FN1

Summary

FN1 (fibronectin 1, HGNC:3778) is a protein-coding gene on chromosome 2q35, encoding Fibronectin (P02751). Fibronectins bind cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin.

This gene encodes fibronectin, a glycoprotein present in a soluble dimeric form in plasma, and in a dimeric or multimeric form at the cell surface and in extracellular matrix. The encoded preproprotein is proteolytically processed to generate the mature protein. Fibronectin is involved in cell adhesion and migration processes including embryogenesis, wound healing, blood coagulation, host defense, and metastasis. The gene has three regions subject to alternative splicing, with the potential to produce 20 different transcript variants, at least one of which encodes an isoform that undergoes proteolytic processing. The full-length nature of some variants has not been determined.

Source: NCBI Gene 2335 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spondylometaphyseal dysplasia, ‘corner fracture’ type (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 28
• Clinical variants (ClinVar): 1,835 total — 12 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 77
• Druggable target: yes
• MANE Select transcript: NM_212482

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3778
Approved symbol	FN1
Name	fibronectin 1
Location	2q35
Locus type	gene with protein product
Status	Approved
Aliases	MSF, CIG, LETS, GFND2, FINC, lnc-ABCA12-8
Ensembl gene	ENSG00000115414
Ensembl biotype	protein_coding
OMIM	135600
Entrez	2335

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 23 protein_coding, 13 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000323926, ENST00000336916, ENST00000354785, ENST00000356005, ENST00000357867, ENST00000359671, ENST00000421182, ENST00000426059, ENST00000432072, ENST00000438981, ENST00000443816, ENST00000446046, ENST00000456923, ENST00000460217, ENST00000461974, ENST00000469569, ENST00000471193, ENST00000473614, ENST00000474036, ENST00000480024, ENST00000480737, ENST00000485567, ENST00000490833, ENST00000492816, ENST00000494446, ENST00000496542, ENST00000498719, ENST00000865084, ENST00000865085, ENST00000865086, ENST00000865087, ENST00000865088, ENST00000865089, ENST00000933287, ENST00000967217, ENST00000967218, ENST00000967219

RefSeq mRNA: 18 — MANE Select: NM_212482 NM_001306129, NM_001306130, NM_001306131, NM_001306132, NM_001365517, NM_001365518, NM_001365519, NM_001365520, NM_001365521, NM_001365522, NM_001365523, NM_001365524, NM_002026, NM_054034, NM_212474, NM_212476, NM_212478, NM_212482

CCDS: CCDS2399, CCDS2400, CCDS42813, CCDS42814, CCDS46510, CCDS46512, CCDS77522, CCDS77523, CCDS77525, CCDS77526, CCDS92940

Canonical transcript exons

ENST00000354785 — 46 exons

Exon	Start	End
ENSE00000965892	215397680	215397848
ENSE00000965897	215392931	215393203
ENSE00001145978	215371909	215372375
ENSE00001146062	215384020	215384184
ENSE00001146105	215397137	215397223
ENSE00001146152	215408298	215408426
ENSE00001146180	215419242	215419385
ENSE00001146209	215423350	215423526
ENSE00001146236	215428180	215428338
ENSE00001146266	215433324	215433461
ENSE00001146412	215391632	215391814
ENSE00001223232	215414837	215414958
ENSE00001245657	215422091	215422243
ENSE00001245669	215424146	215424325
ENSE00001245674	215425094	215425285
ENSE00001245714	215435655	215436068
ENSE00001342398	215384860	215384976
ENSE00001342408	215394528	215394719
ENSE00001342416	215406238	215406510
ENSE00001342419	215407127	215407321
ENSE00001342422	215408108	215408197
ENSE00001342429	215409563	215409739
ENSE00001342433	215409934	215410114
ENSE00001342442	215420673	215420801
ENSE00001342461	215430715	215430852
ENSE00001342465	215431833	215431964
ENSE00001342487	215434696	215434824
ENSE00001816730	215360865	215361626
ENSE00002257477	215404389	215404655
ENSE00002318685	215399257	215399351
ENSE00003487663	215376498	215376674
ENSE00003505568	215379130	215379317
ENSE00003509373	215375629	215375718
ENSE00003509434	215375214	215375393
ENSE00003524885	215382212	215382325
ENSE00003537015	215388212	215388301
ENSE00003548106	215380811	215381080
ENSE00003559914	215370294	215370432
ENSE00003563906	215361969	215362079
ENSE00003596333	215373322	215373411
ENSE00003632252	215365505	215365630
ENSE00003634343	215383328	215383483
ENSE00003637183	215364879	215364985
ENSE00003646281	215367863	215368027
ENSE00003646828	215386689	215386958
ENSE00003674405	215378175	215378262

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 1717.9272 / max 114166.9042, expressed in 1601 samples.

FANTOM5 promoters (42 alternative TSS)

Promoter ID	TPM avg	Samples expressed
33740	1573.6905	1592
33669	12.3517	914
33597	11.2864	925
33666	8.8261	899
33580	8.6873	889
33601	8.5600	861
33726	8.1422	931
33619	7.7261	882
33615	7.1425	880
33626	7.1134	864

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
synovial joint	UBERON:0002217	99.99	gold quality
right coronary artery	UBERON:0001625	99.98	gold quality
decidua	UBERON:0002450	99.97	gold quality
descending thoracic aorta	UBERON:0002345	99.96	gold quality
ascending aorta	UBERON:0001496	99.95	gold quality
thoracic aorta	UBERON:0001515	99.95	gold quality
layer of synovial tissue	UBERON:0007616	99.95	gold quality
tibia	UBERON:0000979	99.94	gold quality
tendon of biceps brachii	UBERON:0008188	99.93	gold quality
stromal cell of endometrium	CL:0002255	99.91	gold quality
aorta	UBERON:0000947	99.91	gold quality
left coronary artery	UBERON:0001626	99.90	gold quality
coronary artery	UBERON:0001621	99.89	gold quality
placenta	UBERON:0001987	99.89	gold quality
cartilage tissue	UBERON:0002418	99.89	gold quality
blood vessel layer	UBERON:0004797	99.89	gold quality
popliteal artery	UBERON:0002250	99.88	gold quality
tibial artery	UBERON:0007610	99.88	gold quality
visceral pleura	UBERON:0002401	99.87	gold quality
saphenous vein	UBERON:0007318	99.86	gold quality
vena cava	UBERON:0004087	99.84	gold quality
periodontal ligament	UBERON:0008266	99.83	gold quality
upper lobe of left lung	UBERON:0008952	99.81	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.81	gold quality
upper lobe of lung	UBERON:0008948	99.80	gold quality
lower esophagus	UBERON:0013473	99.80	gold quality
seminal vesicle	UBERON:0000998	99.78	gold quality
right lobe of liver	UBERON:0001114	99.72	gold quality
liver	UBERON:0002107	99.72	gold quality
right lung	UBERON:0002167	99.72	gold quality

Single-cell (SCXA)

Detected in 41 experiment(s), a significant marker in 37.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	55282.21
E-MTAB-8322	yes	28182.54
E-MTAB-6701	yes	28123.06
E-HCAD-23	yes	12916.97
E-MTAB-8559	yes	9770.64
E-ENAD-20	yes	9067.99
E-MTAB-7008	yes	7153.39
E-MTAB-8410	yes	5807.43
E-CURD-112	yes	5101.02
E-HCAD-36	yes	4544.92
E-GEOD-98556	yes	3096.20
E-CURD-126	yes	2809.36
E-MTAB-8060	yes	2715.60
E-MTAB-8271	yes	2445.21
E-CURD-98	yes	2331.88

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
FN1	Activation
HSPG2	Activation

