Aortic aneurysm, familial thoracic 1
diseaseOn this page
Also known as AAT1FAA1
Summary
Aortic aneurysm, familial thoracic 1 (MONDO:0024559) is a disease with 13 cohort genes and 1 clinical trial.
At a glance
- Prevalence: Unknown (Worldwide) [Orphanet-validated]
- Cohort genes: 13
- ClinVar variants: 46
- Phenotypes (HPO): 19
- Clinical trials: 1
Clinical features
Epidemiology
Prevalence records
1 prevalence record(s), Orphanet:
| Type | Class | Value | Geography | Validation |
|---|---|---|---|---|
| Annual incidence | 1-9 / 1 000 000 | 0.4 | Worldwide | Validated |
Signs & symptoms
Clinical features (HPO)
19 HPO clinical features (Orphanet curated; top 19 by frequency):
| HPO ID | Term | Frequency |
|---|---|---|
| HP:0200146 | Cystic medial necrosis of the aorta | Very frequent (80-99%) |
| HP:0001640 | Cardiomegaly | Frequent (30-79%) |
| HP:0001643 | Patent ductus arteriosus | Frequent (30-79%) |
| HP:0001659 | Aortic regurgitation | Frequent (30-79%) |
| HP:0001677 | Coronaryartery atherosclerosis | Frequent (30-79%) |
| HP:0002616 | Aortic root aneurysm | Frequent (30-79%) |
| HP:0002875 | Exertional dyspnea | Frequent (30-79%) |
| HP:0004933 | Ascending aortic dissection | Frequent (30-79%) |
| HP:0004959 | Descending thoracic aorta aneurysm | Frequent (30-79%) |
| HP:0005162 | Abnormal left ventricular function | Frequent (30-79%) |
| HP:0012499 | Descending aortic dissection | Frequent (30-79%) |
| HP:0012763 | Paroxysmal dyspnea | Frequent (30-79%) |
| HP:0100749 | Chest pain | Frequent (30-79%) |
| HP:0000965 | Cutis marmorata | Occasional (5-29%) |
| HP:0001297 | Stroke | Occasional (5-29%) |
| HP:0002647 | Aortic dissection | Occasional (5-29%) |
| HP:0004944 | Dilatation of the cerebral artery | Occasional (5-29%) |
| HP:0004950 | Peripheral arterial stenosis | Occasional (5-29%) |
| HP:0012163 | Carotid artery dilatation | Occasional (5-29%) |
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | aortic aneurysm, familial thoracic 1 |
| Mondo ID | MONDO:0024559 |
| MeSH | C562834 |
| OMIM | 607086 |
| Orphanet | 229 |
| UMLS | C0345050 |
| MedGen | 91038 |
| GARD | 0015408 |
| Is cancer (heuristic) | no |
Also known as: AAT1 · FAA1
Data availability: 46 ClinVar variants.
Disease family
Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › familial thoracic aortic aneurysm and aortic dissection › aortic aneurysm, familial thoracic 1
Related subtypes (8): aortic aneurysm, familial thoracic 4, aortic aneurysm, familial thoracic 2, aortic aneurysm, familial thoracic 6, aortic aneurysm, familial thoracic 7, aortic aneurysm, familial thoracic 8, aortic aneurysm, familial thoracic 9, aortic aneurysm, familial thoracic 10, aortic aneurysm, familial thoracic 12
Genetics & variants
GWAS landscape
No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.
