TGFBI

Summary

TGFBI (transforming growth factor beta induced, HGNC:11771) is a protein-coding gene on chromosome 5q31.1, encoding Transforming growth factor-beta-induced protein ig-h3 (Q15582). Plays a role in cell adhesion.

This gene encodes an RGD-containing protein that binds to type I, II and IV collagens. The RGD motif is found in many extracellular matrix proteins modulating cell adhesion and serves as a ligand recognition sequence for several integrins. This protein plays a role in cell-collagen interactions and may be involved in endochondrial bone formation in cartilage. The protein is induced by transforming growth factor-beta and acts to inhibit cell adhesion. Mutations in this gene are associated with multiple types of corneal dystrophy.

Source: NCBI Gene 7045 — RefSeq curated summary.

At a glance

• Gene–disease (curated): epithelial-stromal TGFBI dystrophy (Definitive, GenCC) — +6 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 228 total — 12 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 43
• Druggable target: yes
• MANE Select transcript: NM_000358

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11771
Approved symbol	TGFBI
Name	transforming growth factor beta induced
Location	5q31.1
Locus type	gene with protein product
Status	Approved
Aliases	BIGH3, CDB1, CDGG1
Ensembl gene	ENSG00000120708
Ensembl biotype	protein_coding
OMIM	601692
Entrez	7045

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 6 protein_coding, 6 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000442011, ENST00000503087, ENST00000504185, ENST00000504411, ENST00000506699, ENST00000507018, ENST00000508076, ENST00000508767, ENST00000509485, ENST00000509749, ENST00000513497, ENST00000514242, ENST00000514554, ENST00000515433, ENST00000604555

RefSeq mRNA: 1 — MANE Select: NM_000358 NM_000358

CCDS: CCDS47266

Canonical transcript exons

ENST00000442011 — 17 exons

Exon	Start	End
ENSE00001593685	136063186	136063818
ENSE00001743231	136028988	136029189
ENSE00002255819	136046335	136046495
ENSE00003475916	136060834	136060936
ENSE00003481364	136053943	136054080
ENSE00003482055	136052907	136053119
ENSE00003488342	136044058	136044122
ENSE00003503938	136056665	136056795
ENSE00003517162	136055680	136055816
ENSE00003525978	136062663	136062687
ENSE00003547471	136054716	136054861
ENSE00003556816	136061500	136061579
ENSE00003584963	136049439	136049580
ENSE00003596125	136047274	136047420
ENSE00003599067	136046851	136047015
ENSE00003652967	136033763	136033861
ENSE00003693912	136059090	136059214

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 99.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 940.3536 / max 32371.2443, expressed in 1587 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
58673	909.9916	1573
58687	10.9774	952
58690	3.4330	725
58686	2.9225	682
58699	2.5657	647
58692	1.9689	581
58705	1.5350	488
58701	1.3862	474
58691	1.1000	456
58688	1.0145	451

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
amniotic fluid	UBERON:0000173	99.48	gold quality
synovial joint	UBERON:0002217	99.46	gold quality
pericardium	UBERON:0002407	99.44	gold quality
tendon of biceps brachii	UBERON:0008188	99.39	gold quality
monocyte	CL:0000576	99.21	gold quality
mononuclear cell	CL:0000842	99.16	gold quality
leukocyte	CL:0000738	99.14	gold quality
layer of synovial tissue	UBERON:0007616	99.07	gold quality
skin of hip	UBERON:0001554	98.97	gold quality
upper leg skin	UBERON:0004262	98.94	gold quality
skin of abdomen	UBERON:0001416	98.92	gold quality
gall bladder	UBERON:0002110	98.88	gold quality
upper arm skin	UBERON:0004263	98.85	gold quality
periodontal ligament	UBERON:0008266	98.85	gold quality
skin of leg	UBERON:0001511	98.81	gold quality
nipple	UBERON:0002030	98.74	gold quality
zone of skin	UBERON:0000014	98.70	gold quality
cartilage tissue	UBERON:0002418	98.68	gold quality
saphenous vein	UBERON:0007318	98.68	gold quality
granulocyte	CL:0000094	98.60	gold quality
tibial nerve	UBERON:0001323	98.55	gold quality
placenta	UBERON:0001987	98.49	gold quality
left coronary artery	UBERON:0001626	98.41	gold quality
decidua	UBERON:0002450	98.41	gold quality
coronary artery	UBERON:0001621	98.39	gold quality
stromal cell of endometrium	CL:0002255	98.38	gold quality
urethra	UBERON:0000057	98.37	gold quality
right coronary artery	UBERON:0001625	98.26	gold quality
popliteal artery	UBERON:0002250	98.22	gold quality
tibial artery	UBERON:0007610	98.22	gold quality

Single-cell (SCXA)