Upstream regulators (CollecTRI, top): AP1, AR, ATF2, ATF3, CEBPA, CREB1, CTNNB1, DDIT3, DLX4, EGR1, ETS1, FBLN1, FN1, FOS, FOSL1, FOXC1, GATA3, GLI3, HAND2, HIF1A, HOXA7, HR, HTATIP2, JUN, KLF8, LEF1, LMX1B, MYC, NFATC1, NFIA, NFKB1, NFKB, NR0B2, NR1I3, NR3C1, NR3C2, PARP1, PAX3, PGR, PIN1

miRNA regulators (miRDB)

98 targeting FN1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-153-5P	99.89	73.86	6317

Literature-anchored findings (GeneRIF, showing 40)

• Binding of fibronectin by Trichomonas vaginalis is influenced by iron and calcium (PMID:11500098)
• We show a novel alternative pathway of apoptosis that is regulated by the alternatively spliced V region and high-affinity heparin-binding domain of fibronectin (PMID:11751853)
• Potential mechanism of fibronectin deposits in acute renal failure induced by mercuric chloride (PMID:11768240)
• Alternative splicing of the IIICS domain in fibronectin governs the role of the heparin II domain in fibrillogenesis and cell spreading. (PMID:11832485)
• Increased plasma fibronectin levels in patients with acute myocardial infarction complicated with left ventricular thrombus; multivariate analysis showed that plasma fibronectin levels were not an independent predictor of LV thrombus formation. (PMID:11864705)
• Low density lipoprotein receptor-related protein (LRP) functions as a catabolic receptor for Fn (PMID:11867643)
• Laminin-10/11 and fibronectin differentially prevent apoptosis induced by serum removal via phosphatidylinositol 3-kinase/Akt- and MEK1/ERK-dependent pathways (Laminin 10; separate entry for Laminin 11). (PMID:11891225)
• differential role of u-PA and t-PA as inducers of fibronectin mRNA (PMID:11928812)
• investigation of the role of direct contact with stroma and the ECM protein fibronectin in the preservation of normal but not chronic myelogenous leukemia primitive hematopoietic progenitors (PMID:11937267)
• Adhesion of hairy cells to fibronectin inhibits interferon-alpha-induced apoptosis. (PMID:12091360)
• fragment from fibronectin’s III1 module localizes to lipid rafts and stimulates cell growth and contractility (PMID:12105189)
• Human fibronectin and MMP-2 collagen binding domains compete for collagen binding sites and modify cellular activation of MMP-2. (PMID:12225805)
• proximal tubular cell fibronectin production induced by oleate-complexed recombinant human serum albumin was mediated via protein kinase C activation (PMID:12270980)
• These data indicate that fibronectin polymerization is a critical regulator of extracellular matrix organization and stability. (PMID:12388756)
• familial combined hyperlipidemia plasma stimulated secretion of several distinct hepatic proteins, among which fibronectin was identified (PMID:12401883)
• FN may be partly involved in the increase in SPARC (secreted protein, acidic and rich in cysteine) glycoprotein expression by TGF-beta 1 in human periodontal ligament (HPL) cells. (PMID:12468382)
• REVIEW: Substance p-fibronectin-cytokine interactions in myeloproliferative disorders with bone marrow fibrosis. (PMID:12486316)
• Streptococcus pyogenes isolates were able to recruit collagen type IV via surface-bound fibronectin; fibronectin-mediated collagen recruitment represents a novel aggregation, colonization and immune evasion mechanism of S. pyogenes (PMID:12535082)
• FN may have a role in the pathogenesis of papillary thyroid carcinoma (PMID:12538453)
• all six modules of the gelatin-binding domain contribute to the interaction with gelatin either directly by contacting the ligand or indirectly through module-module interactions (PMID:12538576)
• differences in fibronectin gene expression between the SWS port-wine-derived fibroblasts and the Sturge-Weber syndrome (sws) normal skin-derived fibroblasts are consistent with the presence of a hypothesized somatic mutation underlying SWS. (PMID:12621118)
• Fibronectin secretion by renal fibroblasts was increased upon exposure to high glucose, but with delayed kinetics compared to TGF-beta1-induced fibronectin. (PMID:12631068)
• Pathogenic bacteria, Staphylococcus aureus and Streptococcus pyogenes, attach to human fibronectin through a tandem beta-zipper (PMID:12736686)
• AngRem104 is a novel human gene potentially involved in regulation of fibronectin induced by AngII in human mesangial cells. (PMID:12761244)
• An increased concentration of wild-type GFAT in mesangial cells is enhanced both TGF-beta1 and fibronectin. (PMID:12802498)
• Results suggest that tissue or plasma fibronectin may modulate the intestinal epithelial response to repetitive deformation through inhibted activation of p38 and jun kinases. (PMID:12810082)
• an additional marker of malignant potential of thyroid nodular lesions (oncofetal fibronectin) (PMID:14558920)
• levels of fibronectin in the extracellular matrix are regulated by uPAR and integrin receptors (PMID:14602715)
• FN and IGFBP-5 bind to each other, and this binding negatively regulates the ligand-dependent action of IGFBP-5 by triggering IGFBP-5 proteolysis. (PMID:14645245)
• Fibronectin plus TNF-alpha stabilizes granulocyte macrophage-colony-stimulating factor (GM-CSF) mRNA, increases GM-CSF secretion, and prolongs in vitro eosinophil survival. (PMID:14662883)
• Abundant expression of fibronectin is a major feature of leukemic dendritic cells differentiated from patients with acute myeloid leukemia (PMID:14737076)
• the aggrecanase activity of ADAMTS4 is inhibited by fibronectin through interaction with their C-terminal domains (PMID:15161923)
• crystal structure of the 2F1(3)F1 module pair (PMID:15213410)
• human fibronectin binding to streptococcus requires specific recognition of sequential F1 modules (PMID:15247227)
• Adding 110-120 kDa fibronectin fragments to normal blood replicated changes in monocyte CD49e, CD62L, CD11b, & CD86 seen in vivo in HIV-1 patients. FNf caused monocytes to release proteinase-3. Monocyte behavior in HIV-1 patients may be affected by FNf. (PMID:15265957)
• Data show that squamous cell carcinoma cells escape suspension-induced, p53-mediated anoikis by forming multicellular aggregates that use fibronectin survival signals mediated by integrin alpha(v) and focal adhesion kinase. (PMID:15331608)
• fibronectin concentration significantly elevated in ovarian cancer patients with recurrent disease compared with ovarian cancer patients without recurrence (PMID:15384859)
• demonstrate that integrins alpha(5)beta(1) and alpha(v)beta(3) support fibronectin-dependent platelet adhesion and the generation of filopodia but that, in contrast to the integrin alpha(IIb)beta(3), are unable to promote formation of lamellipodia (PMID:15456495)
• Site-directed mutagenesis of amino acids coordinating Ca2+ drastically decreased the binding of C-reactive protein to fibronectin (Fn), indicating that the Ca2+ -binding site indeed formed the Fn-binding site. (PMID:15456743)
• Fibronectin and type IV collagen activate ERalpha AF-1 by the c-Src pathway in breast cancer (PMID:15467744)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	fn1b	ENSDARG00000006526
danio_rerio	fn1a	ENSDARG00000019815
mus_musculus	Fn1	ENSMUSG00000026193
rattus_norvegicus	Fn1	ENSRNOG00000014288
caenorhabditis_elegans		WBGENE00002915

