Aortic valve disease 1

Summary

Aortic valve disease 1 (MONDO:0024523) is a disease caused by NOTCH1 (GenCC Strong), with 14 cohort genes.

At a glance

• Causal gene: NOTCH1 (GenCC Strong)
• Cohort genes: 14
• ClinVar variants: 721

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	aortic valve disease 1
Mondo ID	MONDO:0024523
OMIM	109730
DOID	DOID:0080333
UMLS	C3887892
MedGen	854610
GARD	0018470
Is cancer (heuristic)	no

Also known as: aortic valve disease 1 · aortic valve disease caused by mutation in NOTCH1 · aortic valve disease caused by mutation in Notch1 · AOVD1 · NOTCH1 aortic valve disease · Notch1 aortic valve disease

Data availability: 721 ClinVar variants · 1 GenCC gene-disease record · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart valve disorder › aortic valve disorder › familial bicuspid aortic valve › aortic valve disease 1

Related subtypes (2): aortic valve disease 2, aortic valve disease 3

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

600 retrieved; paginated sample, class counts are floors:

177 conflicting classifications of pathogenicity, 172 benign/likely benign, 110 likely benign, 74 uncertain significance, 38 benign, 18 likely pathogenic, 10 pathogenic, 1 conflicting classifications of pathogenicity; other

