Aortic aneurysm, familial thoracic 6

Summary

Aortic aneurysm, familial thoracic 6 (MONDO:0012730) is a disease caused by ACTA2 (GenCC Strong), with 10 cohort genes.

At a glance

• Causal gene: ACTA2 (GenCC Strong)
• Cohort genes: 10
• ClinVar variants: 465

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	aortic aneurysm, familial thoracic 6
Mondo ID	MONDO:0012730
MeSH	C567085
OMIM	611788
UMLS	C2673186
MedGen	435866
GARD	0015527
Is cancer (heuristic)	no

Also known as: AAT6 · ACTA2 familial thoracic aortic aneurysm and aortic dissection · aortic aneurysm, familial thoracic 6 · aortic aneurysm, familial thoracic type 6 · familial thoracic aortic aneurysm and aortic dissection caused by mutation in ACTA2

Data availability: 465 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › multisystemic smooth muscle dysfunction syndrome › aortic aneurysm, familial thoracic 6

Related subtypes (1): Moyamoya disease 5

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

465 retrieved; paginated sample, class counts are floors:

215 uncertain significance, 169 likely benign, 37 conflicting classifications of pathogenicity, 14 benign/likely benign, 11 pathogenic, 11 pathogenic/likely pathogenic, 6 likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
18276	NM_001613.4(ACTA2):c.445C>T (p.Arg149Cys)	ACTA2	Pathogenic	criteria provided, multiple submitters, no conflicts
18278	NM_001613.4(ACTA2):c.772C>T (p.Arg258Cys)	ACTA2	Pathogenic	criteria provided, multiple submitters, no conflicts
199665	NM_001613.4(ACTA2):c.115C>G (p.Arg39Gly)	ACTA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
199666	NM_001613.4(ACTA2):c.116G>A (p.Arg39His)	ACTA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
199670	NM_001613.4(ACTA2):c.353G>A (p.Arg118Gln)	ACTA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
199671	NM_001613.4(ACTA2):c.446G>T (p.Arg149Leu)	ACTA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2032218	NM_001613.4(ACTA2):c.369+1G>C	ACTA2	Pathogenic	criteria provided, single submitter
239036	NM_001613.4(ACTA2):c.138G>A (p.Met46Ile)	ACTA2	Pathogenic	criteria provided, single submitter
263819	NM_001613.4(ACTA2):c.592C>T (p.Arg198Cys)	ACTA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
263926	NM_001613.4(ACTA2):c.940C>T (p.Arg314Ter)	ACTA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
264311	NM_001613.4(ACTA2):c.593G>A (p.Arg198His)	ACTA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265026	NM_001613.4(ACTA2):c.535C>T (p.Arg179Cys)	ACTA2	Pathogenic	criteria provided, multiple submitters, no conflicts
29598	NM_001613.4(ACTA2):c.536G>A (p.Arg179His)	ACTA2	Pathogenic	criteria provided, multiple submitters, no conflicts
3720953	NM_001613.4(ACTA2):c.133G>T (p.Val45Leu)	ACTA2	Pathogenic	criteria provided, single submitter
4802635	NM_001613.4(ACTA2):c.133G>C (p.Val45Leu)	ACTA2	Pathogenic	criteria provided, single submitter
577891	NM_001613.4(ACTA2):c.941G>A (p.Arg314Gln)	ACTA2	Pathogenic	criteria provided, single submitter
65449	NM_001613.4(ACTA2):c.115C>T (p.Arg39Cys)	ACTA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
65450	NM_001613.4(ACTA2):c.145A>G (p.Met49Val)	ACTA2	Pathogenic	no assertion criteria provided
664017	NM_001613.4(ACTA2):c.138G>T (p.Met46Ile)	ACTA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18277	NM_001613.4(ACTA2):c.773G>A (p.Arg258His)	ACTA2-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2575106	NM_001613.4(ACTA2):c.655T>C (p.Cys219Arg)	ACTA2-AS1	Pathogenic	criteria provided, single submitter
44219	NM_001613.4(ACTA2):c.635G>A (p.Arg212Gln)	ACTA2-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1054067	NM_001613.4(ACTA2):c.55T>C (p.Cys19Arg)	ACTA2	Likely pathogenic	criteria provided, single submitter
1066384	NM_001613.4(ACTA2):c.115C>A (p.Arg39Ser)	ACTA2	Likely pathogenic	criteria provided, single submitter
1328396	NM_001613.4(ACTA2):c.340_343del (p.Pro114fs)	ACTA2	Likely pathogenic	no assertion criteria provided
1421069	NM_001613.4(ACTA2):c.136A>G (p.Met46Val)	ACTA2	Likely pathogenic	criteria provided, single submitter
519576	NM_001613.4(ACTA2):c.146T>C (p.Met49Thr)	ACTA2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
536915	NM_001613.4(ACTA2):c.46T>C (p.Ser16Pro)	ACTA2	Likely pathogenic	criteria provided, single submitter
1053987	NM_001613.4(ACTA2):c.352C>T (p.Arg118Trp)	ACTA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1057228	NM_001613.4(ACTA2):c.404A>G (p.Tyr135Cys)	ACTA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 31 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ACTA2	Strong	Autosomal dominant	aortic aneurysm, familial thoracic 6	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACTA2	Orphanet:2573	Moyamoya disease
ACTA2	Orphanet:404463	Multisystemic smooth muscle dysfunction syndrome
ACTA2	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
TGFBR1	Orphanet:284973	Marfan syndrome type 2
TGFBR1	Orphanet:60030	Loeys-Dietz syndrome
TGFBR1	Orphanet:65748	Multiple self-healing squamous epithelioma
TGFBR1	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
FAS	Orphanet:117	Behçet disease
FAS	Orphanet:3261	Autoimmune lymphoproliferative syndrome
FAS	Orphanet:3437	Vogt-Koyanagi-Harada disease
SLC2A10	Orphanet:3342	Arterial tortuosity syndrome
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
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
MYH11	Orphanet:229	Familial aortic dissection
MYH11	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
MYH11	Orphanet:98829	Acute myeloid leukemia with abnormal bone marrow eosinophils inv(16)(p13q22) or t(16;16)(p13;q22)
MYLK	Orphanet:2241	Megacystis-microcolon-intestinal hypoperistalsis syndrome
MYLK	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection

Cohort genes → proteins

10 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACTA2	HGNC:130	ENSG00000107796	P62736	Actin, aortic smooth muscle	gencc,clinvar
TGFBR1	HGNC:11772	ENSG00000106799	P36897	TGF-beta receptor type-1	clinvar
FAS	HGNC:11920	ENSG00000026103	P25445	Tumor necrosis factor receptor superfamily member 6	clinvar
SLC2A10	HGNC:13444	ENSG00000197496	O95528	Solute carrier family 2, facilitated glucose transporter member 10	clinvar
FASN	HGNC:3594	ENSG00000169710	P49327	Fatty acid synthase	clinvar
FBN1	HGNC:3603	ENSG00000166147	P35555	Fibrillin-1	clinvar
ACTA2-AS1	HGNC:45169	ENSG00000180139		ACTA2 antisense RNA 1	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

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
TGFBR1	TGF-beta receptor type-1	Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3.
FAS	Tumor necrosis factor receptor superfamily member 6	Receptor for TNFSF6/FASLG.
SLC2A10	Solute carrier family 2, facilitated glucose transporter member 10	Facilitative glucose transporter required for the development of the cardiovascular system.
FASN	Fatty acid synthase	Fatty acid synthetase is a multifunctional enzyme that catalyzes the de novo biosynthesis of long-chain saturated fatty acids starting from acetyl-CoA and malonyl-CoA in the presence of NADPH.
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.
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).

Protein-family classification

Druggable: 4 · Difficult: 1 · Unknown: 5 · Druggable fraction: 0.4

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	2	5.5×	0.241
Transporter	1	7.8×	0.303
Scaffold/PPI	1	1.7×	0.727
Enzyme (other)	1	1.2×	0.727
Other/Unknown	5	0.9×	0.756

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACTA2	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
TGFBR1	Kinase	yes	2.7.10.2	TGFB_receptor, Activin_recp, Prot_kinase_dom
FAS	Other/Unknown	no		Death_dom, TNFR/NGFR_Cys_rich_reg, Fas_rcpt
SLC2A10	Transporter	yes		Sugar/inositol_transpt, MFS_sugar_transport-like, Sugar_transporter_CS
FASN	Enzyme (other)	yes	2.3.1.39	Thioesterase, Ac_transferase_dom_sf, Ppantetheine_attach_site
FBN1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
ACTA2-AS1	Other/Unknown	no
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

Expression context

Cohort genes with no expression data: 0.