Paralogs (25): TNC (ENSG00000041982), FCN1 (ENSG00000085265), ANGPT2 (ENSG00000091879), ANGPT4 (ENSG00000101280), FGL1 (ENSG00000104760), TNR (ENSG00000116147), ANGPTL1 (ENSG00000116194), TNN (ENSG00000120332), FGL2 (ENSG00000127951), FIBCD1 (ENSG00000130720), ANGPTL6 (ENSG00000130812), ANGPTL3 (ENSG00000132855), ANGPTL2 (ENSG00000136859), FCN3 (ENSG00000142748), FNDC7 (ENSG00000143107), ANGPT1 (ENSG00000154188), FCN2 (ENSG00000160339), MFAP4 (ENSG00000166482), ANGPTL4 (ENSG00000167772), TNXB (ENSG00000168477), FGG (ENSG00000171557), FGA (ENSG00000171560), FGB (ENSG00000171564), ANGPTL7 (ENSG00000171819), ANGPTL5 (ENSG00000187151)

Protein

Protein identifiers

Fibronectin — P02751 (reviewed: P02751)

Alternative names: Cold-insoluble globulin

All UniProt accessions (3): P02751, H0Y4K8, H0Y7Z1

UniProt curated annotations — full annotation on UniProt →

Function. Fibronectins bind cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin. Fibronectins are involved in cell adhesion, cell motility, opsonization, wound healing, and maintenance of cell shape. Involved in osteoblast compaction through the fibronectin fibrillogenesis cell-mediated matrix assembly process, essential for osteoblast mineralization. Participates in the regulation of type I collagen deposition by osteoblasts. Acts as a ligand for the LILRB4 receptor, inhibiting FCGR1A/CD64-mediated monocyte activation. Binds fibronectin and induces fibril formation. This fibronectin polymer, named superfibronectin, exhibits enhanced adhesive properties. Both anastellin and superfibronectin inhibit tumor growth, angiogenesis and metastasis. Anastellin activates p38 MAPK and inhibits lysophospholipid signaling. Secreted by contracting muscle, induces liver autophagy, a degradative pathway for nutrient mobilization and damage removal, and systemic insulin sensitization via hepatic ITGA5:ITGB1 integrin receptor signaling.

Subunit / interactions. Mostly heterodimers or multimers of alternatively spliced variants, connected by 2 disulfide bonds near the carboxyl ends; to a lesser extent homodimers. Interacts with FBLN1, AMBP, TNR, LGALS3BP and COL13A1. Interacts with FBLN7. Interacts with COMP. Interacts (via type III repeats 9-14) with TNFAIP6 (via CUB domain); this interaction enhances fibronectin fibril assembly. TNFAIP6 may act as a bridging molecule between FN1 and THBS1. Interacts with TNR; the interaction inhibits cell adhesion and neurite outgrowth. Interacts with FST3 and MYOC. Interacts with SVEP1. (Microbial infection) Interacts with S.aureus FnbA. (Microbial infection) Interacts with M.bovis FbpB via the collagen-binding region. (Microbial infection) Interacts with recombinant S.pneumoniae PavA (rqcH). (Microbial infection) Interacts with recombinant S.suis FbpS (rqcH) via fibronectin’s N-terminal 30 kDa region. (Microbial infection) Interacts with fibronectin-binding proteins from other Mycobacteria.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Expressed in the inner limiting membrane and around blood vessels in the retina (at protein level). Plasma FN (soluble dimeric form) is secreted by hepatocytes. Cellular FN (dimeric or cross-linked multimeric forms), made by fibroblasts, epithelial and other cell types, is deposited as fibrils in the extracellular matrix. Ugl-Y1, Ugl-Y2 and Ugl-Y3 are found in urine.

Post-translational modifications. Sulfated. It is not known whether both or only one of Thr-2155 and Thr-2156 are/is glycosylated. Forms covalent cross-links mediated by a transglutaminase, such as F13A or TGM2, between a glutamine and the epsilon-amino group of a lysine residue, forming homopolymers and heteropolymers (e.g. fibrinogen-fibronectin, collagen-fibronectin heteropolymers). Phosphorylated by FAM20C in the extracellular medium. Proteolytic processing produces the C-terminal NC1 peptide, anastellin. Some lysine residues are oxidized to allysine by LOXL3, promoting fibronectin activation and matrix formation. Serotonylated on Gln residues by TGM2 in response to hypoxia.

Disease relevance. Glomerulopathy with fibronectin deposits 2 (GFND2) [MIM:601894] Genetically heterogeneous autosomal dominant disorder characterized clinically by proteinuria, microscopic hematuria, and hypertension that leads to end-stage renal failure in the second to fifth decade of life. The disease is caused by variants affecting the gene represented in this entry. Spondylometaphyseal dysplasia, corner fracture type (SMDCF) [MIM:184255] An autosomal dominant form of spondylometaphyseal dysplasia, a group of short stature disorders distinguished by abnormalities in the vertebrae and the metaphyses of the tubular bones. SMDCF is characterized by flake-like, triangular, or curvilinear ossification centers at the edges of irregular metaphyses that simulate fractures. These corner fractures involve the distal tibia, the ulnar aspect of the distal radius, the proximal humerus, and the proximal femur. They represent irregular ossification at the growth plates and secondary ossification centers. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Expressed by fetal and tumor-associated cells.

Isoforms (17)

UniProt ID	Names	Canonical?
P02751-15	15	yes
P02751-1	1
P02751-2	2, MSF-FN70, Migration stimulation factor FN70
P02751-3	3, V89
P02751-4	4, Fibronectin III-15X
P02751-5	5, Fibronectin (V+I-10)-
P02751-6	6, Fibronectin (V+III-15)-
P02751-7	7, Fibronectin containing EDB domain
P02751-8	8, Fibronectin not containing EDA domain
P02751-9	9, Fibronectin not containing EDA and EDB domains and uses V64 variant of IIICS region
P02751-10	10
P02751-11	11, Fibronectin containing EDB domain, exon x+2
P02751-12	12
P02751-13	13
P02751-14	14
P02751-16	16, Migration stimulation factor, MSF
P02751-17	17

RefSeq proteins (18): NP_001293058, NP_001293059, NP_001293060, NP_001293061, NP_001352446, NP_001352447, NP_001352448, NP_001352449, NP_001352450, NP_001352451, NP_001352452, NP_001352453, NP_002017, NP_473375, NP_997639, NP_997641, NP_997643, NP_997647* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000083	Fibronectin_type1	Domain
IPR000562	FN_type2_dom	Domain
IPR003961	FN3_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR013806	Kringle-like	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR036943	FN_type2_sf	Homologous_superfamily
IPR050991	ECM_Regulatory_Proteins	Family

Pfam: PF00039, PF00040, PF00041

UniProt features (409 total): strand 188, sequence conflict 44, domain 31, disulfide bond 30, turn 23, sequence variant 18, splice variant 14, mutagenesis site 14, region of interest 12, glycosylation site 8, helix 7, chain 5, modified residue 5, cross-link 3, compositionally biased region 2, site 2, signal peptide 1, DNA-binding region 1, short sequence motif 1

Structure

Experimental structures (PDB)

65 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
2CG7	X-RAY DIFFRACTION	1.2
4LXO	X-RAY DIFFRACTION	1.42
5DC4	X-RAY DIFFRACTION	1.48
2CG6	X-RAY DIFFRACTION	1.55
5DC9	X-RAY DIFFRACTION	1.56
5N48	X-RAY DIFFRACTION	1.6
3CAL	X-RAY DIFFRACTION	1.7
3ZRZ	X-RAY DIFFRACTION	1.7
6MFA	X-RAY DIFFRACTION	1.75
1FNA	X-RAY DIFFRACTION	1.8
2RKY	X-RAY DIFFRACTION	1.8
4PZ5	X-RAY DIFFRACTION	1.96
1FNF	X-RAY DIFFRACTION	2
2CK2	X-RAY DIFFRACTION	2
2RKZ	X-RAY DIFFRACTION	2
2RL0	X-RAY DIFFRACTION	2
2GEE	X-RAY DIFFRACTION	2.01
3EJH	X-RAY DIFFRACTION	2.1
5DC0	X-RAY DIFFRACTION	2.23
4JEG	X-RAY DIFFRACTION	2.3
4JE4	X-RAY DIFFRACTION	2.31
8PEQ	X-RAY DIFFRACTION	2.32
3R8Q	X-RAY DIFFRACTION	2.4
3T1W	X-RAY DIFFRACTION	2.4
6MSV	X-RAY DIFFRACTION	2.4
6XAX	X-RAY DIFFRACTION	2.4
6XAY	X-RAY DIFFRACTION	2.48
3M7P	X-RAY DIFFRACTION	2.5
5DFT	X-RAY DIFFRACTION	2.5
5J7C	X-RAY DIFFRACTION	2.54