ClinVar	Variant (HGVS)	Gene	Classification	Review
520784	NM_017617.5(NOTCH1):c.5950C>T (p.Arg1984Ter)	LOC126860794	Pathogenic	criteria provided, multiple submitters, no conflicts
12476	NM_017617.5(NOTCH1):c.3319C>T (p.Arg1107Ter)	NOTCH1	Pathogenic	criteria provided, multiple submitters, no conflicts
12477	NM_017617.5(NOTCH1):c.4512del (p.Cys1505fs)	NOTCH1	Pathogenic	criteria provided, single submitter
221997	NM_017617.5(NOTCH1):c.3765C>A (p.Cys1255Ter)	NOTCH1	Pathogenic	no assertion criteria provided
221998	NM_017617.5(NOTCH1):c.2439C>G (p.Tyr813Ter)	NOTCH1	Pathogenic	criteria provided, single submitter
3075683	NM_017617.5(NOTCH1):c.6919C>T (p.Gln2307Ter)	NOTCH1	Pathogenic	criteria provided, single submitter
3235929	NM_017617.5(NOTCH1):c.2278_2282del (p.Asn760fs)	NOTCH1	Pathogenic	criteria provided, single submitter
3376671	NM_017617.5(NOTCH1):c.5496_5505delinsGGT (p.Asp1833fs)	NOTCH1	Pathogenic	criteria provided, single submitter
374271	NM_017617.5(NOTCH1):c.6348C>G (p.Tyr2116Ter)	NOTCH1	Pathogenic	no assertion criteria provided
4293949	NM_017617.5(NOTCH1):c.873C>G (p.Tyr291Ter)	NOTCH1	Pathogenic	criteria provided, single submitter
1527975	NM_017617.5(NOTCH1):c.3171+1_5935-1del	LOC126860794	Likely pathogenic	criteria provided, single submitter
1684569	NM_017617.5(NOTCH1):c.1542C>A (p.Cys514Ter)	NOTCH1	Likely pathogenic	criteria provided, single submitter
216971	NM_017617.5(NOTCH1):c.2380del (p.Glu794fs)	NOTCH1	Likely pathogenic	criteria provided, single submitter
2571605	NM_017617.5(NOTCH1):c.2266G>T (p.Glu756Ter)	NOTCH1	Likely pathogenic	no assertion criteria provided
2575057	NM_017617.5(NOTCH1):c.7096C>T (p.Gln2366Ter)	NOTCH1	Likely pathogenic	no assertion criteria provided
2578511	NM_017617.5(NOTCH1):c.3282C>A (p.Cys1094Ter)	NOTCH1	Likely pathogenic	criteria provided, single submitter
2626882	NM_017617.5(NOTCH1):c.2112C>A (p.Cys704Ter)	NOTCH1	Likely pathogenic	criteria provided, single submitter
2690894	NM_017617.5(NOTCH1):c.5927T>A (p.Val1976Asp)	NOTCH1	Likely pathogenic	criteria provided, single submitter
3393222	NM_017617.5(NOTCH1):c.6403del (p.Leu2135fs)	NOTCH1	Likely pathogenic	criteria provided, single submitter
3602579	NM_017617.5(NOTCH1):c.5767C>T (p.Gln1923Ter)	NOTCH1	Likely pathogenic	criteria provided, single submitter
3775381	NM_017617.5(NOTCH1):c.3948C>A (p.Cys1316Ter)	NOTCH1	Likely pathogenic	criteria provided, single submitter
3775410	NM_017617.5(NOTCH1):c.599G>T (p.Gly200Val)	NOTCH1	Likely pathogenic	criteria provided, single submitter
4280019	NM_017617.5(NOTCH1):c.2364_2367dup (p.Thr790fs)	NOTCH1	Likely pathogenic	criteria provided, single submitter
4294437	NM_017617.5(NOTCH1):c.5509C>T (p.Gln1837Ter)	NOTCH1	Likely pathogenic	criteria provided, single submitter
4294443	NM_017617.5(NOTCH1):c.1446C>A (p.Tyr482Ter)	NOTCH1	Likely pathogenic	criteria provided, single submitter
4294459	NM_017617.5(NOTCH1):c.6951dup (p.Met2318fs)	NOTCH1	Likely pathogenic	criteria provided, single submitter
4294537	NM_017617.5(NOTCH1):c.4194C>G (p.Tyr1398Ter)	NOTCH1	Likely pathogenic	criteria provided, single submitter
4531264	NM_017617.5(NOTCH1):c.4972_4976delinsCCTCGC (p.Glu1658fs)	NOTCH1	Likely pathogenic	criteria provided, single submitter
180298	NM_000093.5(COL5A1):c.514G>T (p.Val172Phe)	COL5A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
263917	NM_017617.5(NOTCH1):c.6130G>A (p.Ala2044Thr)	LOC126860794	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 11 · 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
NOTCH1	Strong	Autosomal dominant	aortic valve disease 1	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NOTCH1	Orphanet:402075	Familial bicuspid aortic valve
NOTCH1	Orphanet:974	Adams-Oliver syndrome
TBX20	Orphanet:54260	Left ventricular noncompaction
TBX20	Orphanet:99103	Atrial septal defect, ostium secundum type
GATA5	Orphanet:3303	Tetralogy of Fallot
GATA5	Orphanet:334	Hereditary atrial fibrillation
GATA5	Orphanet:402075	Familial bicuspid aortic valve
COL5A1	Orphanet:287	Classical Ehlers-Danlos syndrome
ABCC6	Orphanet:51608	Generalized arterial calcification of infancy
ABCC6	Orphanet:758	Pseudoxanthoma elasticum
SMAD6	Orphanet:402075	Familial bicuspid aortic valve