Variant details and genetic-evidence tiers
ClinVar germline variants
46 retrieved; paginated sample, class counts are floors:
16 conflicting classifications of pathogenicity, 15 uncertain significance, 5 pathogenic, 4 likely pathogenic, 2 likely benign, 2 pathogenic/likely pathogenic, 1 benign, 1 risk factor
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 549890 | NM_000090.4(COL3A1):c.1897G>A (p.Gly633Arg) | COL3A1 | Pathogenic | criteria provided, single submitter |
| 200171 | NM_000138.5(FBN1):c.7039_7040del (p.Met2347fs) | FBN1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 36076 | NM_000138.5(FBN1):c.4467T>A (p.Asn1489Lys) | FBN1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 439701 | NM_000138.5(FBN1):c.7656C>A (p.Cys2552Ter) | FBN1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 267291 | NM_002317.7(LOX):c.839G>T (p.Ser280Ile) | LOX | Pathogenic | no assertion criteria provided |
| 267293 | NM_002317.7(LOX):c.800A>C (p.Gln267Pro) | LOX | Pathogenic | no assertion criteria provided |
| 617847 | NM_002317.7(LOX):c.604G>T (p.Gly202Ter) | LOX | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 617870 | NM_000138.5(FBN1):c.813C>G (p.Cys271Trp) | FBN1 | Likely pathogenic | criteria provided, single submitter |
| 617871 | NM_000138.5(FBN1):c.6866G>T (p.Cys2289Phe) | FBN1 | Likely pathogenic | criteria provided, single submitter |
| 267292 | NM_002317.7(LOX):c.125G>A (p.Trp42Ter) | LOX | Likely pathogenic | criteria provided, single submitter |
| 2502897 | XM_005247492.1:c.2736delG | MYLK | Likely pathogenic | no assertion criteria provided |
| 549889 | NM_005902.4(SMAD3):c.715G>T (p.Glu239Ter) | SMAD3 | risk factor | no assertion criteria provided |
| 161235 | NM_000138.5(FBN1):c.3797A>T (p.Tyr1266Phe) | FBN1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 264197 | NM_000138.5(FBN1):c.2093C>T (p.Pro698Leu) | FBN1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 42296 | NM_000138.5(FBN1):c.185G>A (p.Arg62His) | FBN1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 42355 | NM_000138.5(FBN1):c.4270C>G (p.Pro1424Ala) | FBN1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 617875 | NM_000138.5(FBN1):c.2207A>G (p.Asn736Ser) | FBN1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 375651 | NM_012186.3(FOXE3):c.457G>C (p.Asp153His) | LINC01389 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 521345 | NM_002317.7(LOX):c.235G>A (p.Ala79Thr) | LOX | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 617849 | NM_002317.7(LOX):c.1044T>A (p.Ser348Arg) | LOX | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 617850 | NM_002317.7(LOX):c.460C>T (p.Leu154Phe) | LOX | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 161317 | NM_002474.3(MYH11):c.739C>T (p.Arg247Cys) | MYH11 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 180420 | NM_002474.3(MYH11):c.3757AAG[3] (p.Lys1256del) | MYH11 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 375862 | NM_002474.3(MYH11):c.5176G>A (p.Ala1726Thr) | MYH11 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 263911 | NM_053025.4(MYLK):c.399G>T (p.Gln133His) | MYLK | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 161394 | NM_003242.6(TGFBR2):c.1657T>A (p.Ser553Thr) | TGFBR2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 213915 | NM_003242.6(TGFBR2):c.412T>G (p.Cys138Gly) | TGFBR2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 44651 | NM_003242.6(TGFBR2):c.1159G>A (p.Val387Met) | TGFBR2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 636991 | NM_001613.4(ACTA2):c.107T>C (p.Ile36Thr) | ACTA2 | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 3236332 | NM_001844.5(COL2A1):c.3144A>T (p.Arg1048Ser) | COL2A1 | Uncertain significance | criteria provided, single submitter |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 0 · Orphanet: 59 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| TGFBR2 | Orphanet:144 | Lynch syndrome |
| TGFBR2 | Orphanet:284973 | Marfan syndrome type 2 |