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P02751-F1	70.23	0.05

Antibody-complex structures (SAbDab): 1 — 7NWL

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 663 (important for superfibronectin formation); 666 (important for superfibronectin formation)

Post-translational modifications (8): 47, 32, 876, 881, 2454, 2475, 34, 35

Disulfide bonds (30): 52–78, 76–87, 97–125, 123–135, 141–169, 167–179, 186–215, 213–225, 231–260, 258–270, 308–335, 333–342, 360–386, 374–401, 420–446, 434–461, 470–498, 496–508, 518–545, 543–555 …

Glycosylation sites (8): 279, 430, 528, 542, 877, 1007, 1244, 2199

Mutagenesis-validated functional residues (14):

Position	Phenotype
641	severely compromised ability to form fibronectin aggregates; when associated with a-681 and a-683.
642	little effect on ability to form fibronectin aggregates; when associated with a-682; a-684 and a-692.
663	no effect on secondary structure nor on fibronectin binding nor on activation of p38 k but abolishes polymerization acti
666	no effect on secondary structure nor on fibronectin binding nor on activation of p38 kinase but abolishes polymerization
681	severely compromised ability to form fibronectin aggregates; when associated with a-641 and a-683.
682	little effect on ability to form fibronectin aggregates; when associated with a-642; a-684 and a-692.
683	severely compromised ability to form fibronectin aggregates; when associated with a-641 and a-681.
684	little effect on ability to form fibronectin aggregates; when associated with a-642; a-682 and a-692.
691	slightly enhanced ability to form fibronectin aggregates; when associated with a-694 and a-696.
692	little effect on ability to form fibronectin aggregates; when associated with a-642; a-682 and a-684.
694	slightly enhanced ability to form fibronectin aggregates; when associated with a-691 and a-696.
695	loss of ability to form fibronectin aggregates; when associated with a-697.
696	slightly enhanced ability to form fibronectin aggregates; when associated with a-691 and a-694.
697	loss of ability to form fibronectin aggregates; when associated with a-695.

Function

Pathways and Gene Ontology

Reactome pathways

29 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-1566977	Fibronectin matrix formation
R-HSA-202733	Cell surface interactions at the vascular wall
R-HSA-2129379	Molecules associated with elastic fibres
R-HSA-216083	Integrin cell surface interactions
R-HSA-3000170	Syndecan interactions
R-HSA-3000171	Non-integrin membrane-ECM interactions
R-HSA-3000178	ECM proteoglycans
R-HSA-354192	Integrin signaling
R-HSA-354194	GRB2:SOS provides linkage to MAPK signaling for Integrins
R-HSA-372708	p130Cas linkage to MAPK signaling for integrins
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-5674135	MAP2K and MAPK activation
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-6802946	Signaling by moderate kinase activity BRAF mutants
R-HSA-6802948	Signaling by high-kinase activity BRAF mutants
R-HSA-6802952	Signaling by BRAF and RAF1 fusions
R-HSA-6802955	Paradoxical activation of RAF signaling by kinase inactive BRAF
R-HSA-8874081	MET activates PTK2 signaling
R-HSA-8957275	Post-translational protein phosphorylation
R-HSA-9634597	GPER1 signaling
R-HSA-9638630	Attachment of bacteria to epithelial cells
R-HSA-9649948	Signaling downstream of RAS mutants
R-HSA-9656223	Signaling by RAF1 mutants
R-HSA-9700645	ALK mutants bind TKIs
R-HSA-9725370	Signaling by ALK fusions and activated point mutants
R-HSA-9860927	Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells
R-HSA-9925563	Developmental Lineage of Pancreatic Ductal Cells

MSigDB gene sets: 881 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GOBP_REGULATION_OF_CELL_ACTIVATION, TURASHVILI_BREAST_LOBULAR_CARCINOMA_VS_DUCTAL_NORMAL_UP, MODULE_52, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_PROTEIN_ACTIVATION_CASCADE, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, MODULE_255, GOBP_INFLAMMATORY_RESPONSE, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, GOCC_SECRETORY_GRANULE

GO Biological Process (34): angiogenesis (GO:0001525), neural crest cell migration (GO:0001755), regulation of protein phosphorylation (GO:0001932), autophagy (GO:0006914), acute-phase response (GO:0006953), cell-substrate junction assembly (GO:0007044), cell adhesion (GO:0007155), cell-matrix adhesion (GO:0007160), calcium-independent cell-matrix adhesion (GO:0007161), integrin-mediated signaling pathway (GO:0007229), nervous system development (GO:0007399), heart development (GO:0007507), positive regulation of cell population proliferation (GO:0008284), regulation of cell shape (GO:0008360), response to wounding (GO:0009611), negative regulation of autophagy (GO:0010507), positive regulation of gene expression (GO:0010628), response to muscle activity (GO:0014850), integrin activation (GO:0033622), substrate adhesion-dependent cell spreading (GO:0034446), endodermal cell differentiation (GO:0035987), endothelial cell migration (GO:0043542), positive regulation of axon extension (GO:0045773), positive regulation of fibroblast proliferation (GO:0048146), enteric nervous system development (GO:0048484), biological process involved in interaction with symbiont (GO:0051702), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), regulation of ERK1 and ERK2 cascade (GO:0070372), negative regulation of transforming growth factor beta production (GO:0071635), blood coagulation, fibrin clot formation (GO:0072378), negative regulation of monocyte activation (GO:0150102), neural crest cell migration involved in autonomic nervous system development (GO:1901166), positive regulation of substrate-dependent cell migration, cell attachment to substrate (GO:1904237), wound healing (GO:0042060)

GO Molecular Function (11): protease binding (GO:0002020), signaling receptor binding (GO:0005102), integrin binding (GO:0005178), extracellular matrix structural constituent (GO:0005201), collagen binding (GO:0005518), heparin binding (GO:0008201), peptidase activator activity (GO:0016504), identical protein binding (GO:0042802), proteoglycan binding (GO:0043394), receptor ligand activity (GO:0048018), protein binding (GO:0005515)

GO Cellular Component (12): extracellular region (GO:0005576), fibrinogen complex (GO:0005577), basement membrane (GO:0005604), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), endoplasmic reticulum-Golgi intermediate compartment (GO:0005793), plasma membrane (GO:0005886), apical plasma membrane (GO:0016324), extracellular matrix (GO:0031012), platelet alpha granule lumen (GO:0031093), extracellular exosome (GO:0070062), blood microparticle (GO:0072562)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Extracellular matrix organization	5
Oncogenic MAPK signaling	4
Integrin signaling	2
Response to elevated platelet cytosolic Ca2+	1
Hemostasis	1
Elastic fibre formation	1
Non-integrin membrane-ECM interactions	1
Signal Transduction	1
Platelet Aggregation (Plug Formation)	1
Metabolism of proteins	1
RAF/MAP kinase cascade	1
Signaling by Interleukins	1
MET promotes cell motility	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	3
cell-substrate adhesion	2
signaling receptor binding	2
protein-containing complex binding	2
extracellular matrix	2
cellular anatomical structure	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
neural crest cell development	1
mesenchymal cell migration	1
protein phosphorylation	1
regulation of protein modification process	1
regulation of phosphorylation	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
acute inflammatory response	1
cell junction assembly	1
cell-substrate junction organization	1
cellular process	1
cell-matrix adhesion	1
cell surface receptor signaling pathway	1
system development	1
animal organ development	1
circulatory system development	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
regulation of cell morphogenesis	1
regulation of biological quality	1
response to stress	1
autophagy	1
negative regulation of catabolic process	1
regulation of autophagy	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
response to activity	1
protein-containing complex assembly	1
enzyme binding	1