Cohort genes → proteins

14 cohort genes, 13 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	14

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NOTCH1	HGNC:7881	ENSG00000148400	P46531	Neurogenic locus notch homolog protein 1	gencc,clinvar
TBX20	HGNC:11598	ENSG00000164532	Q9UMR3	T-box transcription factor TBX20	clinvar
LCTL	HGNC:15583	ENSG00000188501	Q6UWM7	Lactase-like protein	clinvar
GATA5	HGNC:15802	ENSG00000130700	Q9BWX5	Transcription factor GATA-5	clinvar
FBN3	HGNC:18794	ENSG00000142449	Q75N90	Fibrillin-3	clinvar
COL5A1	HGNC:2209	ENSG00000130635	P20908	Collagen alpha-1(V) chain	clinvar
DPY19L1	HGNC:22205	ENSG00000173852	Q2PZI1	Protein C-mannosyl-transferase DPY19L1	clinvar
DGCR6	HGNC:2846	ENSG00000183628	Q14129	Protein DGCR6	clinvar
ZNF626	HGNC:30461	ENSG00000188171	Q68DY1	Zinc finger protein 626	clinvar
MIR4673	HGNC:41574	ENSG00000263403		microRNA 4673	clinvar
GUK1	HGNC:4693	ENSG00000143774	Q16774	Guanylate kinase	clinvar
ABCC6	HGNC:57	ENSG00000091262	O95255	ATP-binding cassette sub-family C member 6	clinvar
KLF12	HGNC:6346	ENSG00000118922	Q9Y4X4	Krueppel-like factor 12	clinvar
SMAD6	HGNC:6772	ENSG00000137834	O43541	SMAD family member 6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NOTCH1	Neurogenic locus notch homolog protein 1	Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination.
TBX20	T-box transcription factor TBX20	Acts as a transcriptional activator and repressor required for cardiac development and may have key roles in the maintenance of functional and structural phenotypes in adult heart.
LCTL	Lactase-like protein	Plays a role in formation of the lens suture in the eye, which is important for normal optical properties of the lens.
GATA5	Transcription factor GATA-5	Transcription factor required during cardiovascular development.
FBN3	Fibrillin-3	Fibrillins are structural components of 10-12 nm extracellular calcium-binding microfibrils, which occur either in association with elastin or in elastin-free bundles.
COL5A1	Collagen alpha-1(V) chain	Type V collagen is a member of group I collagen (fibrillar forming collagen).
DPY19L1	Protein C-mannosyl-transferase DPY19L1	C-mannosyltransferase that mediates the C-mannosylation tryptophan residues on target proteins.
DGCR6	Protein DGCR6	May play a role in neural crest cell migration into the third and fourth pharyngeal pouches.
ZNF626	Zinc finger protein 626	May be involved in transcriptional regulation.
GUK1	Guanylate kinase	Catalyzes the phosphorylation of GMP to GDP.
ABCC6	ATP-binding cassette sub-family C member 6	ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds, and xenobiotics from cells.
KLF12	Krueppel-like factor 12	Confers strong transcriptional repression to the AP-2-alpha gene.
SMAD6	SMAD family member 6	Transforming growth factor-beta superfamily receptors signaling occurs through the Smad family of intracellular mediators.

Protein-family classification

Druggable: 2 · Difficult: 5 · Unknown: 7 · Druggable fraction: 0.14

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
Transcription factor	4	2.4×	0.397
Transporter	1	5.6×	0.414
Kinase	1	2.0×	0.670
Scaffold/PPI	1	1.2×	0.707
Other/Unknown	7	0.9×	0.761

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NOTCH1	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom
TBX20	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
LCTL	Other/Unknown	no		Glyco_hydro_1, GH_hydrolase_sf, Glyco_hydro_1_AS
GATA5	Transcription factor	no		Znf_GATA, GATA_N, Znf_NHR/GATA
FBN3	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
COL5A1	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
DPY19L1	Other/Unknown	no		Dpy-19/Dpy-19-like, Dpy19L1
DGCR6	Other/Unknown	no		Gonadal
ZNF626	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
MIR4673	Other/Unknown	no
GUK1	Kinase	yes	2.7.4.8	Guanylate_kin-like_dom, GK/Ca_channel_bsu, Guanylate_kinase
ABCC6	Transporter	yes	7.6.2.3	ABC_transporter-like_ATP-bd, AAA+_ATPase, MRP
KLF12	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
SMAD6	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf

