Focal segmental glomerulosclerosis 1

Summary

Focal segmental glomerulosclerosis 1 (MONDO:0011303) is a disease caused by ACTN4 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: ACTN4 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 197

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	focal segmental glomerulosclerosis 1
Mondo ID	MONDO:0011303
MeSH	C538457
OMIM	603278
Orphanet	93213
DOID	DOID:0111128
UMLS	C4551527
MedGen	1636833
GARD	0015353
Is cancer (heuristic)	no

Also known as: ACTN4 focal segmental glomerulosclerosis · familial idiopathic steroid-resistant nephrotic syndrome with focal segmental glomerulosclerosis · focal segmental glomerulosclerosis 1 · focal segmental glomerulosclerosis caused by mutation in ACTN4 · focal segmental glomerulosclerosis type 1 · FSGS1

Data availability: 197 ClinVar variants · 3 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 1

Related subtypes (7): HIV-associated nephropathy, 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

197 retrieved; paginated sample, class counts are floors:

109 uncertain significance, 25 benign/likely benign, 22 benign, 17 conflicting classifications of pathogenicity, 11 likely benign, 8 likely pathogenic, 5 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
235864	NM_004924.6(ACTN4):c.584G>A (p.Gly195Asp)	ACTN4	Pathogenic	no assertion criteria provided
2500724	NM_004924.6(ACTN4):c.584G>T (p.Gly195Val)	ACTN4	Pathogenic	criteria provided, single submitter
5420	NM_004924.6(ACTN4):c.763A>G (p.Lys255Glu)	ACTN4	Pathogenic	criteria provided, multiple submitters, no conflicts
5421	NM_004924.6(ACTN4):c.776C>T (p.Thr259Ile)	ACTN4	Pathogenic	criteria provided, single submitter
5422	NM_004924.6(ACTN4):c.784T>C (p.Ser262Pro)	ACTN4	Pathogenic	no assertion criteria provided
1028308	NM_004924.6(ACTN4):c.175T>C (p.Trp59Arg)	ACTN4	Likely pathogenic	criteria provided, single submitter
2572429	NM_004924.6(ACTN4):c.493G>A (p.Ala165Thr)	ACTN4	Likely pathogenic	criteria provided, single submitter
3068392	NM_004924.6(ACTN4):c.517T>C (p.Cys173Arg)	ACTN4	Likely pathogenic	criteria provided, single submitter
3236342	NM_004924.6(ACTN4):c.718A>G (p.Met240Val)	ACTN4	Likely pathogenic	criteria provided, single submitter
3900730	NM_004924.6(ACTN4):c.757G>A (p.Asp253Asn)	ACTN4	Likely pathogenic	criteria provided, single submitter
4796795	NM_004924.6(ACTN4):c.773T>C (p.Met258Thr)	ACTN4	Likely pathogenic	criteria provided, single submitter
599063	NM_004924.6(ACTN4):c.510_512del (p.Leu171del)	ACTN4	Likely pathogenic	no assertion criteria provided
599130	NM_004924.6(ACTN4):c.458T>C (p.Phe153Ser)	ACTN4	Likely pathogenic	no assertion criteria provided