Protein interactions and networks

STRING

7594 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FN1	VTN	P01141	999
FN1	VWF	P04275	998
FN1	ITGA5	P08648	998
FN1	ITGB1	P05556	998
FN1	ELN	P15502	998
FN1	ITGAV	P06756	997
FN1	NID1	P14543	997
FN1	ALB	P02768	997
FN1	PLG	P00747	997
FN1	THBS1	P07996	996
FN1	SPP1	P10451	996
FN1	CD44	P16070	996
FN1	DCN	P07585	995
FN1	ITGA2B	P08514	995
FN1	TLR4	O00206	995
FN1	ITGB3	P05106	995

IntAct

365 interactions, top by confidence:

A	B	Type	Score
FN1	FN1	psi-mi:“MI:0407”(direct interaction)	0.890
FN1	FN1	psi-mi:“MI:0195”(covalent binding)	0.890
	FN1	psi-mi:“MI:0407”(direct interaction)	0.840
ITGA5	FN1	psi-mi:“MI:0407”(direct interaction)	0.840
TGM2	FN1	psi-mi:“MI:0407”(direct interaction)	0.810
fnbA	FN1	psi-mi:“MI:0407”(direct interaction)	0.790
FN1	ITGB1	psi-mi:“MI:0915”(physical association)	0.750
FN1	ITGB3	psi-mi:“MI:0915”(physical association)	0.750
FN1	ITGB3	psi-mi:“MI:0407”(direct interaction)	0.750
ITGB3	FN1	psi-mi:“MI:0915”(physical association)	0.750
ITGAV	FN1	psi-mi:“MI:0915”(physical association)	0.740
FN1	fnbB	psi-mi:“MI:0407”(direct interaction)	0.720
fnbB	FN1	psi-mi:“MI:0407”(direct interaction)	0.720
FN1	COL1A1	psi-mi:“MI:0407”(direct interaction)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710

BioGRID (901): UBQLN1 (Two-hybrid), FN1 (Affinity Capture-MS), FN1 (Affinity Capture-MS), FN1 (Affinity Capture-MS), FN1 (Affinity Capture-MS), FN1 (Affinity Capture-MS), FN1 (Affinity Capture-MS), FN1 (Affinity Capture-MS), FN1 (Affinity Capture-MS), FN1 (Affinity Capture-MS), FN1 (Affinity Capture-MS), FN1 (Co-localization), FN1 (Co-localization), FN1 (Co-localization), ITGA5 (Reconstituted Complex)

ESM2 similar proteins: A2AVA0, B5DFC9, O14522, O18016, O18023, O60687, O61307, O75339, O77469, O88322, P02751, P04937, P07589, P0C6B8, P10039, P10493, P11276, P11722, P14543, P24821, P28827, P28828, P35822, P35992, P98092, P98160, Q00546, Q02763, Q02858, Q05546, Q05793, Q06561, Q06807, Q09165, Q14112, Q14118, Q15262, Q19204, Q28275, Q28377

Diamond homologs: A4KX75, D0EM77, D3ZTE0, G5EBU3, G5EGM1, O04529, O18733, O23507, O35548, O44836, O54732, O55761, O60449, O75900, O88272, O88676, O97507, P00748, P02751, P04937, P07589, P08169, P08253, P09237, P11276, P11717, P11722, P14780, P22757, P22897, P24347, P28053, P29136, P33434, P33436, P41245, P41246, P49259, P49260, P50280

SIGNOR signaling

17 interactions.

A	Effect	B	Mechanism
DLK1	up-regulates	FN1	binding
FN1	up-regulates	MAPK3
FN1	up-regulates	“Av/b6 integrin”	binding
FGG	“down-regulates activity”	FN1	binding
FN1	“up-regulates activity”	“A5/b1 integrin”	binding
FN1	“up-regulates activity”	“A8/b1 integrin”	binding
SNAIL/RELA/PARP1	“up-regulates quantity by expression”	FN1	“transcriptional regulation”
TWIST1	“up-regulates quantity by expression”	FN1	“transcriptional regulation”
FN1	“up-regulates activity”	SDC4	binding
“Vincristine sulfate”	“down-regulates activity”	FN1	“chemical inhibition”
SERPINA5	“down-regulates activity”	FN1	binding
FN1	up-regulates	Epithelial-mesenchymal_transition
TCF7	“up-regulates quantity by expression”	FN1	“transcriptional regulation”
FN1	“form complex”	FN1/SDC4	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 143 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signal transduction by L1	6	32.4×	9e-06
Binding and Uptake of Ligands by Scavenger Receptors	5	28.3×	1e-04
Elastic fibre formation	7	24.5×	9e-06
Syndecan interactions	5	22.0×	3e-04
Signaling by PDGF	5	13.2×	2e-03
ECM proteoglycans	7	11.0×	3e-04
Signaling by TGF-beta Receptor Complex	5	10.4×	4e-03
Assembly of collagen fibrils and other multimeric structures	5	10.4×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
platelet-derived growth factor receptor signaling pathway	6	28.6×	4e-05
positive regulation of fibroblast proliferation	7	17.5×	6e-05
positive regulation of protein localization to plasma membrane	5	11.5×	4e-03
integrin-mediated signaling pathway	8	10.9×	1e-04
epidermal growth factor receptor signaling pathway	5	10.5×	6e-03
collagen fibril organization	5	9.5×	7e-03
positive regulation of cell migration	13	6.8×	4e-05
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	8	5.3×	6e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

1835 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	14
Uncertain significance	864
Likely benign	535
Benign	210

Top pathogenic / likely-pathogenic (26)

Variant ID	HGVS	Classification
1067072	NM_212482.4(FN1):c.674G>T (p.Cys225Phe)	Pathogenic
16323	NM_212482.4(FN1):c.5773T>A (p.Trp1925Arg)	Pathogenic
16324	NM_212482.4(FN1):c.5921T>G (p.Leu1974Arg)	Pathogenic
16325	NM_212482.4(FN1):c.2918A>G (p.Tyr973Cys)	Pathogenic
1683462	NM_212482.4(FN1):c.261C>G (p.Cys87Trp)	Pathogenic
192244	NM_212482.4(FN1):c.5775G>C (p.Trp1925Cys)	Pathogenic
192245	NM_212482.4(FN1):c.5921T>C (p.Leu1974Pro)	Pathogenic
192246	NM_212482.4(FN1):c.4412CTC[1] (p.Pro1472del)	Pathogenic
208716	NM_212482.4(FN1):c.3051G>T (p.Trp1017Cys)	Pathogenic
2865864	NM_212482.4(FN1):c.685+1G>A	Pathogenic
549707	NM_212482.4(FN1):c.638G>A (p.Cys213Tyr)	Pathogenic
638046	NM_212482.4(FN1):c.685+1G>C	Pathogenic
1344882	NM_212482.4(FN1):c.7379T>C (p.Ile2460Thr)	Likely pathogenic
1700693	NM_212482.4(FN1):c.6281C>T (p.Pro2094Leu)	Likely pathogenic
2412782	NM_212482.4(FN1):c.685+3A>G	Likely pathogenic
3064820	NM_212482.4(FN1):c.3009_3010dup (p.Gln1004fs)	Likely pathogenic
3064945	NM_212482.4(FN1):c.3010_3011insTC (p.Gln1004fs)	Likely pathogenic
3391107	NM_212482.4(FN1):c.938G>T (p.Gly313Val)	Likely pathogenic
3585436	NM_212482.4(FN1):c.5773T>C (p.Trp1925Arg)	Likely pathogenic
3906951	NM_212482.4(FN1):c.637T>C (p.Cys213Arg)	Likely pathogenic
421465	NM_212482.4(FN1):c.693C>G (p.Cys231Trp)	Likely pathogenic
424643	NM_212482.4(FN1):c.260G>T (p.Cys87Phe)	Likely pathogenic
424646	NM_212482.4(FN1):c.718T>G (p.Tyr240Asp)	Likely pathogenic
424647	NM_212482.4(FN1):c.778T>G (p.Cys260Gly)	Likely pathogenic
549708	NM_212482.4(FN1):c.368G>A (p.Cys123Tyr)	Likely pathogenic
549709	NM_212482.4(FN1):c.506G>A (p.Cys169Tyr)	Likely pathogenic

