Glomerulopathy with fibronectin deposits 2

Summary

Glomerulopathy with fibronectin deposits 2 (MONDO:0011165) is a disease caused by FN1 (GenCC Strong), with 6 cohort genes.

At a glance

• Causal gene: FN1 (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 446

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	glomerulopathy with fibronectin deposits 2
Mondo ID	MONDO:0011165
OMIM	601894
SNOMED CT	722759007
UMLS	C1866075
MedGen	356149
GARD	0009914
Is cancer (heuristic)	no

Also known as: fibronectin glomerulopathy caused by mutation in FN1 · FN1 fibronectin glomerulopathy · GFND2 · glomerular nephritis familial with fibronectin deposits · glomerulopathy with fibronectin deposits 2 · glomerulopathy with fibronectin deposits type 2

Data availability: 446 ClinVar variants · 4 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › urinary system disorder › kidney disorder › glomerular disorder › fibronectin glomerulopathy › glomerulopathy with fibronectin deposits 2

Related subtypes (1): glomerulopathy with fibronectin deposits 1

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

446 retrieved; paginated sample, class counts are floors:

269 uncertain significance, 76 conflicting classifications of pathogenicity, 41 likely benign, 34 benign/likely benign, 18 benign, 6 pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
16323	NM_212482.4(FN1):c.5773T>A (p.Trp1925Arg)	FN1	Pathogenic	no assertion criteria provided
16324	NM_212482.4(FN1):c.5921T>G (p.Leu1974Arg)	FN1	Pathogenic	no assertion criteria provided
16325	NM_212482.4(FN1):c.2918A>G (p.Tyr973Cys)	FN1	Pathogenic	criteria provided, multiple submitters, no conflicts
192244	NM_212482.4(FN1):c.5775G>C (p.Trp1925Cys)	FN1	Pathogenic	no assertion criteria provided
192245	NM_212482.4(FN1):c.5921T>C (p.Leu1974Pro)	FN1	Pathogenic	no assertion criteria provided
192246	NM_212482.4(FN1):c.4412CTC[1] (p.Pro1472del)	FN1	Pathogenic	no assertion criteria provided
1704308	NM_212482.4(FN1):c.7144+1G>A	ATIC	Likely pathogenic	no assertion criteria provided
3585436	NM_212482.4(FN1):c.5773T>C (p.Trp1925Arg)	FN1	Likely pathogenic	criteria provided, single submitter
1482572	NM_212482.4(FN1):c.7070G>A (p.Arg2357His)	ATIC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2717912	NM_212482.4(FN1):c.6878C>T (p.Thr2293Met)	ATIC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1000581	NM_212482.4(FN1):c.141A>C (p.Gln47His)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1007901	NM_212482.4(FN1):c.5735G>A (p.Arg1912His)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1020947	NM_212482.4(FN1):c.869G>A (p.Arg290His)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1025513	NM_212482.4(FN1):c.6506C>T (p.Pro2169Leu)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1036930	NM_212482.4(FN1):c.3491C>T (p.Ala1164Val)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1041916	NM_212482.4(FN1):c.6121C>T (p.Arg2041Trp)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1042834	NM_212482.4(FN1):c.4262C>G (p.Pro1421Arg)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1043875	NM_212482.4(FN1):c.1247A>G (p.Asn416Ser)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1049911	NM_212482.4(FN1):c.3289G>A (p.Glu1097Lys)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1051103	NM_212482.4(FN1):c.3061C>T (p.Arg1021Trp)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1055248	NM_212482.4(FN1):c.5983G>A (p.Asp1995Asn)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1062400	NM_212482.4(FN1):c.1436G>T (p.Arg479Leu)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1063626	NM_212482.4(FN1):c.5608G>T (p.Val1870Leu)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1359662	NM_212482.4(FN1):c.4801C>T (p.Pro1601Ser)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1365477	NM_212482.4(FN1):c.4858G>A (p.Ala1620Thr)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1367318	NM_212482.4(FN1):c.3866C>T (p.Pro1289Leu)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1368764	NM_212482.4(FN1):c.665G>A (p.Arg222His)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1371207	NM_212482.4(FN1):c.587T>A (p.Val196Glu)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1374587	NM_212482.4(FN1):c.6157+4T>C	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1394514	NM_212482.4(FN1):c.6220G>A (p.Glu2074Lys)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 7 · 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
FN1	Strong	Autosomal dominant	glomerulopathy with fibronectin deposits 2	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FN1	Orphanet:84090	Fibronectin glomerulopathy
FN1	Orphanet:93315	Spondylometaphyseal dysplasia, ‘corner fracture’ type
INF2	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
INF2	Orphanet:93114	Autosomal dominant intermediate Charcot-Marie-Tooth disease type E
FOXF1	Orphanet:210122	Congenital alveolar capillary dysplasia
G6PD	Orphanet:466026	Class I glucose-6-phosphate dehydrogenase deficiency
ATIC	Orphanet:250977	AICA-ribosiduria