Detected in 32 experiment(s), a significant marker in 31.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	2965.51
E-MTAB-8559	yes	2553.08
E-MTAB-9388	yes	2167.84
E-CURD-11	yes	2050.75
E-MTAB-9906	yes	1406.61
E-MTAB-9435	yes	1105.03
E-MTAB-10287	yes	628.21
E-GEOD-81383	yes	601.28
E-GEOD-124472	yes	506.53
E-MTAB-8142	yes	102.17
E-MTAB-6701	yes	70.34
E-HCAD-10	yes	56.55
E-HCAD-4	yes	51.62
E-MTAB-8410	yes	46.19
E-HCAD-11	yes	45.64

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI2, JUN, KLF10, RB1, SP1, SP3

miRNA regulators (miRDB)

65 targeting TGFBI, 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-9-5P	100.00	72.28	2361
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-2682-5P	99.73	67.38	1055
HSA-MIR-4716-3P	99.69	66.73	1022

Literature-anchored findings (GeneRIF, showing 40)

• The majority (90%) of ACD patients in Korea carry the R124H mutation. Mutant-specific reverse primers can be used to screen efficiently for CDL1 and ACD. (PMID:11685063)
• This mutation occurs independently in different famlies (PMID:11741113)
• Identification of endothelial cell genes expressed in an in vitro model of angiogenesis: induction of ESM-1, (beta)ig-h3, and NrCAM (PMID:11866539)
• Disease-causing phenotype-genotype BIGH3 mutation is domain specific (PMID:11923233)
• there is a direct correlation between the molecular defect and the clinical course of BIGH3-linked CDs. (PMID:11927442)
• four of the fas-1 domains in betaig-h3 mediate MRC-5 fibroblast adhesion and that this was specifically inhibited by a function-blocking monoclonal antibody specific for the alphavbeta5 integrin (PMID:12270930)
• induced by TGF-beta1 in pancreatic cancer cell lines and is over-expressed in pancreatic cancer cells in vivo (PMID:12379307)
• loss of Betaig-h3 (Bigh3) expression is a frequent event in human cancer and causally related to acquisition of tumorigenic phenotype in asbestos-treated bronchial epithelial cells (PMID:12386809)
• expressed in the periodontal ligament and regulates its mineralization (PMID:12454095)
• Results suggest that alpha6beta4 integrin-mediated interactions of astrocytes with beta(ig)-h3 transduce intracellular signals through the focal adhesion proteins, which may regulate certain aspects of astrocyte response to brain injury. (PMID:12499048)
• A novel nonsense mutation with a compound heterozygous mutation in TGFBI gene in lattice corneal dystrophy type I. (PMID:12586172)
• Beta ig-h3 may be important in regulating cell apoptosis by providing soluble RGD peptides. It may act as a tumor suppressor, mediating TGF-beta’s function. (PMID:12673209)
• betaig-h3 bears alphavbeta3 integrin-interacting motifs that mediate endothelial cell adhesion and migration and angiogenesis (PMID:12704192)
• betaig-h3 is extensively associated with collagen VI in some tissues and that it plays an important modulating role in collagen VI microfibril function (PMID:12719415)
• betaig-h3 may be important in development of diabetic nephropathy. Level of urinary betaig-h3 may be useful as early marker reflecting disease onset and progression. (PMID:12911551)
• Blood levels are higher in coronary artery disease patients compared with normal values. (PMID:12940514)
• Substitution of arginine for leucine at position 569 of the TGFBI gene results in a form of lattice corneal dystrophy. (PMID:14597039)
• The TGFBI gene is not responsible for causing keratoconus in these patients. (PMID:14701952)
• R555W and R124H mutations were co-segregated with the disease phenotype and thus caused GCD and ACD (granular and avellino corneal dystrophy. (PMID:14767644)
• R124H and R555W mutations in BIGH3 gene were found in the patients with Avellino and granular corneal dystrophies. (PMID:14767905)
• The molecular genetic analysis of TGFBI can offer rapid, accurate diagnosis of patients with atypical corneal appearance. (PMID:15013897)
• Genetic analysis revealed a heterozygous CGC/CAC change in exon 4 of the beta iG-H3 gene, resulting in an arginine to histidine substitution at codon 124. (PMID:15059726)
• Two mutations in the TGFBI gene (A546D and P551Q) cosegregated with LCD in an extensively studied family that lacked the R124C mutation that frequently accompanies this form of corneal amyloidosis. (PMID:15111592)
• Corneal amyloidosis with an autosomal dominant mode of inheritance is characterized clinically by the presence of refractile polymorphic corneal opacities, which is caused by an A546D mutation in the TGFBI gene (PMID:15177960)
• Hereditary corneal dystrophies involve codon 124 mutation (Review) (PMID:15179309)
• Urinary levels of betaig-h3 are elevated in type 2 diabetic patients with nephropathy and may be used as a marker of diabetic nephropathy. (PMID:15223229)
• This unusual case of an individual with the R124C mutation of TGFBI gene without histopathological evidence of amyloid deposition (PMID:15302666)
• We present a phenotypic variant of lattice corneal dystrophy associated with the Ala546Asp and Pro551Gln missense changes in exon 12 of the TGFBI gene. (PMID:15531312)
• TGFBI gene mutation analysis is important as well for the early differential diagnosis of corneal dystrophies and genetic consulting in high-risk families. (PMID:15564760)
• Arg124Cys and Arg555Trp appear to be the predominant mutations causing lattice and granular corneal dystrophies, respectively. (PMID:15623763)
• The present study provides, for the first time, information about 28 genetic polymorphisms in TGFBI and positive associations of those polymorphisms with levels of insulin and BMI in the Korean population. (PMID:15712349)
• Recombinant beta ig-h3 and its FAS1 domain significantly inhibit in vitro osteoblast differentiation as evaluated by matrix mineralization/bone nodule formation. (PMID:15780949)
• This is the first report of a single-nucleotide mutation at codon 540 of TGFBI leading to lattice corneal dystrophy (LCD), and the first to demonstrate that the amyloid deposits in LCD contain proteolytic fragments of keratoepithelin. (PMID:15790870)
• Beta ig-h3 induces keratinocyte differentiation via modulation of involucrin and transglutaminase expression through the integrin alpha3beta1 and the phosphatidylinositol 3-kinase/Akt signaling pathway (PMID:15805105)
• A novel V505D mutation in the TGFBI gene causes LCDI (lattice corneal dystrophy, type I). (PMID:15838722)
• We report a novel corneal dystrophy phenotype secondary to the Gly623Asp mutation in the TGFBI gene that is associated with clinical features of both lattice corneal dystrophy and a Bowman’s layer dystrophy. (PMID:15885785)
• A C–>T mutation at residue 1710 of TGFBI complementary DNA, corresponding to an Arg555Trp mutation in keratoepithelin, was found in affected members of both families. (PMID:16087849)
• The identification of this mutation allows the unambiguous classification of this corneal dystrophy as LCD type I in a family from Eastern Europe. (PMID:16329070)
• downregulation of TGFBI gene is a frequent event and related to the tumor progression in human lung cancer (PMID:16329146)
• TGF-beta-induced protein (betaig-h3) was identified as being most prominently up-regulated in immature dendritic cells. (PMID:16368891)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tgfbi	ENSDARG00000071586
mus_musculus	Tgfbi	ENSMUSG00000035493
rattus_norvegicus	Tgfbi	ENSRNOG00000012216
drosophila_melanogaster	Fas1	FBGN0285925
caenorhabditis_elegans	F26E4.7	WBGENE00009162