| TGFBR2 | Orphanet:60030 | Loeys-Dietz syndrome |
| TGFBR2 | Orphanet:91387 | Familial thoracic aortic aneurysm and aortic dissection |
| TGFBR2 | Orphanet:99977 | Squamous cell carcinoma of the esophagus |
| ACTA2 | Orphanet:2573 | Moyamoya disease |
| ACTA2 | Orphanet:404463 | Multisystemic smooth muscle dysfunction syndrome |
| ACTA2 | Orphanet:91387 | Familial thoracic aortic aneurysm and aortic dissection |
| COL2A1 | Orphanet:137678 | Spondyloepiphyseal dysplasia with metatarsal shortening |
| COL2A1 | Orphanet:166100 | Autosomal dominant otospondylomegaepiphyseal dysplasia |
| COL2A1 | Orphanet:1856 | Spondyloperipheral dysplasia-short ulna syndrome |
| COL2A1 | Orphanet:209867 | Autosomal dominant rhegmatogenous retinal detachment |
| COL2A1 | Orphanet:2380 | Legg-Calvé-Perthes disease |
| COL2A1 | Orphanet:459051 | Spondyloepiphyseal dysplasia, Stanescu type |
| COL2A1 | Orphanet:485 | Kniest dysplasia |
| COL2A1 | Orphanet:85166 | Platyspondylic dysplasia, Torrance type |
| COL2A1 | Orphanet:85198 | Dysspondyloenchondromatosis |
| COL2A1 | Orphanet:86820 | Familial avascular necrosis of femoral head |
| COL2A1 | Orphanet:90653 | Stickler syndrome type 1 |
| COL2A1 | Orphanet:93279 | Mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis |
| COL2A1 | Orphanet:93296 | Achondrogenesis type 2 |
| COL2A1 | Orphanet:93297 | Hypochondrogenesis |
| COL2A1 | Orphanet:93315 | Spondylometaphyseal dysplasia, ‘corner fracture’ type |
| COL2A1 | Orphanet:93316 | Spondylometaphyseal dysplasia, Schmidt type |
| COL2A1 | Orphanet:93346 | Spondyloepimetaphyseal dysplasia congenita, Strudwick type |
| COL2A1 | Orphanet:94068 | Spondyloepiphyseal dysplasia congenita |
| COL3A1 | Orphanet:231160 | Familial cerebral saccular aneurysm |
| COL3A1 | Orphanet:2500 | Acrogeria |
| COL3A1 | Orphanet:286 | Vascular Ehlers-Danlos syndrome |
| COL3A1 | Orphanet:636941 | Vascular Ehlers-Danlos-polymicrogyria syndrome |
| COL3A1 | Orphanet:86 | Familial abdominal aortic aneurysm |
| FBN1 | Orphanet:1885 | Isolated ectopia lentis |
| FBN1 | Orphanet:2084 | Glaucoma-ectopia lentis-microspherophakia-stiff joints-short stature syndrome |
| FBN1 | Orphanet:2462 | Shprintzen-Goldberg syndrome |
| FBN1 | Orphanet:2623 | Geleophysic dysplasia |
| FBN1 | Orphanet:2833 | Stiff skin syndrome |
| FBN1 | Orphanet:284963 | Marfan syndrome type 1 |
| FBN1 | Orphanet:284979 | Neonatal Marfan syndrome |
| FBN1 | Orphanet:300382 | Progeroid and marfanoid aspect-lipodystrophy syndrome |
| FBN1 | Orphanet:3449 | Weill-Marchesani syndrome |
| FBN1 | Orphanet:91387 | Familial thoracic aortic aneurysm and aortic dissection |
| FBN1 | Orphanet:969 | Acromicric dysplasia |
| FOXE3 | Orphanet:708 | Peters anomaly |
| FOXE3 | Orphanet:83461 | Congenital primary aphakia |
| FOXE3 | Orphanet:91387 | Familial thoracic aortic aneurysm and aortic dissection |
| LOX | Orphanet:91387 | Familial thoracic aortic aneurysm and aortic dissection |
| SMAD3 | Orphanet:284984 | Aneurysm-osteoarthritis syndrome |
| SMAD3 | Orphanet:60030 | Loeys-Dietz syndrome |
| SMAD3 | Orphanet:91387 | Familial thoracic aortic aneurysm and aortic dissection |
| MYH11 | Orphanet:2241 | Megacystis-microcolon-intestinal hypoperistalsis syndrome |
Cohort genes → proteins
13 cohort genes, 12 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 13 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| TGFBR2 | HGNC:11773 | ENSG00000163513 | P37173 | TGF-beta receptor type-2 | clinvar |
| ACTA2 | HGNC:130 | ENSG00000107796 | P62736 | Actin, aortic smooth muscle | clinvar |
| COL2A1 | HGNC:2200 | ENSG00000139219 | P02458 | Collagen alpha-1(II) chain | clinvar |
| COL3A1 | HGNC:2201 | ENSG00000168542 | P02461 | Collagen alpha-1(III) chain | clinvar |
| FBN1 | HGNC:3603 | ENSG00000166147 | P35555 | Fibrillin-1 | clinvar |
| FOXE3 | HGNC:3808 | ENSG00000186790 | Q13461 | Forkhead box protein E3 | clinvar |
| LINC01389 | HGNC:50661 | ENSG00000225762 | long intergenic non-protein coding RNA 1389 | clinvar | |