Cohort genes → proteins

6 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FN1	HGNC:3778	ENSG00000115414	P02751	Fibronectin	gencc,clinvar
INF2	HGNC:23791	ENSG00000203485	Q27J81	Inverted formin-2	clinvar
FOXF1	HGNC:3809	ENSG00000103241	Q12946	Forkhead box protein F1	clinvar
G6PD	HGNC:4057	ENSG00000160211	P11413	Glucose-6-phosphate 1-dehydrogenase	clinvar
FN1-DT	HGNC:55775	ENSG00000230695		FN1 divergent transcript	clinvar
ATIC	HGNC:794	ENSG00000138363	P31939	Bifunctional purine biosynthesis protein ATIC	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FN1	Fibronectin	Fibronectins bind cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin.
INF2	Inverted formin-2	Severs actin filaments and accelerates their polymerization and depolymerization.
FOXF1	Forkhead box protein F1	Probable transcription activator for a number of lung-specific genes.
G6PD	Glucose-6-phosphate 1-dehydrogenase	Catalyzes the rate-limiting step of the oxidative pentose-phosphate pathway, which represents a route for the dissimilation of carbohydrates besides glycolysis.
ATIC	Bifunctional purine biosynthesis protein ATIC	Bifunctional enzyme that catalyzes the last two steps of purine biosynthesis.

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.5

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)	2	4.0×	0.333
Antibody/Immunoglobulin	1	4.9×	0.377
Transcription factor	1	1.4×	0.719
Other/Unknown	2	0.6×	0.936

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FN1	Antibody/Immunoglobulin	yes		Fibronectin_type1, FN_type2_dom, FN3_dom
INF2	Other/Unknown	no		WH2_dom, FH3_dom, GTPase-bd
FOXF1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
G6PD	Enzyme (other)	yes	1.1.1.49	G6P_DH, G6P_DH_AS, G6P_DH_NAD-bd
FN1-DT	Other/Unknown	no
ATIC	Enzyme (other)	yes	2.1.2.3	PurH-like, MGS-like_dom, Cytidine_deaminase-like

Expression context

Cohort genes with no expression data: 0.

5 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	2
stromal cell of endometrium	2
decidua	1
right coronary artery	1
synovial joint	1
nerve	1
tibial nerve	1
mucosa of stomach	1
muscle layer of sigmoid colon	1
right lung	1
granulocyte	1
right testis	1
calcaneal tendon	1
myometrium	1
mucosa of transverse colon	1
rectum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FN1	292	ubiquitous	marker	synovial joint, right coronary artery, decidua
INF2	260	ubiquitous	marker	sural nerve, nerve, tibial nerve
FOXF1	202	broad	marker	muscle layer of sigmoid colon, mucosa of stomach, right lung
G6PD	218	ubiquitous	marker	stromal cell of endometrium, granulocyte, right testis
FN1-DT	96		yes	sural nerve, calcaneal tendon, myometrium
ATIC	290	ubiquitous	marker	mucosa of transverse colon, stromal cell of endometrium, rectum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FN1	8,860
G6PD	4,226
ATIC	3,960
INF2	2,070
FOXF1	1,694
FN1-DT	0

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FN1	P02751	65
G6PD	P11413	25
INF2	Q27J81	10
ATIC	P31939	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FOXF1	Q12946	59.41