SpliceAI

5532 predictions. Top by Δscore:

Variant	Effect	Δscore
2:215361623:CATT:C	acceptor_gain	1.0000
2:215361962:CACT:C	donor_loss	1.0000
2:215361963:ACTT:A	donor_loss	1.0000
2:215361964:CT:C	donor_loss	1.0000
2:215361965:TTAC:T	donor_loss	1.0000
2:215361966:TACA:T	donor_loss	1.0000
2:215361967:A:AC	donor_gain	1.0000
2:215361967:ACAGT:A	donor_loss	1.0000
2:215361968:C:CC	donor_gain	1.0000
2:215361968:C:T	donor_loss	1.0000
2:215361968:CA:C	donor_gain	1.0000
2:215361968:CAG:C	donor_gain	1.0000
2:215361968:CAGT:C	donor_gain	1.0000
2:215361968:CAGTG:C	donor_gain	1.0000
2:215364878:CCCG:C	donor_gain	1.0000
2:215365503:A:AC	donor_gain	1.0000
2:215365504:C:CC	donor_gain	1.0000
2:215365524:T:A	donor_gain	1.0000
2:215367861:A:AC	donor_gain	1.0000
2:215367862:C:CC	donor_gain	1.0000
2:215367862:CTAG:C	donor_gain	1.0000
2:215367891:T:TA	donor_gain	1.0000
2:215367921:AAAG:A	donor_gain	1.0000
2:215367952:T:C	donor_gain	1.0000
2:215368025:TGA:T	acceptor_gain	1.0000
2:215368028:C:CC	acceptor_gain	1.0000
2:215370443:CGG:C	acceptor_gain	1.0000
2:215370444:G:T	acceptor_gain	1.0000
2:215370452:C:CT	acceptor_gain	1.0000
2:215370452:C:T	acceptor_gain	1.0000

AlphaMissense

16125 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:215364933:C:A	W2399C	1.000
2:215364933:C:G	W2399C	1.000
2:215365584:C:A	W2355C	1.000
2:215365584:C:G	W2355C	1.000
2:215367945:C:A	W2312C	1.000
2:215367945:C:G	W2312C	1.000
2:215376612:A:G	W1925R	1.000
2:215376612:A:T	W1925R	1.000
2:215393141:A:G	W1287R	1.000
2:215393141:A:T	W1287R	1.000
2:215409642:C:A	W740C	1.000
2:215409642:C:G	W740C	1.000
2:215409644:A:G	W740R	1.000
2:215409644:A:T	W740R	1.000
2:215422185:C:A	W484C	1.000
2:215422185:C:G	W484C	1.000
2:215423408:C:A	W445C	1.000
2:215423408:C:G	W445C	1.000
2:215431849:C:A	W177C	1.000
2:215431849:C:G	W177C	1.000
2:215431873:A:C	C169W	1.000
2:215431875:A:G	C169R	1.000
2:215431958:C:G	C141S	1.000
2:215431959:A:G	C141R	1.000
2:215431959:A:T	C141S	1.000
2:215433335:C:T	C135Y	1.000
2:215433336:A:G	C135R	1.000
2:215433364:G:C	C125W	1.000
2:215433366:A:G	C125R	1.000
2:215433370:A:C	C123W	1.000

dbSNP variants (sampled 300 via entrez): RS1000014098 (2:215401539 T>C), RS1000060627 (2:215366574 A>C), RS1000066010 (2:215372887 T>C), RS1000122374 (2:215429941 A>C), RS1000180424 (2:215364404 A>G), RS1000186580 (2:215360675 A>G), RS1000225109 (2:215405059 A>C,T), RS1000296117 (2:215412000 A>G), RS1000318956 (2:215398616 C>A), RS1000336678 (2:215379412 T>C,G), RS1000352801 (2:215370287 T>G), RS1000371415 (2:215398269 C>T), RS1000412001 (2:215366970 T>A), RS1000500874 (2:215418710 G>A), RS1000515708 (2:215435175 C>A,T)

Disease associations

OMIM: gene MIM:135600 | disease phenotypes: MIM:184255, MIM:601894, MIM:301050, MIM:137950, MIM:135150, MIM:614101

GenCC curated gene-disease

Disease	Classification	Inheritance
spondylometaphyseal dysplasia, ‘corner fracture’ type	Definitive	Autosomal dominant
glomerulopathy with fibronectin deposits 2	Strong	Autosomal dominant
fibronectin glomerulopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
spondylometaphyseal dysplasia, ‘corner fracture’ type	Definitive	AD
glomerulopathy with fibronectin deposits 2	Moderate	AD

Mondo (11): spondylometaphyseal dysplasia, ‘corner fracture’ type (MONDO:0008479), glomerulopathy with fibronectin deposits 2 (MONDO:0011165), X-linked Alport syndrome (MONDO:0010520), nephrotic syndrome (MONDO:0005377), glomerulopathy with fibronectin deposits 1 (MONDO:0024527), Birt-Hogg-Dube syndrome 1 (MONDO:0800445), spondylometaphyseal dysplasia (MONDO:0016763), neurodevelopmental disorder (MONDO:0700092), plasma fibronectin deficiency (MONDO:0013575), chronic kidney disease (MONDO:0005300), fibronectin glomerulopathy (MONDO:0007671)

Orphanet (6): Fibronectin glomerulopathy (Orphanet:84090), Spondylometaphyseal dysplasia, ‘corner fracture’ type (Orphanet:93315), Alport syndrome (Orphanet:63), X-linked Alport syndrome (Orphanet:88917), Birt-Hogg-Dubé syndrome (Orphanet:122), Spondylometaphyseal dysplasia (Orphanet:254)

HPO phenotypes

77 total (30 of 77 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000100	Nephrotic syndrome
HP:0000164	Abnormality of the dentition
HP:0000218	High palate
HP:0000307	Pointed chin
HP:0000324	Facial asymmetry
HP:0000358	Posteriorly rotated ears
HP:0000384	Preauricular skin tag
HP:0000385	Small earlobe
HP:0000411	Protruding ear
HP:0000470	Short neck
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000520	Proptosis
HP:0000545	Myopia
HP:0000768	Pectus carinatum
HP:0000822	Hypertension
HP:0000926	Platyspondyly
HP:0001342	Cerebral hemorrhage
HP:0001376	Limitation of joint mobility
HP:0001891	Iron deficiency anemia
HP:0001966	Abnormal glomerular mesangium morphology
HP:0002515	Waddling gait
HP:0002650	Scoliosis
HP:0002657	Spondylometaphyseal dysplasia
HP:0002659	Increased susceptibility to fractures
HP:0002812	Coxa vara
HP:0002857	Genu valgum