Paralogs (1): POSTN (ENSG00000133110)

Protein

Protein identifiers

Transforming growth factor-beta-induced protein ig-h3 — Q15582 (reviewed: Q15582)

Alternative names: Kerato-epithelin, RGD-containing collagen-associated protein

All UniProt accessions (9): A0A0S2Z4Q2, D6RBX4, Q15582, H0Y8L3, H0Y8M8, H0Y9D7, H0YAB8, H0YAH8, S4R3C6

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in cell adhesion. May play a role in cell-collagen interactions.

Subunit / interactions. Binds to type I, II, and IV collagens.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Highly expressed in the corneal epithelium. Expressed in heart, placenta, lung, liver, skeletal muscle, kidney and pancreas.

Post-translational modifications. Gamma-carboxylation is controversial. Gamma-carboxyglutamated; gamma-carboxyglutamate residues are formed by vitamin K dependent carboxylation; these residues may be required for binding to calcium. According to a more recent report, does not contain vitamin K-dependent gamma-carboxyglutamate residues. The EMI domain contains 2 expected intradomain disulfide bridges (Cys-49-Cys85 and Cys-84-Cys-97) and one unusual interdomain disulfide bridge to the second FAS1 domain (Cys-74-Cys-339). This arrangement violates the predicted disulfide bridge pattern of an EMI domain.