| LOX | HGNC:6664 | ENSG00000113083 | P28300 | Protein-lysine 6-oxidase | clinvar |
| SMAD3 | HGNC:6769 | ENSG00000166949 | P84022 | SMAD family member 3 | clinvar |
| MYH11 | HGNC:7569 | ENSG00000133392 | P35749 | Myosin-11 | clinvar |
| MYLK | HGNC:7590 | ENSG00000065534 | Q15746 | Myosin light chain kinase, smooth muscle | clinvar |
| PKD1 | HGNC:9008 | ENSG00000008710 | P98161 | Polycystin-1 | clinvar |
| PRKD1 | HGNC:9407 | ENSG00000184304 | Q15139 | Serine/threonine-protein kinase D1 | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| TGFBR2 | TGF-beta receptor type-2 | Transmembrane serine/threonine kinase forming with the TGF-beta type I serine/threonine kinase receptor, TGFBR1, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. |
| ACTA2 | Actin, aortic smooth muscle | Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells. |
| COL2A1 | Collagen alpha-1(II) chain | Type II collagen is specific for cartilaginous tissues. |
| COL3A1 | Collagen alpha-1(III) chain | Collagen type III occurs in most soft connective tissues along with type I collagen. |
| FBN1 | Fibrillin-1 | Structural component of the 10-12 nm diameter microfibrils of the extracellular matrix, which conveys both structural and regulatory properties to load-bearing connective tissues. |
| FOXE3 | Forkhead box protein E3 | Transcription factor that controls lens epithelial cell growth through regulation of proliferation, apoptosis and cell cycle. |
| LOX | Protein-lysine 6-oxidase | Responsible for the post-translational oxidative deamination of peptidyl lysine residues in precursors to fibrous collagen and elastin. |
| SMAD3 | SMAD family member 3 | Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. |
| MYH11 | Myosin-11 | Muscle contraction. |
| MYLK | Myosin light chain kinase, smooth muscle | Calcium/calmodulin-dependent myosin light chain kinase implicated in smooth muscle contraction via phosphorylation of myosin light chains (MLC). |
| PKD1 | Polycystin-1 | Component of a heteromeric calcium-permeable ion channel formed by PKD1 and PKD2 that is activated by interaction between PKD1 and a Wnt family member, such as WNT3A and WNT9B. |
| PRKD1 | Serine/threonine-protein kinase D1 | Serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of MAPK8/JNK1 and Ras signaling, Golgi membrane integrity and tr… |
Protein-family classification
Druggable: 5 · Difficult: 2 · Unknown: 6 · Druggable fraction: 0.38
Family distribution
Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.
| Family | Genes | Fold | FDR |
|---|---|---|---|
| Kinase | 3 | 6.4× | 0.061 |
| Antibody/Immunoglobulin | 1 | 2.2× | 0.837 |
| Scaffold/PPI | 1 | 1.3× | 0.837 |
| Enzyme (other) | 1 | 0.9× | 0.837 |
| Other/Unknown | 6 | 0.8× | 0.837 |
| Transcription factor | 1 | 0.6× | 0.837 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| TGFBR2 | Kinase | yes | 2.7.10.2 | TGFB_receptor, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom |
| ACTA2 | Other/Unknown | no | Actin, Actin_CS, Actin/actin-like_CS | |
| COL2A1 | Other/Unknown | no | Fib_collagen_C, VWF_dom, Collagen | |
| COL3A1 | Other/Unknown | no | Fib_collagen_C, VWF_dom, Collagen | |
| FBN1 | Other/Unknown | no | EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom | |
| FOXE3 | Transcription factor | no | Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2 | |
| LINC01389 | Other/Unknown | no | ||
| LOX | Enzyme (other) | yes | 1.4.3.13 | Lysyl_oxidase, Lysyl_oxidase_CS, |
| SMAD3 | Other/Unknown | no | SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf | |
| MYH11 | Scaffold/PPI | no | IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail | |
| MYLK | Kinase | yes | 2.7.11.18 | Prot_kinase_dom, Ig_sub2, Ig_sub |
| PKD1 | Antibody/Immunoglobulin | yes | GPS, LRRNT, PC1 | |
| PRKD1 | Kinase | yes | 2.7.11.13 | Prot_kinase_dom, PH_domain, PKC_DAG/PE |
Expression context
Cohort genes with no expression data: 0.
11 cohort genes are a single-cell marker in ≥1 SCXA experiment.
