
LMX1B	1,514
ARHGAP24	1,406

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CD2AP	Q9Y5K6	12

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LMX1B	O60663	70.79
ARHGAP24	Q8N264	66.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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	1	237.9×	0.021	CD2AP
Cell-Cell communication	1	68.8×	0.032	CD2AP
RHOA GTPase cycle	1	37.3×	0.032	ARHGAP24
CDC42 GTPase cycle	1	36.1×	0.032	ARHGAP24
RAC1 GTPase cycle	1	30.5×	0.032	ARHGAP24

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
response to glial cell derived neurotrophic factor	1	2808.7×	0.010	CD2AP
transforming growth factor beta1 production	1	1872.4×	0.010	CD2AP
negative regulation of Rac protein signal transduction	1	1404.3×	0.010	ARHGAP24
renal albumin absorption	1	1123.5×	0.010	CD2AP
negative regulation of transforming growth factor beta1 production	1	936.2×	0.010	CD2AP
localization of cell	1	936.2×	0.010	CD2AP
negative regulation of ruffle assembly	1	802.5×	0.010	ARHGAP24
response to transforming growth factor beta	1	624.1×	0.010	CD2AP
substrate-dependent cell migration, cell extension	1	510.7×	0.010	CD2AP
podocyte differentiation	1	468.1×	0.010	CD2AP
immunological synapse formation	1	432.1×	0.010	CD2AP
endothelium development	1	432.1×	0.010	CD2AP
nerve growth factor signaling pathway	1	432.1×	0.010	CD2AP
collateral sprouting	1	401.2×	0.010	CD2AP
negative regulation of small GTPase mediated signal transduction	1	401.2×	0.010	CD2AP
wound healing, spreading of epidermal cells	1	351.1×	0.010	ARHGAP24
neurotrophin TRK receptor signaling pathway	1	351.1×	0.010	CD2AP
protein heterooligomerization	1	351.1×	0.010	CD2AP
Rab protein signal transduction	1	330.4×	0.010	CD2AP
obsolete D-glucose import	1	280.9×	0.011	CD2AP
lymph node development	1	267.5×	0.011	CD2AP
stress-activated MAPK cascade	1	234.1×	0.012	CD2AP
filopodium assembly	1	216.1×	0.012	CD2AP
cell-cell junction organization	1	208.1×	0.012	CD2AP
dopaminergic neuron differentiation	1	208.1×	0.012	LMX1B
membrane organization	1	170.2×	0.014	CD2AP
actin filament polymerization	1	160.5×	0.014	CD2AP
maintenance of blood-brain barrier	1	160.5×	0.014	CD2AP
dorsal/ventral pattern formation	1	140.4×	0.015	LMX1B
cell-cell adhesion mediated by cadherin	1	137.0×	0.015	CD2AP

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ARHGAP24	0	0
CD2AP	0	0
LMX1B	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CD2AP	1	Binding:1

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	ARHGAP24, CD2AP, LMX1B

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)
ARHGAP24	0	—
CD2AP	1	—
LMX1B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.