Disease relevance. Corneal dystrophy, epithelial basement membrane (EBMD) [MIM:121820] A bilateral anterior corneal dystrophy characterized by grayish epithelial fingerprint lines, geographic map-like lines, and dots (or microcysts) on slit-lamp examination. Pathologic studies show abnormal, redundant basement membrane and intraepithelial lacunae filled with cellular debris. The disease is caused by variants affecting the gene represented in this entry. Corneal dystrophy, Groenouw type 1 (CDGG1) [MIM:121900] A rare form of stromal corneal dystrophy characterized by multiple small deposits in the superficial central corneal stroma, and progressive visual impairment. The disease is caused by variants affecting the gene represented in this entry. Corneal dystrophy, lattice type 1 (CDL1) [MIM:122200] A form of lattice corneal dystrophy, a class of inherited stromal amyloidoses characterized by pathognomonic branching lattice figures in the cornea. CDL1 is characterized by progressive visual impairment, and the presence of delicate, double-contoured, interdigitating, elongated deposits that form a reticular pattern in the corneal stroma. Systemic amyloidosis is absent. Recurrent corneal ulceration sometimes occurs. The disease is caused by variants affecting the gene represented in this entry. Corneal dystrophy, Thiel-Behnke type (CDTB) [MIM:602082] A bilateral disorder of the cornea characterized by progressive honeycomb-like, subepithelial corneal opacities with recurrent erosions. The disease is caused by variants affecting the gene represented in this entry. Corneal dystrophy, Reis-Bucklers type (CDRB) [MIM:608470] A bilateral disorder of the cornea characterized by intermittent attacks of ocular irritation, recurrent painful corneal erosions starting in childhood, corneal opacities in a geographic pattern at the level of the Bowman layer, and a progressive decrease of visual acuity. The lesions are primarily in Bowman membrane with secondary involvement of the epithelium and superficial part of the stroma. Bowman membrane is almost completely replaced by pathologic materials including disoriented collagen fibrils. The disease is caused by variants affecting the gene represented in this entry. Corneal dystrophy, lattice type 3A (CDL3A) [MIM:608471] A form of lattice corneal dystrophy, a class of inherited stromal amyloidoses characterized by pathognomonic branching lattice figures in the cornea. CDL3A is characterized by decreased visual acuity, and the presence of thick, ropy branching lattice lines and accumulations of amyloid deposits in the corneal stroma. Systemic amyloidosis is absent. CDL3A clinically resembles to lattice corneal dystrophy type 3, but differs in that its age of onset is 70 to 90 years. It has an autosomal dominant inheritance pattern. The disease is caused by variants affecting the gene represented in this entry. Corneal dystrophy, Avellino type (CDA) [MIM:607541] A corneal disease resulting in reduced visual acuity and characterized by gray, crumb-like granular deposits in the anterior third of the stroma in each corneal button. Fusiform amyloid deposits, histochemically and morphologically identical to those of lattice corneal dystrophy, are found in the deeper stroma. Additional features include recurrent corneal erosions, and glare and decreased night vision. The disease is caused by variants affecting the gene represented in this entry.

Induction. By TGF-beta.

RefSeq proteins (1): NP_000349* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000782	FAS1_domain	Domain
IPR011489	EMI_domain	Domain
IPR016666	TGFBI/POSTN	Family
IPR036378	FAS1_dom_sf	Homologous_superfamily
IPR050904	Adhesion/Biosynth-related	Family

Pfam: PF02469

UniProt features (121 total): sequence variant 38, strand 36, helix 30, disulfide bond 5, domain 5, turn 2, modified residue 2, signal peptide 1, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
7ASG	X-RAY DIFFRACTION	2
2VXP	X-RAY DIFFRACTION	2.5
7AS7	X-RAY DIFFRACTION	2.65
5NV6	X-RAY DIFFRACTION	2.93
7ASC	X-RAY DIFFRACTION	4.8
8HIA	ELECTRON MICROSCOPY	4.9
1X3B	SOLUTION NMR
2LTB	SOLUTION NMR
2LTC	SOLUTION NMR
8HGA	SOLID-STATE NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15582-F1	90.33	0.85

Functional residue map

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

Post-translational modifications (2): 37, 65

Disulfide bonds (5): 49–85, 74–339, 84–97, 214–317, 473–478

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-977225	Amyloid fiber formation
R-HSA-392499	Metabolism of proteins

MSigDB gene sets: 479 (showing top): VERHAAK_AML_WITH_NPM1_MUTATED_DN, MODULE_52, TAATAAT_MIR126, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_CARTILAGE_DEVELOPMENT, SWEET_KRAS_ONCOGENIC_SIGNATURE, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, PAL_PRMT5_TARGETS_UP, MODULE_45, GOZGIT_ESR1_TARGETS_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_E_UP, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_1, BROWNE_HCMV_INFECTION_48HR_DN, MODULE_75, GOCC_TRANS_GOLGI_NETWORK

GO Biological Process (7): angiogenesis (GO:0001525), chondrocyte differentiation (GO:0002062), cell adhesion (GO:0007155), negative regulation of cell adhesion (GO:0007162), visual perception (GO:0007601), cell population proliferation (GO:0008283), extracellular matrix organization (GO:0030198)

GO Molecular Function (7): integrin binding (GO:0005178), extracellular matrix structural constituent (GO:0005201), collagen binding (GO:0005518), identical protein binding (GO:0042802), cell adhesion molecule binding (GO:0050839), extracellular matrix binding (GO:0050840), protein binding (GO:0005515)

GO Cellular Component (8): extracellular region (GO:0005576), basement membrane (GO:0005604), obsolete extracellular space (GO:0005615), trans-Golgi network (GO:0005802), plasma membrane (GO:0005886), extracellular matrix (GO:0031012), extracellular exosome (GO:0070062), cell periphery (GO:0071944)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
protein-containing complex binding	2
extracellular matrix	2
protein binding	2
binding	2
cellular anatomical structure	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
cell differentiation	1
cartilage development	1
cell adhesion	1
regulation of cell adhesion	1
negative regulation of cellular process	1
sensory perception of light stimulus	1
extracellular structure organization	1
external encapsulating structure organization	1
signaling receptor binding	1
cell adhesion molecule binding	1
structural molecule activity	1
Golgi apparatus subcompartment	1
membrane	1
cell periphery	1
external encapsulating structure	1
extracellular vesicle	1