Breadth distribution (Bgee present_calls)
| Bucket | Genes |
|---|---|
| narrow (1-5 tissues) | 0 |
| moderate (6-20) | 0 |
| broad (>20) | 13 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| tibia | 3 |
| parietal pleura | 2 |
| cauda epididymis | 2 |
| saphenous vein | 2 |
| cartilage tissue | 2 |
| skin of hip | 2 |
| male germ line stem cell (sensu Vertebrata) in testis | 2 |
| mucosa of transverse colon | 2 |
| primordial germ cell in gonad | 2 |
| seminal vesicle | 2 |
| pericardium | 1 |
| blood vessel layer | 1 |
| corpus epididymis | 1 |
| visceral pleura | 1 |
| decidua | 1 |
| synovial joint | 1 |
| calcaneal tendon | 1 |
| stromal cell of endometrium | 1 |
| hindlimb stylopod muscle | 1 |
| tendon of biceps brachii | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| TGFBR2 | 289 | ubiquitous | marker | pericardium, tibia, parietal pleura |
| ACTA2 | 289 | ubiquitous | marker | cauda epididymis, blood vessel layer, saphenous vein |
| COL2A1 | 145 | broad | marker | tibia, cartilage tissue, corpus epididymis |
| COL3A1 | 281 | ubiquitous | marker | skin of hip, parietal pleura, visceral pleura |
| FBN1 | 275 | ubiquitous | marker | synovial joint, skin of hip, decidua |
| FOXE3 | 36 | tissue_specific | yes | primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, mucosa of transverse colon |
| LINC01389 | 130 | broad | yes | primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, mucosa of transverse colon |
| LOX | 242 | ubiquitous | marker | stromal cell of endometrium, calcaneal tendon, tibia |
| SMAD3 | 288 | ubiquitous | marker | tendon of biceps brachii, cartilage tissue, hindlimb stylopod muscle |
| MYH11 | 143 | broad | marker | right coronary artery, lower esophagus, lower esophagus muscularis layer |
| MYLK | 289 | ubiquitous | marker | cauda epididymis, saphenous vein, seminal vesicle |
| PKD1 | 290 | marker | right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex | |
| PRKD1 | 239 | ubiquitous | marker | ventricular zone, seminal vesicle, thoracic aorta |
Protein interactions among cohort
Intra-cohort edges: 8.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| SMAD3 | 6,440 |
| TGFBR2 | 5,777 |
| LOX | 5,479 |
| MYH11 | 3,818 |
| FBN1 | 3,640 |
| COL3A1 | 3,629 |
| MYLK | 2,763 |
| COL2A1 | 2,491 |
| PRKD1 | 2,131 |
| PKD1 | 1,370 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| COL3A1 | FBN1 | string_interaction |
| COL3A1 | LOX | intact |
| FBN1 | LOX | intact |
| FBN1 | MYLK | string_interaction |
| FBN1 | TGFBR2 | string_interaction |
| MYH11 | MYLK | string_interaction |
| PKD1 | PRKD1 | string_interaction |
| SMAD3 | TGFBR2 | string_interaction |
Structural data
PDB: 8 · AlphaFold-only: 4 · No structure: 1
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| TGFBR2 | P37173 | 22 |
| PKD1 | P98161 | 13 |
| SMAD3 | P84022 | 12 |
| COL2A1 | P02458 | 11 |
| COL3A1 | P02461 | 11 |
| FBN1 | P35555 | 11 |
| MYLK | Q15746 | 8 |
| MYH11 | P35749 | 1 |
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| ACTA2 | P62736 | 95.43 |
| PRKD1 | Q15139 | 68.99 |
| LOX | P28300 | 68.06 |
| FOXE3 | Q13461 | 66.68 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 109. Enrichment computed across 13 evidence-associated genes (11 with Reactome annotation).