10 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)	10
unknown	0

Top tissues across cohort

Tissue	Cohort genes
saphenous vein	3
cauda epididymis	2
tibia	2
right coronary artery	2
blood vessel layer	1
visceral pleura	1
left ovary	1
rectum	1
right ovary	1
bronchial epithelial cell	1
epithelium of bronchus	1
endometrium epithelium	1
right hemisphere of cerebellum	1
skin of abdomen	1
decidua	1
skin of hip	1
synovial joint	1
popliteal artery	1
tibial artery	1
cartilage tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACTA2	289	ubiquitous	marker	cauda epididymis, blood vessel layer, saphenous vein
TGFBR1	269	ubiquitous	marker	saphenous vein, tibia, visceral pleura
FAS	280	ubiquitous	marker	rectum, left ovary, right ovary
SLC2A10	235	ubiquitous	marker	tibia, bronchial epithelial cell, epithelium of bronchus
FASN	273	ubiquitous	marker	right hemisphere of cerebellum, endometrium epithelium, skin of abdomen
FBN1	275	ubiquitous	marker	synovial joint, skin of hip, decidua
ACTA2-AS1	162		marker	right coronary artery, popliteal artery, tibial artery
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

Protein interactions among cohort

Intra-cohort edges: 8.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FASN	6,551
SMAD3	6,440
TGFBR1	4,828
MYH11	3,818
FBN1	3,640
FAS	3,314
MYLK	2,763
SLC2A10	2,046
ACTA2	774
ACTA2-AS1	0

Intra-cohort edges

A	B	Sources
FBN1	MYLK	string_interaction
FBN1	SLC2A10	string_interaction
FBN1	TGFBR1	string_interaction
MYH11	MYLK	string_interaction
MYH11	SLC2A10	string_interaction
MYLK	SLC2A10	string_interaction
SLC2A10	TGFBR1	string_interaction
SMAD3	TGFBR1	string_interaction

Structural data

PDB: 7 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TGFBR1	P36897	44
FASN	P49327	34
SMAD3	P84022	12
FBN1	P35555	11
MYLK	Q15746	8
FAS	P25445	7
MYH11	P35749	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACTA2	P62736	95.43
SLC2A10	O95528	74.78