Protein interactions and networks

STRING

2920 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TGFBI	FN1	P02751	993
TGFBI	TGIF2	Q9GZN2	884
TGFBI	TGIF2LY	Q8IUE0	846
TGFBI	TGIF2LX	Q8IUE1	840
TGFBI	BGN	P13247	789
TGFBI	DCN	P07585	758
TGFBI	ITGB3	P05106	743
TGFBI	COL1A2	P02464	680
TGFBI	COL1A1	P02452	644
TGFBI	COL4A1	P02462	638
TGFBI	PABPC5	Q96DU9	635
TGFBI	SERPINE1	P05121	630
TGFBI	COL4A2	P08572	626
TGFBI	MMP9	P14780	610
TGFBI	TGFBR3	Q03167	607

IntAct

38 interactions, top by confidence:

A	B	Type	Score
TGFBI	FAM9B	psi-mi:“MI:0915”(physical association)	0.670
FAM9B	TGFBI	psi-mi:“MI:0915”(physical association)	0.670
TGFBI	TGFBI	psi-mi:“MI:0407”(direct interaction)	0.600
S100P	TGFBI	psi-mi:“MI:0915”(physical association)	0.560
TGFBI	POSTN	psi-mi:“MI:0915”(physical association)	0.560
POSTN	TGFBI	psi-mi:“MI:0915”(physical association)	0.560
TGFBI	POSTN	psi-mi:“MI:0403”(colocalization)	0.560
POSTN	TGFBI	psi-mi:“MI:0403”(colocalization)	0.560
ITGB2	TGFBI	psi-mi:“MI:0915”(physical association)	0.520
CFTR	CNOT1	psi-mi:“MI:0914”(association)	0.480
TGFBI	Postn	psi-mi:“MI:0915”(physical association)	0.460
TGFBI	Postn	psi-mi:“MI:0403”(colocalization)	0.460
steC	SCD	psi-mi:“MI:0914”(association)	0.460
TGFBI	HTRA1	psi-mi:“MI:0570”(protein cleavage)	0.440
TGFBI	E6	psi-mi:“MI:0915”(physical association)	0.370
	VWA8	psi-mi:“MI:0914”(association)	0.350
	E2F3	psi-mi:“MI:0914”(association)	0.350

BioGRID (30): FAM9B (Two-hybrid), S100P (Two-hybrid), TGFBI (Affinity Capture-MS), TGFBI (Two-hybrid), TGFBI (Protein-RNA), TGFBI (Reconstituted Complex), TGFBI (Proximity Label-MS), TGFBI (Affinity Capture-MS), TGFBI (Reconstituted Complex), MMP9 (Affinity Capture-Western), TGFBI (Biochemical Activity), KIF13B (Affinity Capture-MS), HNRNPA1L2 (Affinity Capture-MS), TGFBI (Affinity Capture-MS), TGFBI (Proximity Label-MS)

ESM2 similar proteins: A0A8M9PFP2, A1XQY1, A2A863, A2VE29, B0S5G3, D3YXG0, I2C090, O11780, P02786, P06684, P08650, P10674, P10675, P16144, P19827, P55906, P56652, P82198, P97278, P97280, Q06033, Q0VCM5, Q15063, Q15582, Q28146, Q29052, Q2V905, Q5R9Q9, Q5RDH6, Q61702, Q62009, Q63372, Q64632, Q8BJD1, Q8CFM6, Q8R4U0, Q8R4Y4, Q8R553, Q8VDA1, Q8WWQ8

Diamond homologs: C1AFY9, O11780, O33752, P0A669, P0CAX7, P55906, P73392, P74615, P82198, P9WNF2, P9WNF3, P9WNF4, P9WNF5, Q15063, Q15582, Q49614, Q95215, Q62009, Q8CFM6, Q8R4U0, Q8WWQ8, Q9ZWA8, D4B388, Q8LEJ6, Q8R4Y4, Q9NY15

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
KLF10	“up-regulates quantity by expression”	TGFBI	“transcriptional regulation”
TGFBI	“up-regulates activity”	“A3/b1 integrin”	binding
TGFBI	“up-regulates activity”	“A4/b1 integrin”
TGFBI	“up-regulates activity”	“A5/b1 integrin”
TGFBI	“up-regulates activity”	“a7/b1 integrin”	binding
TGFBI	“up-regulates activity”	“A6/b4 integrin”	binding
TGFBI	“up-regulates activity”	“A1/b1 integrin”	binding
TGFBI	“up-regulates activity”	“Av/b3 integrin”	binding
TGFBI	“up-regulates activity”	“Av/b5 integrin”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	6
Uncertain significance	135
Likely benign	18
Benign	15