Pathways by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| Loss of Function of TGFBR1 in Cancer | 2 | 415.3× | 2e-04 | TGFBR2, SMAD3 |
| Loss of Function of SMAD2/3 in Cancer | 2 | 346.1× | 2e-04 | TGFBR2, SMAD3 |
| Signaling by TGF-beta Receptor Complex in Cancer | 2 | 346.1× | 2e-04 | TGFBR2, SMAD3 |
| SMAD2/3 Phosphorylation Motif Mutants in Cancer | 2 | 346.1× | 2e-04 | TGFBR2, SMAD3 |
| TGFBR1 KD Mutants in Cancer | 2 | 346.1× | 2e-04 | TGFBR2, SMAD3 |
| TGF-beta receptor signaling activates SMADs | 3 | 89.0× | 2e-04 | TGFBR2, FBN1, SMAD3 |
| Smooth Muscle Contraction | 3 | 72.4× | 2e-04 | ACTA2, MYH11, MYLK |
| Assembly of collagen fibrils and other multimeric structures | 3 | 54.6× | 3e-04 | COL2A1, COL3A1, LOX |
| Non-integrin membrane-ECM interactions | 3 | 42.1× | 5e-04 | ACTA2, COL2A1, COL3A1 |
| Integrin cell surface interactions | 3 | 36.6× | 7e-04 | COL2A1, COL3A1, FBN1 |
| Fibronectin matrix formation | 2 | 103.8× | 0.001 | COL2A1, COL3A1 |
| NOTCH4 Intracellular Domain Regulates Transcription | 2 | 103.8× | 0.001 | ACTA2, SMAD3 |
| RHO GTPases activate PAKs | 2 | 98.9× | 0.001 | MYH11, MYLK |
| Developmental Lineage of Mammary Gland Myoepithelial Cells | 2 | 98.9× | 0.001 | ACTA2, MYH11 |
| Signaling by NOTCH4 | 2 | 90.3× | 0.002 | ACTA2, SMAD3 |
| Downregulation of TGF-beta receptor signaling | 2 | 74.2× | 0.002 | TGFBR2, SMAD3 |
| Muscle contraction | 3 | 21.0× | 0.002 | ACTA2, MYH11, MYLK |
| MET activates PTK2 signaling | 2 | 69.2× | 0.002 | COL2A1, COL3A1 |
| Signaling by TGFBR3 | 2 | 67.0× | 0.002 | TGFBR2, SMAD3 |
| Elastic fibre formation | 2 | 61.1× | 0.003 | FBN1, LOX |
| Collagen chain trimerization | 2 | 47.2× | 0.004 | COL2A1, COL3A1 |
| Signaling by PDGF | 2 | 46.1× | 0.004 | COL2A1, COL3A1 |
| NCAM1 interactions | 2 | 45.1× | 0.004 | COL2A1, COL3A1 |
| Developmental Lineage of Pancreatic Ductal Cells | 2 | 41.5× | 0.005 | COL2A1, COL3A1 |
| Signaling by TGF-beta Receptor Complex | 2 | 36.4× | 0.006 | TGFBR2, SMAD3 |
| Collagen degradation | 2 | 31.9× | 0.007 | COL2A1, COL3A1 |
| Signaling by NOTCH | 2 | 31.9× | 0.007 | ACTA2, SMAD3 |
| Collagen biosynthesis and modifying enzymes | 2 | 31.0× | 0.007 | COL2A1, COL3A1 |
| TGFBR2 MSI Frameshift Mutants in Cancer | 1 | 519.1× | 0.007 | TGFBR2 |
| ECM proteoglycans | 2 | 27.3× | 0.008 | COL2A1, COL3A1 |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| elastic fiber assembly | 3 | 383.0× | 2e-05 | COL3A1, LOX, MYH11 |
| heart development | 5 | 32.8× | 4e-05 | TGFBR2, COL3A1, FBN1, LOX, PKD1 |
| aorta smooth muscle tissue morphogenesis | 2 | 702.2× | 3e-04 | COL3A1, MYLK |
| regulation of striated muscle tissue development | 2 | 468.1× | 6e-04 | LOX, SMAD3 |
| cellular response to transforming growth factor beta stimulus | 3 | 69.1× | 6e-04 | ACTA2, FBN1, SMAD3 |
| response to angiotensin | 2 | 312.1× | 8e-04 | COL3A1, SMAD3 |
| collagen fibril organization | 3 | 56.2× | 8e-04 | COL2A1, COL3A1, LOX |
| in utero embryonic development | 4 | 24.0× | 8e-04 | TGFBR2, COL3A1, SMAD3, PKD1 |
| transforming growth factor beta receptor signaling pathway | 3 | 39.8× | 0.002 | TGFBR2, COL3A1, SMAD3 |
| activin receptor signaling pathway | 2 | 147.8× | 0.002 | TGFBR2, SMAD3 |
| anatomical structure morphogenesis | 3 | 34.8× | 0.002 | FOXE3, SMAD3, PKD1 |
| smooth muscle contraction | 2 | 133.8× | 0.002 | MYH11, MYLK |
| regulation of transforming growth factor beta receptor signaling pathway | 2 | 133.8× | 0.002 | LOX, SMAD3 |
| cartilage condensation | 2 | 127.7× | 0.003 | COL2A1, PKD1 |