1023729	NM_004924.6(ACTN4):c.1340C>T (p.Ser447Leu)	ACTN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1055307	NM_004924.6(ACTN4):c.2708C>T (p.Thr903Met)	ACTN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1382056	NM_004924.6(ACTN4):c.1712A>G (p.Asp571Gly)	ACTN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1406574	NM_004924.6(ACTN4):c.2671G>A (p.Ala891Thr)	ACTN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1513414	NM_004924.6(ACTN4):c.1291+4C>T	ACTN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1551330	NM_004924.6(ACTN4):c.2520C>T (p.Thr840=)	ACTN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1719884	NM_004924.6(ACTN4):c.789C>G (p.Ser263Arg)	ACTN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1936740	NM_004924.6(ACTN4):c.2698T>A (p.Ser900Thr)	ACTN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1977588	NM_004924.6(ACTN4):c.1236C>A (p.Asp412Glu)	ACTN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2438852	NM_004924.6(ACTN4):c.163-9C>T	ACTN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2788520	NM_004924.6(ACTN4):c.1422C>T (p.Ala474=)	ACTN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3583812	NM_004924.6(ACTN4):c.1552-20C>G	ACTN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3583814	NM_004924.6(ACTN4):c.1733C>T (p.Pro578Leu)	ACTN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3600406	NM_004924.6(ACTN4):c.1328C>T (p.Thr443Met)	ACTN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
599123	NM_004924.6(ACTN4):c.1279G>A (p.Ala427Thr)	ACTN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
738988	NM_004924.6(ACTN4):c.306G>T (p.Gly102=)	ACTN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
522528	NM_001025616.3(ARHGAP24):c.892C>T (p.Arg298Cys)	ARHGAP24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
ACTN4	Strong	Autosomal dominant	focal segmental glomerulosclerosis 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACTN4	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
ARHGAP24	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
NUP107	Orphanet:2065	Galloway-Mowat syndrome
NUP107	Orphanet:243	46,XX gonadal dysgenesis
NUP107	Orphanet:656	Hereditary steroid-resistant nephrotic 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
ACTN4	HGNC:166	ENSG00000130402	O43707	Alpha-actinin-4	gencc,clinvar
ARHGAP24	HGNC:25361	ENSG00000138639	Q8N264	Rho GTPase-activating protein 24	clinvar
NUP107	HGNC:29914	ENSG00000111581	P57740	Nuclear pore complex protein Nup107	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACTN4	Alpha-actinin-4	F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures.
ARHGAP24	Rho GTPase-activating protein 24	Rho GTPase-activating protein involved in cell polarity, cell morphology and cytoskeletal organization.
NUP107	Nuclear pore complex protein Nup107	Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACTN4	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
ARHGAP24	Scaffold/PPI	no		RhoGAP_dom, PH_domain, Rho_GTPase_activation_prot
NUP107	Other/Unknown	no		Nup84/Nup107