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 104. Enrichment computed across 10 evidence-associated genes (9 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 9 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	507.6×	1e-04	TGFBR1, SMAD3
Loss of Function of SMAD2/3 in Cancer	2	423.0×	1e-04	TGFBR1, SMAD3
Signaling by TGF-beta Receptor Complex in Cancer	2	423.0×	1e-04	TGFBR1, SMAD3
SMAD2/3 Phosphorylation Motif Mutants in Cancer	2	423.0×	1e-04	TGFBR1, SMAD3
TGFBR1 KD Mutants in Cancer	2	423.0×	1e-04	TGFBR1, SMAD3
TGF-beta receptor signaling activates SMADs	3	108.8×	1e-04	TGFBR1, FBN1, SMAD3
Smooth Muscle Contraction	3	88.5×	1e-04	ACTA2, MYH11, MYLK
NOTCH4 Intracellular Domain Regulates Transcription	2	126.9×	0.001	ACTA2, SMAD3
RHO GTPases activate PAKs	2	120.8×	0.001	MYH11, MYLK
Developmental Lineage of Mammary Gland Myoepithelial Cells	2	120.8×	0.001	ACTA2, MYH11
Signaling by NOTCH4	2	110.3×	0.001	ACTA2, SMAD3
Muscle contraction	3	25.7×	0.001	ACTA2, MYH11, MYLK
Downregulation of TGF-beta receptor signaling	2	90.6×	0.002	TGFBR1, SMAD3
Signaling by TGFBR3	2	81.9×	0.002	TGFBR1, SMAD3
Defective SLC2A10 causes arterial tortuosity syndrome (ATS)	1	1268.9×	0.005	SLC2A10
Signaling by TGF-beta Receptor Complex	2	44.5×	0.005	TGFBR1, SMAD3
Signal Transduction	5	5.7×	0.005	ACTA2, TGFBR1, SMAD3, MYH11, MYLK
Signaling by NOTCH	2	39.0×	0.006	ACTA2, SMAD3
Loss of Function of SMAD4 in Cancer	1	423.0×	0.010	SMAD3
SMAD4 MH2 Domain Mutants in Cancer	1	423.0×	0.010	SMAD3
SMAD2/3 MH2 Domain Mutants in Cancer	1	423.0×	0.010	SMAD3
Loss of Function of TGFBR2 in Cancer	1	423.0×	0.010	TGFBR1
TGFBR2 Kinase Domain Mutants in Cancer	1	423.0×	0.010	TGFBR1
Deubiquitination	2	27.6×	0.010	TGFBR1, SMAD3
Signaling by TGFB family members	2	25.6×	0.011	TGFBR1, SMAD3
TGFBR1 LBD Mutants in Cancer	1	317.2×	0.013	TGFBR1
FasL/ CD95L signaling	1	253.8×	0.015	FAS
RUNX3 regulates BCL2L11 (BIM) transcription	1	253.8×	0.015	SMAD3
RUNX3 regulates CDKN1A transcription	1	181.3×	0.020	SMAD3
TGFBR3 regulates TGF-beta signaling	1	158.6×	0.022	TGFBR1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cellular response to transforming growth factor beta stimulus	4	122.8×	5e-06	ACTA2, TGFBR1, FBN1, SMAD3
trophoblast cell migration	2	535.0×	6e-04	TGFBR1, SMAD3
positive regulation of extracellular matrix assembly	2	416.1×	7e-04	TGFBR1, SMAD3
activin receptor signaling pathway	2	197.1×	0.002	TGFBR1, SMAD3
smooth muscle contraction	2	178.3×	0.002	MYH11, MYLK
positive regulation of gene expression	4	17.2×	0.002	ACTA2, TGFBR1, SLC2A10, SMAD3
embryonic cranial skeleton morphogenesis	2	129.1×	0.003	TGFBR1, SMAD3
positive regulation of apoptotic signaling pathway	2	129.1×	0.003	TGFBR1, FAS
positive regulation of SMAD protein signal transduction	2	85.1×	0.006	TGFBR1, SMAD3
tonic smooth muscle contraction	1	1872.4×	0.007	MYLK
negative regulation of connective tissue growth factor production	1	1872.4×	0.007	SLC2A10
extracellular structure organization	1	1872.4×	0.007	TGFBR1
negative regulation of lung blood pressure	1	1872.4×	0.007	SMAD3
positive regulation of hepatic stellate cell contraction	1	1872.4×	0.007	ACTA2
regulation of miRNA transcription	1	1872.4×	0.007	SMAD3
positive regulation of epithelial to mesenchymal transition	2	70.7×	0.007	TGFBR1, SMAD3
positive regulation of stress fiber assembly	2	69.3×	0.007	TGFBR1, SMAD3
extrinsic apoptotic signaling pathway	2	68.1×	0.007	FAS, SMAD3
positive regulation of cell migration	3	20.6×	0.007	TGFBR1, SMAD3, MYLK
wound healing	2	50.6×	0.008	TGFBR1, SMAD3
positive regulation of transforming growth factor beta3 production	1	936.2×	0.010	SMAD3
positive regulation of hepatic stellate cell migration	1	936.2×	0.010	ACTA2
negative regulation of proteoglycan biosynthetic process	1	936.2×	0.010	SLC2A10
epicardium morphogenesis	1	936.2×	0.010	TGFBR1
skeletal muscle myosin thick filament assembly	1	624.1×	0.011	MYH11
Fas signaling pathway	1	624.1×	0.011	FAS
post-embryonic eye morphogenesis	1	624.1×	0.011	FBN1
paraxial mesoderm morphogenesis	1	624.1×	0.011	SMAD3
angiogenesis involved in coronary vascular morphogenesis	1	624.1×	0.011	TGFBR1
juxtaglomerular apparatus development	1	624.1×	0.011	ACTA2