GWAS associations

28 associations (top):

Study	Trait	p-value
GCST002222_54	LDL cholesterol	3.000000e-08
GCST003302_5	Cholesterol, total	1.000000e-08
GCST004233_25	LDL cholesterol levels	2.000000e-09
GCST004235_51	Total cholesterol levels	5.000000e-08
GCST004278_53	Pulse pressure	9.000000e-19
GCST004278_62	Pulse pressure	7.000000e-09
GCST004787_3	Coronary artery disease (myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, angina or chromic ischemic heart disease)	3.000000e-13
GCST005194_43	Coronary artery disease	5.000000e-11
GCST005195_73	Coronary artery disease	2.000000e-13
GCST005196_214	Coronary artery disease	3.000000e-19
GCST007096_174	Pulse pressure	1.000000e-21
GCST007097_39	Pulse pressure	3.000000e-09
GCST007097_40	Pulse pressure	7.000000e-11
GCST007099_36	Systolic blood pressure	1.000000e-12
GCST007267_295	Systolic blood pressure	1.000000e-09
GCST007268_7	Diastolic blood pressure	1.000000e-16
GCST007269_80	Pulse pressure	3.000000e-16
GCST007625_4	Negative urgency	5.000000e-07
GCST007990_5	Coronary artery disease	1.000000e-08
GCST010243_251	Apolipoprotein B levels	2.000000e-09
GCST010245_22	LDL cholesterol levels	7.000000e-09
GCST010479_62	Coronary artery disease	2.000000e-14
GCST010866_43	Coronary artery disease	3.000000e-11
GCST011365_23	Myocardial infarction	1.000000e-08
GCST011369_7	Iron status biomarkers (ferritin levels)	2.000000e-10
GCST90002388_310	Lymphocyte count	2.000000e-09
GCST90002393_389	Monocyte count	1.000000e-10
GCST90002407_33	White blood cell count	1.000000e-10

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0005763	pulse pressure measurement
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0006946	behavioural disinhibition measurement
EFO:0004615	apolipoprotein B measurement
EFO:0004459	ferritin measurement
EFO:0004587	lymphocyte count
EFO:0005091	monocyte count

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D058249	Birt-Hogg-Dube Syndrome	C04.700.212; C16.320.700.212
D007676	Kidney Failure, Chronic	C12.050.351.968.419.780.750.500; C12.200.777.419.780.750.500; C12.950.419.780.750.500; C23.550.291.500.906.500
D009404	Nephrotic Syndrome	C12.050.351.968.419.630.643; C12.200.777.419.630.643; C12.950.419.630.643
D065886	Neurodevelopmental Disorders	F03.625
C562900	Glomerulopathy with Giant Fibrillar Deposits (supp.)
C536826	Glomerulopathy with fibronectin deposits (supp.)
C535793	Spondylometaphyseal dysplasia, ‘corner fracture’ type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3810 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

Binding affinities (BindingDB)

3 measured of 4 human assays (4 total across all organisms); most potent 3 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
AP24149	IC50	9.1 nM
AP24247	IC50	17 nM
AP24245	IC50	198 nM

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.26	Kd	5.5	nM	CHEMBL404104
8.19	Kd	6.5	nM	CHEMBL404103
7.52	Kd	30	nM	CHEMBL256614
7.48	Kd	33	nM	CHEMBL441895

PubChem BioAssay actives

8 with measured affinity, of 8 total; 8 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-(4-dimethylphosphorylphenyl)-9-[(E)-2-(5-methyl-1H-indazol-4-yl)ethenyl]purin-6-amine	1799594: In Vitro Kinase Assay from Article 10.1111/j.1747-0285.2009.00905.x: “Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template.”	ic50	0.0005	uM
tetrasodium;(2R,3S,4S,5R,6R)-6-[(2R,3R,4R,5S)-6-[3-[5-(dithiolan-3-yl)pentanoylamino]anilino]-2,3,4,5-tetrahydroxyhexoxy]-4-hydroxy-3-[(2R,3R,4R,5S,6R)-4-hydroxy-5-methoxy-3-(sulfonatoamino)-6-(sulfonatooxymethyl)oxan-2-yl]oxy-5-sulfonatooxyoxane-2-carboxylate	322431: Binding affinity to fibronectin using surface plasmon resonance imaging sensor method	kd	0.0055	uM
trisodium;(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S)-6-[3-[5-(dithiolan-3-yl)pentanoylamino]anilino]-2,3,4,5-tetrahydroxyhexoxy]-4,5-dihydroxy-3-[(2R,3R,4R,5S,6R)-4-hydroxy-5-methoxy-3-(sulfonatoamino)-6-(sulfonatooxymethyl)oxan-2-yl]oxyoxane-2-carboxylate	322431: Binding affinity to fibronectin using surface plasmon resonance imaging sensor method	kd	0.0065	uM
9-[(E)-2-(2,6-dimethylphenyl)ethenyl]-N-(4-dimethylphosphorylphenyl)purin-6-amine	1799594: In Vitro Kinase Assay from Article 10.1111/j.1747-0285.2009.00905.x: “Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template.”	ic50	0.0091	uM
N-(4-dimethylphosphorylphenyl)-9-[(E)-2-(1H-indazol-4-yl)ethenyl]purin-6-amine	1799594: In Vitro Kinase Assay from Article 10.1111/j.1747-0285.2009.00905.x: “Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template.”	ic50	0.0170	uM
trisodium;(2R,3S,4S,5R,6R)-6-[(2R,3R,4R,5S)-6-[3-[5-(dithiolan-3-yl)pentanoylamino]anilino]-2,3,4,5-tetrahydroxyhexoxy]-4-hydroxy-3-[(2R,3R,4R,5S,6R)-4-hydroxy-6-(hydroxymethyl)-5-methoxy-3-(sulfonatoamino)oxan-2-yl]oxy-5-sulfonatooxyoxane-2-carboxylate	322431: Binding affinity to fibronectin using surface plasmon resonance imaging sensor method	kd	0.0300	uM
disodium;(2S,3S,4R,5R,6R)-3-[(2R,3R,4R,5S,6R)-3-amino-4-hydroxy-5-methoxy-6-(sulfonatooxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4R,5S)-6-[3-[5-(dithiolan-3-yl)pentanoylamino]anilino]-2,3,4,5-tetrahydroxyhexoxy]-4,5-dihydroxyoxane-2-carboxylate	322431: Binding affinity to fibronectin using surface plasmon resonance imaging sensor method	kd	0.0330	uM
N-(4-dimethylphosphorylphenyl)-9-[(E)-2-(1H-indol-4-yl)ethenyl]purin-6-amine	1799594: In Vitro Kinase Assay from Article 10.1111/j.1747-0285.2009.00905.x: “Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template.”	ic50	0.1980	uM