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
2136335	NM_000358.3(TGFBI):c.1877A>G (p.His626Arg)	Pathogenic
3239366	NM_000358.3(TGFBI):c.1877A>C (p.His626Pro)	Pathogenic
7866	NM_000358.3(TGFBI):c.1663C>T (p.Arg555Trp)	Pathogenic
7867	NM_000358.3(TGFBI):c.1664G>A (p.Arg555Gln)	Pathogenic
7868	NM_000358.3(TGFBI):c.370C>T (p.Arg124Cys)	Pathogenic
7869	NM_000358.3(TGFBI):c.371G>A (p.Arg124His)	Pathogenic
7870	NM_000358.3(TGFBI):c.1618_1620del (p.Phe540del)	Pathogenic
7872	NM_000358.3(TGFBI):c.371G>T (p.Arg124Leu)	Pathogenic
7873	NM_000358.3(TGFBI):c.370C>A (p.Arg124Ser)	Pathogenic
7875	NM_000358.3(TGFBI):c.1619T>C (p.Phe540Ser)	Pathogenic
7876	NM_000358.3(TGFBI):c.1868G>A (p.Gly623Asp)	Pathogenic
7877	NM_000358.3(TGFBI):c.1526T>G (p.Leu509Arg)	Pathogenic
1300214	NM_000358.3(TGFBI):c.1612A>C (p.Thr538Pro)	Likely pathogenic
1300215	NM_000358.3(TGFBI):c.1864A>C (p.Asn622His)	Likely pathogenic
1333310	NM_000358.3(TGFBI):c.1855A>G (p.Met619Val)	Likely pathogenic
2498979	NM_000358.3(TGFBI):c.1640T>G (p.Phe547Cys)	Likely pathogenic
2572628	NM_000358.3(TGFBI):c.1517_1518insCAAGGG (p.Met506delinsIleLysGly)	Likely pathogenic
984425	NM_000358.3(TGFBI):c.1772C>A (p.Ser591Tyr)	Likely pathogenic

SpliceAI

2234 predictions. Top by Δscore:

Variant	Effect	Δscore
5:136029188:GG:G	donor_gain	1.0000
5:136029189:GG:G	donor_gain	1.0000
5:136033862:G:GG	donor_gain	1.0000
5:136044056:A:AG	acceptor_gain	1.0000
5:136044057:G:GG	acceptor_gain	1.0000
5:136046423:GCC:G	donor_gain	1.0000
5:136046493:GCT:G	donor_gain	1.0000
5:136046496:G:GG	donor_gain	1.0000
5:136046847:CTA:C	acceptor_loss	1.0000
5:136046850:G:GC	acceptor_loss	1.0000
5:136046850:GGAA:G	acceptor_gain	1.0000
5:136047267:T:TA	acceptor_gain	1.0000
5:136047270:GCA:G	acceptor_loss	1.0000
5:136047271:CA:C	acceptor_loss	1.0000
5:136047272:A:AG	acceptor_gain	1.0000
5:136047272:AGATT:A	acceptor_gain	1.0000
5:136047273:G:GA	acceptor_gain	1.0000
5:136047273:GA:G	acceptor_gain	1.0000
5:136047273:GATT:G	acceptor_gain	1.0000
5:136047273:GATTG:G	acceptor_gain	1.0000
5:136047416:TTCGG:T	donor_gain	1.0000
5:136047417:TCGG:T	donor_gain	1.0000
5:136047419:GG:G	donor_gain	1.0000
5:136047419:GGGT:G	donor_loss	1.0000
5:136047420:GG:G	donor_gain	1.0000
5:136047420:GGT:G	donor_loss	1.0000
5:136047421:G:GG	donor_gain	1.0000
5:136047421:GT:G	donor_loss	1.0000
5:136047422:T:G	donor_loss	1.0000
5:136048240:G:A	acceptor_gain	1.0000

AlphaMissense

4435 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:136033773:T:A	C49S	1.000
5:136033773:T:C	C49R	1.000
5:136033774:G:A	C49Y	1.000
5:136033774:G:C	C49S	1.000
5:136033830:T:A	W68R	1.000
5:136033830:T:C	W68R	1.000
5:136033832:G:C	W68C	1.000
5:136033832:G:T	W68C	1.000
5:136044074:T:C	C84R	1.000
5:136044113:T:A	C97S	1.000
5:136044113:T:C	C97R	1.000
5:136044114:G:C	C97S	1.000
5:136046480:G:C	W148C	1.000
5:136046480:G:T	W148C	1.000
5:136047328:G:T	G227W	1.000
5:136029164:A:C	S37R	0.999
5:136029166:C:A	S37R	0.999
5:136029166:C:G	S37R	0.999
5:136029177:G:A	G41D	0.999
5:136033774:G:T	C49F	0.999
5:136033775:T:G	C49W	0.999
5:136033777:C:A	A50D	0.999
5:136033821:T:A	C65S	0.999
5:136033821:T:C	C65R	0.999
5:136033822:G:A	C65Y	0.999
5:136033822:G:C	C65S	0.999
5:136033822:G:T	C65F	0.999
5:136033823:C:G	C65W	0.999
5:136033848:T:A	C74S	0.999
5:136033848:T:C	C74R	0.999