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 35. Enrichment computed across 6 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by ALK fusions and activated point mutants	2	75.1×	0.009	FN1, ATIC
Formation of lateral plate mesoderm	1	571.0×	0.021	FOXF1
NFE2L2 regulates pentose phosphate pathway genes	1	356.9×	0.021	G6PD
Purine ribonucleoside monophosphate biosynthesis	1	259.6×	0.021	ATIC
Regulation of CDH11 gene transcription	1	259.6×	0.021	FOXF1
Pentose phosphate pathway	1	237.9×	0.021	G6PD
ALK mutants bind TKIs	1	237.9×	0.021	FN1
p130Cas linkage to MAPK signaling for integrins	1	190.3×	0.022	FN1
GRB2:SOS provides linkage to MAPK signaling for Integrins	1	178.4×	0.022	FN1
Fibronectin matrix formation	1	142.8×	0.024	FN1
Attachment of bacteria to epithelial cells	1	124.1×	0.024	FN1
Syndecan interactions	1	105.7×	0.024	FN1
Integrin signaling	1	105.7×	0.024	FN1
MET activates PTK2 signaling	1	95.2×	0.024	FN1
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	89.2×	0.024	FN1
Signaling by high-kinase activity BRAF mutants	1	79.3×	0.024	FN1
Molecules associated with elastic fibres	1	77.2×	0.024	FN1
MAP2K and MAPK activation	1	71.4×	0.024	FN1
Signaling by RAF1 mutants	1	69.6×	0.024	FN1
Signaling by moderate kinase activity BRAF mutants	1	63.4×	0.024	FN1
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	63.4×	0.024	FN1
Signaling downstream of RAS mutants	1	63.4×	0.024	FN1
GPER1 signaling	1	62.1×	0.024	FN1
Developmental Lineage of Pancreatic Ductal Cells	1	57.1×	0.025	FN1
Signaling by BRAF and RAF1 fusions	1	42.6×	0.033	FN1
Non-integrin membrane-ECM interactions	1	38.6×	0.034	FN1
ECM proteoglycans	1	37.6×	0.034	FN1
Integrin cell surface interactions	1	33.6×	0.037	FN1
TP53 Regulates Metabolic Genes	1	32.4×	0.037	G6PD
Degradation of the extracellular matrix	1	29.4×	0.039	FN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
detection of wounding	1	3370.4×	0.007	FOXF1
ribose phosphate biosynthetic process	1	3370.4×	0.007	G6PD
embryonic ectodermal digestive tract morphogenesis	1	3370.4×	0.007	FOXF1
right lung morphogenesis	1	3370.4×	0.007	FOXF1
response to iron(III) ion	1	1685.2×	0.007	G6PD
pentose biosynthetic process	1	1685.2×	0.007	G6PD
lateral mesodermal cell differentiation	1	1685.2×	0.007	FOXF1
positive regulation of calcium ion transmembrane transport via high voltage-gated calcium channel	1	1685.2×	0.007	G6PD
dihydrofolate metabolic process	1	1123.5×	0.007	ATIC
trachea development	1	1123.5×	0.007	FOXF1
negative regulation of monocyte activation	1	1123.5×	0.007	FN1
calcium-independent cell-matrix adhesion	1	842.6×	0.007	FN1
pentose-phosphate shunt, oxidative branch	1	842.6×	0.007	G6PD
epithelial cell differentiation involved in mammary gland alveolus development	1	842.6×	0.007	FOXF1
positive regulation of substrate-dependent cell migration, cell attachment to substrate	1	842.6×	0.007	FN1
respiratory tube development	1	674.1×	0.007	FOXF1
venous blood vessel development	1	674.1×	0.007	FOXF1
negative regulation of transforming growth factor beta production	1	674.1×	0.007	FN1
mesenchyme migration	1	674.1×	0.007	FOXF1
ductus arteriosus closure	1	674.1×	0.007	FOXF1
‘de novo’ IMP biosynthetic process	1	561.7×	0.007	ATIC
cell-substrate junction assembly	1	561.7×	0.007	FN1
negative regulation of mast cell degranulation	1	561.7×	0.007	FOXF1
tetrahydrofolate biosynthetic process	1	561.7×	0.007	ATIC
biological process involved in interaction with symbiont	1	561.7×	0.007	FN1
ureter development	1	561.7×	0.007	FOXF1
heart development	2	31.5×	0.007	FN1, FOXF1
morphogenesis of a branching structure	1	421.3×	0.008	FOXF1
brainstem development	1	421.3×	0.008	ATIC
midgut development	1	421.3×	0.008	FOXF1

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 6 evidence-associated genes (67%) 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
G6PD	BREXANOLONE
ATIC	PEMETREXED

Top cohort targets by molecule count

Symbol	Molecules	Max phase
G6PD	8	4
ATIC	3	4
FN1	0	0
INF2	0	0
FOXF1	0	0
FN1-DT	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BREXANOLONE	4	G6PD
APOMORPHINE HYDROCHLORIDE	4	G6PD
PRASTERONE	4	G6PD
PEMETREXED	4	ATIC
METHOTREXATE	4	ATIC
SULFASALAZINE	4	ATIC
EBSELEN	3	G6PD
PICEID	2	G6PD
SEPRANOLONE	2	G6PD
PREGNENOLONE	1	G6PD
16.ALPHA.-BROMOEPIANDROSTERONE	1	G6PD

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ATIC	95	Binding:95
G6PD	49	Binding:46, ADMET:2, Functional:1
FN1	1	Binding:1
INF2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
G6PD	1.1.1.49	glucose-6-phosphate dehydrogenase (NADP+)
ATIC	2.1.2.3, 3.5.4.10	phosphoribosylaminoimidazolecarboxamide formyltransferase, IMP cyclohydrolase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
G6PD	1

Chemical tractability of cohort targets

11 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)
BREXANOLONE	4	G6PD
APOMORPHINE HYDROCHLORIDE	4	G6PD
PRASTERONE	4	G6PD
PEMETREXED	4	ATIC
METHOTREXATE	4	ATIC
SULFASALAZINE	4	ATIC
EBSELEN	3	G6PD
PICEID	2	G6PD
SEPRANOLONE	2	G6PD
PREGNENOLONE	1	G6PD
16.ALPHA.-BROMOEPIANDROSTERONE	1	G6PD

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	G6PD, ATIC
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	FN1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	INF2, FOXF1, FN1-DT

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FN1	1	—
INF2	1	—
FOXF1	0	—
FN1-DT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.