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)	14
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	2
sural nerve	2
ganglionic eminence	2
stromal cell of endometrium	2
skeletal muscle tissue	2
colonic epithelium	1
ventricular zone	1
visceral pleura	1
cardiac atrium	1
heart	1
right atrium auricular region	1
tibial nerve	1
ileal mucosa	1
jejunal mucosa	1
left uterine tube	1
cortical plate	1
embryo	1
periodontal ligament	1
tendon of biceps brachii	1
pons	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NOTCH1	272	ubiquitous	marker	ventricular zone, colonic epithelium, visceral pleura
TBX20	52	broad	marker	right atrium auricular region, cardiac atrium, heart
LCTL	123	broad	yes	sural nerve, tibial nerve, buccal mucosa cell
GATA5	106	broad	yes	ileal mucosa, left uterine tube, jejunal mucosa
FBN3	131	tissue_specific	marker	cortical plate, embryo, ganglionic eminence
COL5A1	248	ubiquitous	marker	stromal cell of endometrium, periodontal ligament, tendon of biceps brachii
DPY19L1	286	ubiquitous	marker	ganglionic eminence, pons, stromal cell of endometrium
DGCR6	134	ubiquitous	marker	skeletal muscle tissue, hindlimb stylopod muscle, gastrocnemius
ZNF626	227	ubiquitous	marker	buccal mucosa cell, calcaneal tendon, tendon
MIR4673	64		yes	sural nerve, skeletal muscle tissue, muscle of leg
GUK1	300	ubiquitous	marker	right frontal lobe, prefrontal cortex, amygdala
ABCC6	136		marker	right lobe of liver, liver, duodenum
KLF12	267	ubiquitous	marker	corpus epididymis, superficial temporal artery, pigmented layer of retina
SMAD6	277	ubiquitous	marker	right lung, renal glomerulus, metanephric glomerulus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOTCH1	7,411
GUK1	3,686
COL5A1	2,600
GATA5	2,434
SMAD6	2,006
FBN3	1,607
TBX20	1,425
KLF12	1,346
DPY19L1	862
LCTL	700

Intra-cohort edges

A	B	Sources
GATA5	TBX20	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 9 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NOTCH1	P46531	29
GUK1	Q16774	14
ABCC6	O95255	4
COL5A1	P20908	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LCTL	Q6UWM7	92.71
DPY19L1	Q2PZI1	88.51
DGCR6	Q14129	86.83
SMAD6	O43541	72.34
ZNF626	Q68DY1	71.50
TBX20	Q9UMR3	67.87
GATA5	Q9BWX5	59.91
KLF12	Q9Y4X4	51.57
FBN3	Q75N90

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 62. Enrichment computed across 14 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
Defective ABCC6 causes PXE	1	1268.9×	0.049	ABCC6
Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling	1	253.8×	0.057	NOTCH1
Defective LFNG causes SCDO3	1	253.8×	0.057	NOTCH1
Pre-NOTCH Processing in the Endoplasmic Reticulum	1	211.5×	0.057	NOTCH1
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	181.3×	0.057	NOTCH1
Regulation of NFE2L2 gene expression	1	158.6×	0.057	NOTCH1
NFE2L2 regulating tumorigenic genes	1	105.7×	0.057	NOTCH1
RUNX2 regulates bone development	1	90.6×	0.057	SMAD6
RUNX3 regulates NOTCH signaling	1	90.6×	0.057	NOTCH1
Constitutive Signaling by NOTCH1 HD Domain Mutants	1	84.6×	0.057	NOTCH1
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	1	79.3×	0.057	NOTCH1
Pre-NOTCH Processing in Golgi	1	70.5×	0.057	NOTCH1
MECP2 regulates neuronal receptors and channels	1	66.8×	0.057	NOTCH1
Fibronectin matrix formation	1	63.4×	0.057	COL5A1
NOTCH4 Intracellular Domain Regulates Transcription	1	63.4×	0.057	NOTCH1
Attachment of bacteria to epithelial cells	1	55.2×	0.057	COL5A1
Azathioprine ADME	1	55.2×	0.057	GUK1
ABC transporter disorders	1	48.8×	0.057	ABCC6
NOTCH3 Intracellular Domain Regulates Transcription	1	48.8×	0.057	NOTCH1
Syndecan interactions	1	47.0×	0.057	COL5A1
Cardiogenesis	1	47.0×	0.057	TBX20
Notch-HLH transcription pathway	1	45.3×	0.057	NOTCH1
Formation of paraxial mesoderm	1	45.3×	0.057	NOTCH1
MET activates PTK2 signaling	1	42.3×	0.057	COL5A1
Signaling by BMP	1	39.6×	0.057	SMAD6
Activated NOTCH1 Transmits Signal to the Nucleus	1	39.6×	0.057	NOTCH1
Interconversion of nucleotide di- and triphosphates	1	39.6×	0.057	GUK1
Elastic fibre formation	1	37.3×	0.058	FBN3
Nuclear events stimulated by ALK signaling in cancer	1	36.2×	0.058	NOTCH1
Molecules associated with elastic fibres	1	34.3×	0.059	FBN3