dbSNP variants (sampled 300 via entrez): RS1000336005 (5:136047233 C>G,T), RS1000358721 (5:136053663 T>C), RS1000457988 (5:136028919 T>C), RS1000569318 (5:136049644 T>C), RS1000585933 (5:136029119 C>G,T), RS1000751863 (5:136034744 A>C), RS1000979078 (5:136057304 G>A,C), RS1000989962 (5:136030980 GT>G,GTT), RS1001011684 (5:136057122 C>T), RS1001041348 (5:136028902 C>A), RS1001093875 (5:136063411 A>C,G), RS1001292629 (5:136051247 T>A,C), RS1001406400 (5:136031478 A>G), RS1001529194 (5:136053202 A>G), RS1001581985 (5:136047662 A>G)

Disease associations

OMIM: gene MIM:601692 | disease phenotypes: MIM:121900, MIM:608471, MIM:608470, MIM:607541, MIM:121820, MIM:122200, MIM:602082

GenCC curated gene-disease

Disease	Classification	Inheritance
epithelial-stromal TGFBI dystrophy	Definitive	Autosomal dominant
granular corneal dystrophy type I	Definitive	Autosomal dominant
Thiel-Behnke corneal dystrophy	Definitive	Autosomal dominant
Reis-Bucklers corneal dystrophy	Definitive	Autosomal dominant
granular corneal dystrophy type II	Definitive	Autosomal dominant
lattice corneal dystrophy type I	Definitive	Autosomal dominant
epithelial basement membrane dystrophy	Supportive	Autosomal dominant

Mondo (10): corneal granular dystrophy (MONDO:0001490), epithelial-stromal TGFBI dystrophy (MONDO:0000764), granular corneal dystrophy type I (MONDO:0007377), corneal dystrophy, lattice type 3A (MONDO:0012044), corneal dystrophy (MONDO:0018102), Reis-Bucklers corneal dystrophy (MONDO:0012043), granular corneal dystrophy type II (MONDO:0011855), epithelial basement membrane dystrophy (MONDO:0007375), lattice corneal dystrophy type I (MONDO:0007380), Thiel-Behnke corneal dystrophy (MONDO:0011185)

Orphanet (7): Granular corneal dystrophy type I (Orphanet:98962), Corneal dystrophy (Orphanet:34533), Lattice corneal dystrophy type I (Orphanet:98964), Reis-Bücklers corneal dystrophy (Orphanet:98961), Granular corneal dystrophy type II (Orphanet:98963), Epithelial basement membrane dystrophy (Orphanet:98956), Thiel-Behnke corneal dystrophy (Orphanet:98960)

HPO phenotypes

43 total (30 of 43 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000481	Abnormal cornea morphology
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000495	Recurrent corneal erosions
HP:0000505	Visual impairment
HP:0000518	Cataract
HP:0000529	Progressive visual loss
HP:0000531	Corneal crystals
HP:0000559	Corneal scarring
HP:0000572	Visual loss
HP:0000613	Photophobia
HP:0000622	Blurred vision
HP:0001131	Corneal dystrophy
HP:0001149	Lattice corneal dystrophy
HP:0003584	Late onset
HP:0003593	Infantile onset
HP:0003596	Middle age onset
HP:0003621	Juvenile onset
HP:0007663	Reduced visual acuity
HP:0007690	Map-dot-fingerprint corneal dystrophy
HP:0007755	Juvenile epithelial corneal dystrophy
HP:0007759	Opacification of the corneal stroma
HP:0007802	Granular corneal dystrophy
HP:0007809	Punctate corneal dystrophy
HP:0007827	Nodular corneal dystrophy
HP:0007881	Central corneal dystrophy
HP:0007924	Slow decrease in visual acuity
HP:0007957	Corneal opacity
HP:0008039	Subepithelial corneal opacities

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002343_3	Response to cytidine analogues (gemcitabine)	4.000000e-06
GCST002987_6	Stroke	3.000000e-07
GCST003981_8	Insomnia	2.000000e-08
GCST006585_1656	Blood protein levels	4.000000e-61