CTD chemical–gene interactions

311 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Glucose	affects reaction, decreases secretion, decreases expression, increases abundance, decreases reaction (+3 more)	13
bisphenol A	affects reaction, affects expression, affects methylation, decreases expression, decreases methylation (+1 more)	10
sodium arsenite	affects cotreatment, increases abundance, decreases reaction, increases expression, decreases expression	8
Particulate Matter	increases expression, affects expression, increases reaction, decreases expression, decreases reaction (+1 more)	8
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression, decreases methylation	7
Cadmium Chloride	decreases expression, affects reaction, decreases reaction, increases abundance, increases expression (+1 more)	7
Doxorubicin	decreases expression, increases expression, affects response to substance, decreases response to substance, increases response to substance (+2 more)	6
Estradiol	affects cotreatment, increases expression, decreases expression	6
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, increases expression	6
Tretinoin	decreases expression, decreases reaction, affects cotreatment, increases expression	6
methylmercuric chloride	increases expression, affects cotreatment	5
Cadmium	increases expression, affects expression, decreases expression, affects binding, affects reaction (+2 more)	5
Hydrogen Peroxide	decreases reaction, increases secretion, decreases expression, increases expression, affects reaction	5
Lipopolysaccharides	affects response to substance, increases reaction, increases secretion, affects reaction, affects cotreatment (+4 more)	5
trichostatin A	affects cotreatment, increases expression, decreases reaction, decreases expression	4
bisphenol S	decreases methylation, increases expression	4
Resveratrol	increases expression, decreases expression, increases reaction, affects secretion, decreases reaction	4
Arsenic Trioxide	affects cotreatment, decreases expression, increases expression	4
Troglitazone	decreases expression, decreases reaction, increases reaction, increases expression, decreases secretion	4
Cisplatin	decreases response to substance, increases expression, increases activity, affects cotreatment, decreases expression	4
Quercetin	decreases expression, decreases reaction, increases expression	4
Rotenone	decreases reaction, increases expression, increases secretion, increases phosphorylation, decreases expression (+1 more)	4
Silicon Dioxide	decreases reaction, increases expression, increases reaction, affects secretion, decreases expression (+1 more)	4
aristolochic acid I	decreases reaction, affects cotreatment, increases secretion, decreases expression, increases expression	3
cobaltous chloride	decreases reaction, decreases expression, increases expression	3
ochratoxin A	decreases expression, affects reaction, decreases reaction, increases expression	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases reaction, increases expression, affects cotreatment	3
Rosiglitazone	decreases reaction, increases reaction, increases expression, decreases expression	3
Acetaldehyde	increases reaction, decreases reaction, increases expression	3
Acetylcysteine	decreases reaction, increases expression, increases secretion	3

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL951301	Binding	Binding affinity to fibronectin using surface plasmon resonance imaging sensor method	Sugar Chips immobilized with synthetic sulfated disaccharides of heparin/heparan sulfate partial structure. — Bioorg Med Chem Lett

Cellosaurus cell lines

15 cell lines: 13 cancer cell line, 2 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8G6	Abcam HCT 116 FN1 KO	Cancer cell line	Male
CVCL_B8VZ	Abcam MCF-7 FN1 KO	Cancer cell line	Female
CVCL_B9IF	Abcam A-549 FN1 KO	Cancer cell line	Male
CVCL_C0FQ	FHUSTCi001-A	Induced pluripotent stem cell	Male
CVCL_C0I1	LMM3 FNwt2	Cancer cell line	Female
CVCL_C0I2	LMM3 FNwt10	Cancer cell line	Female
CVCL_C0I3	LMM3 FN RGD/LAV	Cancer cell line	Female
CVCL_C0I4	LMM3 FN RGD/LGD	Cancer cell line	Female
CVCL_D0Q0	XJHi001-A	Induced pluripotent stem cell	Female
CVCL_D1SH	Abcam U-87MG FN1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00308321	PHASE4	UNKNOWN	Long Term Tapering or Standard Steroids for Nephrotic Syndrome
NCT01021540	PHASE4	COMPLETED	Prospective Study Evaluating the Effect of Repository Corticotropin in the Treatment of Various Nephrotic Syndromes
NCT01028287	PHASE4	COMPLETED	Adrenocorticotropic Hormone (ACTH) Treatment of Nephrotic Range Proteinuria in Diabetic Nephropathy (NRDN)
NCT01162005	PHASE4	COMPLETED	Therapeutic Effect of Tacrolimus on Primary Nephrotic Syndrome in Children
NCT01895894	PHASE4	COMPLETED	Mycophenolate Mofetil in Pediatric Steroid Dependent Nephrotic Syndrome
NCT02238418	PHASE4	COMPLETED	Efficacy of Usual Vitamin D Supplementation and Its Impact on Children and Adolescents Calciuria.
NCT02382575	PHASE4	UNKNOWN	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Resistant Nephrotic Syndrome
NCT02427880	PHASE4	COMPLETED	Role of Acetazolamide and Hydrochlorothiazide Followed by Furosemide in Treating Nephrotic Edema
NCT03210688	PHASE4	COMPLETED	Active Vitamin D And Reduced Dose Prednisolone for Treatment in Minimal Change Nephropathy
NCT03347357	PHASE4	COMPLETED	Pharmacokinetics of Tacrolimus in Children
NCT05696977	PHASE4	UNKNOWN	Effect of Obesity on Cyclosporine Blood Trough Level in Nephrotic Syndrome Patients
NCT05966818	PHASE4	UNKNOWN	Effect of Dapagliflozin in Non-Diabetic Patients With Nephrotic Syndrome.
NCT06026787	PHASE4	COMPLETED	Clinical Value of Adding Dapagliflozin in Patients With Nephrotic Syndrome
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00354731	PHASE3	COMPLETED	Efficacy of Pentoxifylline on Primary Nephrotic Syndrome
NCT00615667	PHASE3	COMPLETED	Prospective, Multicenter Study of the Efficacy and Tolerance of Tacrolimus on Refractory Nephrotic Syndrome (RNS)
NCT00981838	PHASE3	COMPLETED	Rituximab in Multirelapsing Minimal Change Disease (MCD) or Focal Segmental Glomerulosclerosis (FSGS)
NCT01197040	PHASE3	COMPLETED	Evaluation of Low Dose Corticosteroids Efficiency, Associated With Myfortic ® in the Treatment of Nephrotic Syndrome
NCT01309477	PHASE3	COMPLETED	The Efficacy and Tolerance of Tacrolimus Sustained-release Capsules on Refractory Nephrotic Syndrome (RNS)
NCT02132195	PHASE3	COMPLETED	Adrenocorticotropic Hormone (ACTH) for Frequently Relapsing and Steroid Dependent Nephrotic Syndrome
NCT02257697	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mizoribine in the Treatment of Refractory Nephrotic Syndrome
NCT02438982	PHASE3	COMPLETED	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Dependent Nephrotic Syndrome
NCT03141970	PHASE3	COMPLETED	Prednisolone Trial in Children Younger Than 4 Years
NCT03501459	PHASE3	UNKNOWN	Lymphocyte Markers As Predictors Of Responsiveness To Rituximab Among Patients With Idiopathic Nephrotic Syndrome
NCT05079789	PHASE3	TERMINATED	Amiloride in Nephrotic Syndrome
NCT05716880	PHASE3	RECRUITING	Ketoanalogues for Muscle Mass Loss in Nephrotic Syndrome
NCT06635720	PHASE3	ACTIVE_NOT_RECRUITING	REduced-dose Steroid PrOtocol for Childhood Nephrotic SyndromE (RESPONSE)
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT04937907	PHASE2	COMPLETED	Study of Hydroxychloroquine in Patients With X-linked Alport Syndrome in China (CHXLAS)
NCT07523581	PHASE2	NOT_YET_RECRUITING	EXACT Study: A Blinded Study in Patients With Alport Syndrome to Evaluate Exaluren Efficacy and Safety
NCT00001212	PHASE2	COMPLETED	Drug Therapy in Lupus Nephropathy
NCT00001959	PHASE2	COMPLETED	Pirfenidone to Treat Kidney Disease (Focal Segmental Glomerulosclerosis)
NCT00004466	PHASE2	TERMINATED	Pilot Study of Atorvastatin in Children With Chronic Hyperlipidemia Secondary to Nephrotic Syndrome
NCT00004990	PHASE2	COMPLETED	Once-A-Month Steroid Treatment for Patients With Focal Segmental Glomerulosclerosis
NCT00977977	PHASE2	RECRUITING	Rituximab Plus Cyclosporine in Idiopathic Membranous Nephropathy
NCT02394106	PHASE2	TERMINATED	Ofatumumab in Children With Drug Resistant Idiopathic Nephrotic Syndrome