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
aortic valve morphogenesis	4	144.0×	3e-06	NOTCH1, TBX20, GATA5, SMAD6
cardiac chamber formation	2	936.2×	2e-04	NOTCH1, TBX20
mesenchymal cell development	2	401.2×	8e-04	NOTCH1, TBX20
pericardium morphogenesis	2	351.1×	8e-04	NOTCH1, TBX20
cardiac muscle tissue morphogenesis	2	234.1×	0.002	NOTCH1, TBX20
negative regulation of cardiac muscle hypertrophy	2	187.2×	0.002	NOTCH1, GATA5
pulmonary valve morphogenesis	2	156.0×	0.003	NOTCH1, SMAD6
endocardial cushion morphogenesis	2	140.4×	0.003	NOTCH1, TBX20
outflow tract septum morphogenesis	2	108.0×	0.004	TBX20, SMAD6
negative regulation of ossification	2	104.0×	0.004	NOTCH1, SMAD6
positive regulation of cardiac muscle cell proliferation	2	104.0×	0.004	NOTCH1, TBX20
negative regulation of SMAD protein signal transduction	2	100.3×	0.004	TBX20, SMAD6
positive regulation of BMP signaling pathway	2	75.9×	0.006	NOTCH1, TBX20
tricuspid valve development	1	1404.3×	0.007	TBX20
coronary sinus valve morphogenesis	1	1404.3×	0.007	NOTCH1
Notch signaling pathway involved in regulation of secondary heart field cardioblast proliferation	1	1404.3×	0.007	NOTCH1
dGDP biosynthetic process	1	1404.3×	0.007	GUK1
foregut morphogenesis	1	1404.3×	0.007	NOTCH1
embryonic heart tube elongation	1	1404.3×	0.007	TBX20
integrin biosynthetic process	1	1404.3×	0.007	COL5A1
dATP metabolic process	1	1404.3×	0.007	GUK1
GDP biosynthetic process	1	1404.3×	0.007	GUK1
lateral mesoderm formation	1	1404.3×	0.007	TBX20
regulation of epithelial cell proliferation involved in prostate gland development	1	1404.3×	0.007	NOTCH1
venous endothelial cell differentiation	1	1404.3×	0.007	NOTCH1
positive regulation of cardiac endothelial to mesenchymal transition	1	1404.3×	0.007	GATA5
positive regulation of Notch signaling pathway	2	58.5×	0.007	NOTCH1, GATA5
negative regulation of osteoblast differentiation	2	49.3×	0.007	NOTCH1, SMAD6
negative regulation of BMP signaling pathway	2	48.4×	0.007	NOTCH1, SMAD6
heart looping	2	44.6×	0.008	NOTCH1, TBX20

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 13

Druggability breadth: 4 of 14 evidence-associated genes (29%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NOTCH1	1	2
TBX20	0	0
LCTL	0	0
GATA5	0	0
FBN3	0	0
COL5A1	0	0
DPY19L1	0	0
DGCR6	0	0
ZNF626	0	0
MIR4673	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VAREGACESTAT	2	NOTCH1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
NOTCH1	23	Binding:19, ADMET:4
ABCC6	10	Functional:9, Binding:1
GUK1	6	Binding:6

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GUK1	2.7.4.8	guanylate kinase
ABCC6	7.6.2.3	ABC-type glutathione-S-conjugate transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 13; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 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)
VAREGACESTAT	2	NOTCH1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	NOTCH1
C	Druggable family + PDB, no drug	2	GUK1, ABCC6
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	11	TBX20, LCTL, GATA5, FBN3, COL5A1, DPY19L1, DGCR6, ZNF626, MIR4673, KLF12 (+1 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TBX20	0	—
LCTL	0	—
GATA5	0	—
FBN3	0	—
COL5A1	0	—
DPY19L1	0	—
DGCR6	0	—
ZNF626	0	—
MIR4673	0	—
GUK1	6	—
ABCC6	10	—
KLF12	0	—
SMAD6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.