Focal segmental glomerulosclerosis 5

Summary

Focal segmental glomerulosclerosis 5 (MONDO:0013191) is a disease caused by INF2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: INF2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 1,553

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	focal segmental glomerulosclerosis 5
Mondo ID	MONDO:0013191
MeSH	C567687
OMIM	613237
DOID	DOID:0111130
UMLS	C2750475
MedGen	413315
GARD	0015636
Is cancer (heuristic)	no

Also known as: focal segmental glomerulosclerosis 5 · focal segmental glomerulosclerosis caused by mutation in INF2 · focal segmental glomerulosclerosis type 5 · FSGS5 · INF2 focal segmental glomerulosclerosis

Data availability: 1,553 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 5

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

600 retrieved; paginated sample, class counts are floors:

293 likely benign, 188 uncertain significance, 58 conflicting classifications of pathogenicity, 31 benign, 18 benign/likely benign, 6 likely pathogenic, 4 pathogenic/likely pathogenic, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1050	NM_022489.4(INF2):c.556T>C (p.Ser186Pro)	INF2	Pathogenic	no assertion criteria provided
1051	NM_022489.4(INF2):c.653G>A (p.Arg218Gln)	INF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1052	NM_022489.4(INF2):c.652C>T (p.Arg218Trp)	INF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1053	NM_022489.4(INF2):c.641G>A (p.Arg214His)	INF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1054	NM_022489.4(INF2):c.125T>C (p.Leu42Pro)	INF2	Pathogenic	no assertion criteria provided
1999164	NM_022489.4(INF2):c.218G>A (p.Gly73Asp)	INF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179196	NM_022489.4(INF2):c.1735+1G>A	INF2	Likely pathogenic	criteria provided, single submitter
1184454	NM_022489.4(INF2):c.485T>C (p.Leu162Pro)	INF2	Likely pathogenic	criteria provided, single submitter
1344668	NM_022489.4(INF2):c.353T>A (p.Ile118Asn)	INF2	Likely pathogenic	no assertion criteria provided
1518638	NM_022489.4(INF2):c.470G>A (p.Gly157Asp)	INF2	Likely pathogenic	criteria provided, single submitter
1697256	NM_022489.4(INF2):c.605A>G (p.Asn202Ser)	INF2	Likely pathogenic	criteria provided, single submitter
2572531	NM_022489.4(INF2):c.604A>G (p.Asn202Asp)	INF2	Likely pathogenic	criteria provided, single submitter
1003777	NM_022489.4(INF2):c.509C>T (p.Thr170Met)	INF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1009065	NM_022489.4(INF2):c.2602C>T (p.Arg868Cys)	INF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1014934	NM_022489.4(INF2):c.695G>A (p.Arg232His)	INF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1019747	NM_022489.4(INF2):c.1262CACCCC[1] (p.Pro423_Pro428del)	INF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1021555	NM_022489.4(INF2):c.359G>A (p.Ser120Asn)	INF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1024088	NM_022489.4(INF2):c.2101G>A (p.Ala701Thr)	INF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1040453	NM_022489.4(INF2):c.3209G>A (p.Arg1070Gln)	INF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1041727	NM_022489.4(INF2):c.3257T>C (p.Leu1086Pro)	INF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1112132	NM_022489.4(INF2):c.636C>T (p.Arg212=)	INF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1128266	NM_022489.4(INF2):c.2776-5T>C	INF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1137635	NM_022489.4(INF2):c.1458C>T (p.Phe486=)	INF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1201695	NM_022489.4(INF2):c.1615G>A (p.Val539Met)	INF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1303866	NM_022489.4(INF2):c.1316C>T (p.Pro439Leu)	INF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1312229	NM_022489.4(INF2):c.3611C>T (p.Ser1204Leu)	INF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1315296	NM_022489.4(INF2):c.1774G>A (p.Ala592Thr)	INF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1330811	NM_022489.4(INF2):c.1979G>A (p.Arg660Gln)	INF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1386847	NM_022489.4(INF2):c.2254C>T (p.Arg752Cys)	INF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1393855	NM_022489.4(INF2):c.1792G>A (p.Asp598Asn)	INF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
INF2	Strong	Autosomal dominant	focal segmental glomerulosclerosis 5	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
INF2	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
INF2	Orphanet:93114	Autosomal dominant intermediate Charcot-Marie-Tooth disease type E

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
INF2	HGNC:23791	ENSG00000203485	Q27J81	Inverted formin-2	gencc,clinvar
PLD4	HGNC:23792	ENSG00000166428	Q96BZ4	5’-3’ exonuclease PLD4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
INF2	Inverted formin-2	Severs actin filaments and accelerates their polymerization and depolymerization.
PLD4	5’-3’ exonuclease PLD4	5’->3’ exonuclease that hydrolyzes the phosphodiester bond of single-stranded DNA (ssDNA) and RNA molecules to form nucleoside 3’-monophosphates and 5’-end 5’-hydroxy deoxyribonucleotide/ribonucleotide fragments.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
INF2	Other/Unknown	no		WH2_dom, FH3_dom, GTPase-bd
PLD4	Other/Unknown	no		PLipase_D/transphosphatidylase, PLDc_3, Diverse_PLD-related

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
nerve	1
sural nerve	1
tibial nerve	1
granulocyte	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
INF2	260	ubiquitous	marker	sural nerve, nerve, tibial nerve
PLD4	163	broad	marker	granulocyte, leukocyte, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
INF2	2,070
PLD4	1,054

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
INF2	Q27J81	10
PLD4	Q96BZ4	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Synthesis of PG	1	1268.9×	0.002	PLD4
Role of phospholipids in phagocytosis	1	456.8×	0.002	PLD4
Synthesis of IP3 and IP4 in the cytosol	1	423.0×	0.002	PLD4

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of mitochondrial fission	1	1053.2×	0.005	INF2
regulation of cytokine production involved in inflammatory response	1	936.2×	0.005	PLD4
actin filament polymerization	1	240.7×	0.012	INF2
phagocytosis	1	120.4×	0.015	PLD4
hematopoietic progenitor cell differentiation	1	118.7×	0.015	PLD4
establishment of localization in cell	1	80.2×	0.019	PLD4
lipid metabolic process	1	45.8×	0.028	PLD4
inflammatory response	1	18.9×	0.059	PLD4
innate immune response	1	16.8×	0.059	PLD4

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
INF2	0	0
PLD4	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
PLD4	10	Binding:10
INF2	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	INF2, PLD4

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)
INF2	1	—
PLD4	10	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.