| SMAD protein signal transduction | 2 | 122.1× | 0.003 | TGFBR2, SMAD3 |
| embryonic cranial skeleton morphogenesis | 2 | 96.8× | 0.004 | TGFBR2, SMAD3 |
| tissue homeostasis | 2 | 93.6× | 0.004 | COL2A1, COL3A1 |
| digestive tract development | 2 | 87.8× | 0.004 | COL3A1, PKD1 |
| skin development | 2 | 73.9× | 0.006 | COL3A1, PKD1 |
| positive regulation of protein import into nucleus | 2 | 70.2× | 0.006 | SMAD3, PRKD1 |
| regulation of gene expression | 3 | 20.9× | 0.006 | TGFBR2, COL2A1, LOX |
| positive regulation of SMAD protein signal transduction | 2 | 63.8× | 0.007 | TGFBR2, SMAD3 |
| lens development in camera-type eye | 2 | 62.4× | 0.007 | TGFBR2, FOXE3 |
| positive regulation of tolerance induction to self antigen | 1 | 1404.3× | 0.007 | TGFBR2 |
| positive regulation of B cell tolerance induction | 1 | 1404.3× | 0.007 | TGFBR2 |
| tonic smooth muscle contraction | 1 | 1404.3× | 0.007 | MYLK |
| ascending aorta development | 1 | 1404.3× | 0.007 | LOX |
| descending aorta development | 1 | 1404.3× | 0.007 | LOX |
| negative regulation of lung blood pressure | 1 | 1404.3× | 0.007 | SMAD3 |
| positive regulation of hepatic stellate cell contraction | 1 | 1404.3× | 0.007 | ACTA2 |
Therapeutics
Drug target analysis
Approved (phase 4): 5 · Phase ≥3: 5 · Phased (≥1): 5 · Undrugged: 8
Druggability breadth: 8 of 13 evidence-associated genes (62%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).
Genes with an approved drug
The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.
| Symbol | Example approved molecule |
|---|---|
| TGFBR2 | PONATINIB |
| LOX | PYRITHIONE |
| SMAD3 | FLUORESCEIN |
| MYLK | PONATINIB |
| PRKD1 | INGENOL MEBUTATE |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| MYLK | 28 | 4 |
| PRKD1 | 26 | 4 |
| TGFBR2 | 22 | 4 |
| LOX | 4 | 4 |
| SMAD3 | 2 | 4 |
| ACTA2 | 0 | 0 |
| COL2A1 | 0 | 0 |
| COL3A1 | 0 | 0 |
| FBN1 | 0 | 0 |
| FOXE3 | 0 | 0 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| PONATINIB | 4 | MYLK, TGFBR2 |
| VEMURAFENIB | 4 | TGFBR2 |
| FEDRATINIB | 4 | MYLK, TGFBR2 |
| SORAFENIB | 4 | TGFBR2 |
| DABRAFENIB | 4 | TGFBR2 |
| TOVORAFENIB | 4 | MYLK, TGFBR2 |
| PAZOPANIB | 4 | TGFBR2 |
| DASATINIB | 4 | MYLK, TGFBR2 |
| PYRITHIONE | 4 | LOX |
| ZILEUTON | 4 | LOX |
| DISULFIRAM | 4 | LOX |
| FLUORESCEIN | 4 | SMAD3 |
| AFATINIB | 4 | MYLK |
| RUXOLITINIB | 4 | MYLK |
| NIFEDIPINE | 4 | MYLK |
| BOSUTINIB | 4 | MYLK |
| GILTERITINIB | 4 | MYLK |
| NINTEDANIB | 4 | MYLK, PRKD1 |
| SUNITINIB | 4 | MYLK, PRKD1 |
| QUIZARTINIB | 4 | MYLK |
| MIDOSTAURIN | 4 | MYLK, PRKD1 |
| INGENOL MEBUTATE | 4 | PRKD1 |
| TAMOXIFEN | 4 | PRKD1 |
| NERATINIB | 4 | PRKD1 |
| BRIGATINIB | 4 | PRKD1 |
| CRIZOTINIB | 4 | PRKD1 |
| GEFITINIB | 4 | PRKD1 |
| CANERTINIB | 3 | TGFBR2 |
| ALVOCIDIB | 3 | PRKD1, TGFBR2 |
| LESTAURTINIB | 3 | MYLK, PRKD1, TGFBR2 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 4.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| PRKD1 | 660 | Binding:650, Functional:10 |
| MYLK | 303 | Binding:303 |
| TGFBR2 | 188 | Binding:188 |
| PKD1 | 27 | Binding:27 |
| SMAD3 | 24 | Binding:18, Functional:6 |
| LOX | 15 | Binding:15 |
| COL2A1 | 2 | Binding:2 |
Cohort enzymes (BRENDA EC)
| Symbol | EC numbers | Names |
|---|---|---|
| TGFBR2 | 2.7.10.2 | non-specific protein-tyrosine kinase |
| LOX | 1.4.3.13 | protein-lysine 6-oxidase |
| MYLK | 2.7.11.18 | myosin-light-chain kinase |
| PRKD1 | 2.7.11.13 | protein kinase C |
Cohort genes with high screening signal
≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.