Therapeutics

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 4 · Phased (≥1): 4 · Undrugged: 6

Druggability breadth: 5 of 10 evidence-associated genes (50%) 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
TGFBR1	MOMELOTINIB
FASN	RABEPRAZOLE
SMAD3	FLUORESCEIN
MYLK	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TGFBR1	28	4
MYLK	28	4
FASN	8	4
SMAD3	2	4
ACTA2	0	0
FAS	0	0
SLC2A10	0	0
FBN1	0	0
ACTA2-AS1	0	0
MYH11	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	TGFBR1
DABRAFENIB	4	TGFBR1
NINTEDANIB	4	MYLK, TGFBR1
DASATINIB	4	MYLK, TGFBR1
CRIZOTINIB	4	TGFBR1
RABEPRAZOLE	4	FASN
PANTOPRAZOLE	4	FASN
OMEPRAZOLE	4	FASN
ORLISTAT	4	FASN
LANSOPRAZOLE	4	FASN
FLUORESCEIN	4	SMAD3
PONATINIB	4	MYLK
AFATINIB	4	MYLK
FEDRATINIB	4	MYLK
RUXOLITINIB	4	MYLK
NIFEDIPINE	4	MYLK
BOSUTINIB	4	MYLK
GILTERITINIB	4	MYLK
TOVORAFENIB	4	MYLK
SUNITINIB	4	MYLK
QUIZARTINIB	4	MYLK
MIDOSTAURIN	4	MYLK
SARACATINIB	3	TGFBR1
CANERTINIB	3	TGFBR1
TESEVATINIB	3	TGFBR1
CEDIRANIB	3	TGFBR1
LESTAURTINIB	3	MYLK, TGFBR1
EPIGALOCATECHIN GALLATE	3	FASN
FASUDIL	3	MYLK
DOVITINIB	3	MYLK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
TGFBR1	541	Binding:516, Functional:13, ADMET:12
MYLK	303	Binding:303
FASN	142	Binding:136, Functional:6
SMAD3	24	Binding:18, Functional:6
FAS	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TGFBR1	2.7.10.2, 2.7.11.30	non-specific protein-tyrosine kinase, receptor protein serine/threonine kinase
FASN	2.3.1.39, 2.3.1.85	[acyl-carrier-protein] S-malonyltransferase, fatty-acid synthase system
MYLK	2.7.11.18	myosin-light-chain kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TGFBR1	541
FASN	142
MYLK	303

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; 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)
MOMELOTINIB	4	TGFBR1
DABRAFENIB	4	TGFBR1
NINTEDANIB	4	MYLK, TGFBR1
DASATINIB	4	MYLK, TGFBR1
CRIZOTINIB	4	TGFBR1
RABEPRAZOLE	4	FASN
PANTOPRAZOLE	4	FASN
OMEPRAZOLE	4	FASN
ORLISTAT	4	FASN
LANSOPRAZOLE	4	FASN
FLUORESCEIN	4	SMAD3
PONATINIB	4	MYLK
AFATINIB	4	MYLK
FEDRATINIB	4	MYLK
RUXOLITINIB	4	MYLK
NIFEDIPINE	4	MYLK
BOSUTINIB	4	MYLK
GILTERITINIB	4	MYLK
TOVORAFENIB	4	MYLK
SUNITINIB	4	MYLK
QUIZARTINIB	4	MYLK
MIDOSTAURIN	4	MYLK
SARACATINIB	3	TGFBR1
CANERTINIB	3	TGFBR1
TESEVATINIB	3	TGFBR1
CEDIRANIB	3	TGFBR1
LESTAURTINIB	3	MYLK, TGFBR1
EPIGALOCATECHIN GALLATE	3	FASN
FASUDIL	3	MYLK
DOVITINIB	3	MYLK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	TGFBR1, FASN, SMAD3, MYLK
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	SLC2A10
E	Difficult family or no structure, no drug	5	ACTA2, FAS, FBN1, ACTA2-AS1, MYH11

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC2A10	0	MYLK
ACTA2	0	—
FAS	8	—
FBN1	0	—
ACTA2-AS1	0	—
MYH11	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.