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
popliteal artery	1
smooth muscle tissue	1
tibial artery	1
metanephros cortex	1
pons	1
renal medulla	1
oocyte	1
secondary oocyte	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACTN4	145	ubiquitous	marker	popliteal artery, tibial artery, smooth muscle tissue
ARHGAP24	263	ubiquitous	marker	renal medulla, pons, metanephros cortex
NUP107	283	ubiquitous	marker	secondary oocyte, oocyte, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NUP107	3,524
ACTN4	3,303
ARHGAP24	1,406

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NUP107	P57740	7
ACTN4	O43707	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARHGAP24	Q8N264	66.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 46. Enrichment computed across 3 evidence-associated genes (3 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 3 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	158.6×	0.026	ACTN4
Postmitotic nuclear pore complex (NPC) reformation	1	135.9×	0.026	NUP107
IPs transport between nucleus and cytosol	1	126.9×	0.026	NUP107
IP3 and IP4 transport between cytosol and nucleus	1	126.9×	0.026	NUP107
IP6 and IP7 transport between cytosol and nucleus	1	126.9×	0.026	NUP107
Transport of Ribonucleoproteins into the Host Nucleus	1	119.0×	0.026	NUP107
Regulation of Glucokinase by Glucokinase Regulatory Protein	1	119.0×	0.026	NUP107
Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)	1	119.0×	0.026	NUP107
NEP/NS2 Interacts with the Cellular Export Machinery	1	115.3×	0.026	NUP107
Nuclear import of Rev protein	1	112.0×	0.026	NUP107
Vpr-mediated nuclear import of PICs	1	112.0×	0.026	NUP107
Transport of the SLBP independent Mature mRNA	1	108.8×	0.026	NUP107
SUMOylation of SUMOylation proteins	1	108.8×	0.026	NUP107
Transport of the SLBP Dependant Mature mRNA	1	105.7×	0.026	NUP107
Rev-mediated nuclear export of HIV RNA	1	105.7×	0.026	NUP107
Nuclear Pore Complex (NPC) Disassembly	1	102.9×	0.026	NUP107
SUMOylation of ubiquitinylation proteins	1	97.6×	0.026	NUP107
NS1 Mediated Effects on Host Pathways	1	95.2×	0.026	NUP107
Transport of Mature mRNA Derived from an Intronless Transcript	1	90.6×	0.026	NUP107
Viral Messenger RNA Synthesis	1	86.5×	0.026	NUP107
SUMOylation of DNA replication proteins	1	82.8×	0.026	NUP107
SUMOylation of RNA binding proteins	1	79.3×	0.026	NUP107
snRNP Assembly	1	70.5×	0.028	NUP107
tRNA processing in the nucleus	1	65.6×	0.029	NUP107
Response to elevated platelet cytosolic Ca2+	1	54.4×	0.032	ACTN4
SUMOylation of chromatin organization proteins	1	52.9×	0.032	NUP107
Transport of Mature mRNA derived from an Intron-Containing Transcript	1	50.8×	0.032	NUP107
ISG15 antiviral mechanism	1	50.1×	0.032	NUP107
SUMOylation of DNA damage response and repair proteins	1	48.8×	0.032	NUP107
Regulation of HSF1-mediated heat shock response	1	46.4×	0.032	NUP107

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
post-transcriptional tethering of RNA polymerase II gene DNA at nuclear periphery	1	1872.4×	0.006	NUP107
positive regulation of sodium:proton antiporter activity	1	1872.4×	0.006	ACTN4
negative regulation of Rac protein signal transduction	1	1404.3×	0.006	ARHGAP24
vesicle transport along actin filament	1	802.5×	0.006	ACTN4
negative regulation of ruffle assembly	1	802.5×	0.006	ARHGAP24
nephron development	1	624.1×	0.006	NUP107
nuclear pore complex assembly	1	561.7×	0.006	NUP107
peroxisome proliferator activated receptor signaling pathway	1	510.7×	0.006	ACTN4
negative regulation of substrate adhesion-dependent cell spreading	1	374.5×	0.007	ACTN4
wound healing, spreading of epidermal cells	1	351.1×	0.007	ARHGAP24
muscle cell development	1	312.1×	0.008	ACTN4
female gonad development	1	267.5×	0.008	NUP107
retinoic acid receptor signaling pathway	1	216.1×	0.009	ACTN4
nucleocytoplasmic transport	1	130.6×	0.014	NUP107
tumor necrosis factor-mediated signaling pathway	1	110.1×	0.016	ACTN4
mRNA export from nucleus	1	98.5×	0.016	NUP107
positive regulation of non-canonical NF-kappaB signal transduction	1	85.1×	0.018	ACTN4
protein import into nucleus	1	48.0×	0.030	NUP107
regulation of apoptotic process	1	27.8×	0.049	ACTN4
actin cytoskeleton organization	1	26.4×	0.049	ACTN4
angiogenesis	1	20.8×	0.057	ARHGAP24
positive regulation of cell migration	1	20.6×	0.057	ACTN4
protein transport	1	14.6×	0.076	ACTN4
cell differentiation	1	9.7×	0.108	ARHGAP24
signal transduction	1	5.3×	0.183	ARHGAP24
positive regulation of transcription by RNA polymerase II	1	5.0×	0.188	ACTN4

Therapeutics

Drug target analysis

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

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
ACTN4	1	2
ARHGAP24	0	0
NUP107	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	ACTN4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ACTN4	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	ACTN4

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	ACTN4
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ARHGAP24, NUP107

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)
ARHGAP24	0	—
NUP107	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.