| Symbol | ChEMBL assays |
|---|---|
| TGFBR2 | 188 |
| MYLK | 303 |
| PRKD1 | 660 |
Pharmacogenomics
Cohort genes with a PharmGKB record: 12; with CPIC/DPWG dosing guidelines: 0.
No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).
Chemical tractability of cohort targets
30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.
| Compound | Max phase | Cohort target (bioactivity) |
|---|---|---|
| PONATINIB | 4 | MYLK, TGFBR2 |
| VEMURAFENIB | 4 | TGFBR2 |
| FEDRATINIB | 4 | MYLK, TGFBR2 |
| SORAFENIB | 4 | TGFBR2 |
| DABRAFENIB | 4 | TGFBR2 |
| TOVORAFENIB | 4 | MYLK, TGFBR2 |
| PAZOPANIB | 4 | TGFBR2 |
| DASATINIB | 4 | MYLK, TGFBR2 |
| PYRITHIONE | 4 | LOX |
| ZILEUTON | 4 | LOX |
| DISULFIRAM | 4 | LOX |
| FLUORESCEIN | 4 | SMAD3 |
| AFATINIB | 4 | MYLK |
| RUXOLITINIB | 4 | MYLK |
| NIFEDIPINE | 4 | MYLK |
| BOSUTINIB | 4 | MYLK |
| GILTERITINIB | 4 | MYLK |
| NINTEDANIB | 4 | MYLK, PRKD1 |
| SUNITINIB | 4 | MYLK, PRKD1 |
| QUIZARTINIB | 4 | MYLK |
| MIDOSTAURIN | 4 | MYLK, PRKD1 |
| INGENOL MEBUTATE | 4 | PRKD1 |
| TAMOXIFEN | 4 | PRKD1 |
| NERATINIB | 4 | PRKD1 |
| BRIGATINIB | 4 | PRKD1 |
| CRIZOTINIB | 4 | PRKD1 |
| GEFITINIB | 4 | PRKD1 |
| CANERTINIB | 3 | TGFBR2 |
| ALVOCIDIB | 3 | PRKD1, TGFBR2 |
| LESTAURTINIB | 3 | MYLK, PRKD1, TGFBR2 |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 5 | TGFBR2, LOX, SMAD3, MYLK, PRKD1 |
| B | Phased (≥1) drug, not yet approved | 0 | |
| C | Druggable family + PDB, no drug | 1 | PKD1 |
| D | Druggable family + AlphaFold only, no drug | 0 | |
| E | Difficult family or no structure, no drug | 7 | ACTA2, COL2A1, COL3A1, FBN1, FOXE3, LINC01389, MYH11 |
Undrugged target profiles
8 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| PKD1 | 27 | PRKD1 |
| ACTA2 | 0 | — |
| COL2A1 | 2 | — |
| COL3A1 | 0 | — |
| FBN1 | 0 | — |
| FOXE3 | 0 | — |
| LINC01389 | 0 | — |
| MYH11 | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 1.
Phase distribution (across all retrieved trials)
| Phase | Trials |
|---|---|
| Not specified | 1 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT02753023 | Not specified | UNKNOWN | Registry Of Acute meDical Emergencies in Brazil |