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007876	insomnia measurement

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D003317	Corneal Dystrophies, Hereditary	C11.204.236; C11.270.162; C16.320.290.162
C563923	Corneal Dystrophy, Lattice Type IIIA (supp.)
C535474	Corneal dystrophy Avellino type (supp.)
C535476	Corneal dystrophy of Bowman layer, type 1 (supp.)
C535942	Corneal dystrophy, Thiel-Behnke type (supp.)
C535477	Corneal dystrophy, epithelial basement membrane (supp.)
C537304	Groenouw type I corneal dystrophy (supp.)
C537881	Lattice corneal dystrophy type 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295829 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases abundance, increases expression, affects expression, decreases expression	4
Doxorubicin	decreases response to substance, affects expression, increases expression	4
Tetrachlorodibenzodioxin	affects cotreatment, increases expression	4
Lipopolysaccharides	decreases reaction, increases secretion, affects expression, increases expression, affects reaction	3
Smoke	decreases expression, increases expression	3
Tobacco Smoke Pollution	increases expression, affects expression, decreases expression	3
Tretinoin	decreases expression, increases expression	3
graphene oxide	increases expression	2
potassium chromate(VI)	affects cotreatment, increases expression, decreases expression	2
chromium hexavalent ion	increases abundance, increases expression, affects expression	2
lipopolysaccharide, Escherichia coli O111 B4	decreases reaction, increases expression, increases secretion, affects reaction	2
Acetaminophen	affects expression, decreases expression	2
Arsenic	affects methylation, decreases expression, increases abundance	2
Cadmium	decreases expression, increases abundance, increases expression	2
Estradiol	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Triterpenes	increases expression, increases secretion, affects localization, increases phosphorylation, decreases reaction	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
Raloxifene Hydrochloride	affects expression, affects cotreatment, decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
bisphenol A	affects expression	1
lead acetate	increases expression	1
trichostatin A	decreases expression	1
arsenite	decreases methylation	1
sodium bichromate	decreases expression	1
sodium arsenite	decreases expression, increases abundance	1
cobaltous chloride	decreases secretion	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118984	Binding	Binding affinity to TGFBI in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05279157	PHASE2	COMPLETED	Autologous Adipose-Derived Adult Stem Cell Implantation for Corneal Diseases (ADASCs-CT-CD)
NCT02373397	Not specified	TERMINATED	Cacicol20® in Corneal Wound Healing and Nerve Regeneration After Phototherapeutic Keratectomy
NCT02766907	Not specified	COMPLETED	Optimizing the Ocular Surface Prior to Cataract Surgery
NCT05770492	Not specified	UNKNOWN	Deep Learning Assisted Epithelial Basement Membrane Dystrophy Detection
NCT06618508	Not specified	NOT_YET_RECRUITING	Manual Debridement vs Phototherapeutic Keratectomy in the Treatment of Corneal Basement Membrane Dystrophy
NCT06914817	Not specified	NOT_YET_RECRUITING	Brillouin Microscopy Used to Evaluate Corneal Mechanical Properties
NCT06213402	Not specified	RECRUITING	RADeep Multicenter European Epidemiological Platform for Patients Diagnosed With Rare Anemia Disorders (RADs)
NCT04484402	PHASE1/PHASE2	COMPLETED	Treatment of Patients With Inflammatory-dystrophic Diseases of the Cornea Using Autologous Stem Cells
NCT02932852	EARLY_PHASE1	UNKNOWN	Autologous Adipose-Derived Adult Stem Cell Transplantation for Corneal Diseases
NCT01084850	Not specified	UNKNOWN	Corneal Endothelium Morphology and Central Thickness in Type II Diabetes Mellitus and Normal Subjects
NCT02173847	Not specified	COMPLETED	Laser Assisted Procedures in Penetrating Keratoplasty
NCT02736877	Not specified	UNKNOWN	Corneal Transplantation Guided by OCT RESCAN
NCT02746055	Not specified	UNKNOWN	Study of the Prevalence of TGFBI Corneal Dystrophies
NCT03461991	Not specified	COMPLETED	Correlation Between In-vivo Anatomy of Corneal Dystrophies as Assessed by High- Resolution Optical Coherence Tomography (OCT) Measurement and Histological Examination
NCT03504800	Not specified	RECRUITING	OCT in Diagnosis of Irregular Corneas
NCT04129021	Not specified	RECRUITING	High Resolution, High-speed Multimodal Ophthalmic Imaging
NCT04164407	Not specified	UNKNOWN	Keratoconus, Corneal Diseases and Transplant Registry
NCT04384094	Not specified	UNKNOWN	Defining the Operating Parameters for a Rebound-esthesiometer
NCT04424550	Not specified	COMPLETED	Comparative Results After DSAEK, UT-DSAEK and DMEK for Fuchs Endothelial Corneal Dystophy
NCT05742321	Not specified	RECRUITING	Analysis of the Genotype/Phenotype Relationship in the Fuchs’ Corneal Endothelial Dystrophy in France
NCT05891106	Not specified	COMPLETED	AONDA Therapeutic Indication Study I
NCT05927740	Not specified	COMPLETED	The Efficacy of Hyperemesis Gravidarum on Macular Thickness, Corneal Thickness and Intraocular Pressure in Pregnancy
NCT05956535	Not specified	COMPLETED	Air Optix® Night and Day® Aqua Therapeutic Wear
NCT06491615	Not specified	RECRUITING	National Ophthalmic Genotyping and Phenotyping Network (eyeGENE (Registered Trademark)), Stage 3 - Expansion of DNA and Data Repositories for Rare Inherited Ophthalmic Diseases
NCT06844123	Not specified	RECRUITING	Microsurgical Robot-assisted Corneal Transplant
NCT06881771	Not specified	RECRUITING	FECD-TRACE: Fuchs’ Endothelial Corneal Dystrophy TRAjectory and Correlation With Genotype in the United Kingdom