Rubinstein-Taybi syndrome due to CREBBP mutations

Summary

Rubinstein-Taybi syndrome due to CREBBP mutations (MONDO:0008393) is a disease caused by CREBBP (GenCC Definitive), with 5 cohort genes.

At a glance

• Causal gene: CREBBP (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 721
• Phenotypes (HPO): 122

Clinical features

Signs & symptoms

Clinical features (HPO)

122 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000218	High palate	Very frequent (80-99%)
HP:0000273	Facial grimacing	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000369	Low-set ears	Very frequent (80-99%)
HP:0000494	Downslanted palpebral fissures	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0002553	Highly arched eyebrow	Very frequent (80-99%)
HP:0005322	Prominent nasal septum	Very frequent (80-99%)
HP:0006200	Widened distal phalanges	Very frequent (80-99%)
HP:0008897	Postnatal growth retardation	Very frequent (80-99%)
HP:0010055	Broad hallux	Very frequent (80-99%)
HP:0011304	Broad thumb	Very frequent (80-99%)
HP:0012758	Neurodevelopmental delay	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000077	Abnormality of the kidney	Frequent (30-79%)
HP:0000119	Abnormality of the genitourinary system	Frequent (30-79%)
HP:0000189	Narrow palate	Frequent (30-79%)
HP:0000444	Convex nasal ridge	Frequent (30-79%)
HP:0000478	Abnormality of the eye	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000712	Emotional lability	Frequent (30-79%)
HP:0000722	Compulsive behaviors	Frequent (30-79%)
HP:0000733	Abnormal repetitive mannerisms	Frequent (30-79%)
HP:0000756	Agoraphobia	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001513	Obesity	Frequent (30-79%)
HP:0001627	Abnormal heart morphology	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002870	Obstructive sleep apnea	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0007086	Social and occupational deterioration	Frequent (30-79%)
HP:0008752	Laryngeal cartilage malformation	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0009765	Low hanging columella	Frequent (30-79%)
HP:0009834	Abnormal proximal phalanx morphology of the hand	Frequent (30-79%)
HP:0009836	Broad distal phalanx of finger	Frequent (30-79%)
HP:0011087	Talon cusp	Frequent (30-79%)
HP:0012760	Reduced social responsiveness	Frequent (30-79%)
HP:0025269	Panic attack	Frequent (30-79%)
HP:0030680	Abnormal cardiovascular system morphology	Frequent (30-79%)
HP:0100710	Impulsivity	Frequent (30-79%)
HP:0100852	Abnormal fear/anxiety-related behavior	Frequent (30-79%)
HP:0410263	Brain imaging abnormality	Frequent (30-79%)
HP:0000010	Recurrent urinary tract infections	Occasional (5-29%)
HP:0000034	Hydrocele testis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Rubinstein-Taybi syndrome due to CREBBP mutations
Mondo ID	MONDO:0008393
OMIM	180849
Orphanet	353277
NCIT	C153290
UMLS	C4551859
MedGen	1639327
GARD	0017534
Is cancer (heuristic)	no

Also known as: broad thumbs and great toes, characteristic facies, and mental retardation · CREBBP Rubinstein-Taybi syndrome · RSTS · RSTS1 · Rubinstein-Taybi syndrome 1 · Rubinstein-Taybi syndrome caused by mutation in CREBBP · Rubinstein-Taybi syndrome due to CREBBP mutations · Rubinstein-Taybi syndrome type 1

Data availability: 721 ClinVar variants · 3 GenCC gene-disease records · 9 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › syndromic intellectual disability › Rubinstein-Taybi syndrome › Rubinstein-Taybi syndrome due to CREBBP mutations

Related subtypes (2): Rubinstein-Taybi syndrome due to EP300 haploinsufficiency, chromosome 16p13.3 deletion syndrome

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:

197 uncertain significance, 159 pathogenic, 84 conflicting classifications of pathogenicity, 84 likely pathogenic, 32 benign/likely benign, 25 likely benign, 16 pathogenic/likely pathogenic, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
545604	NM_004380.2(CREBBP):c.[4112T>A;4118C>A]		Pathogenic	criteria provided, single submitter
1029838	NM_004380.3(CREBBP):c.47_48delinsT (p.Lys16fs)	CREBBP	Pathogenic	criteria provided, single submitter
1071243	NM_004380.3(CREBBP):c.4679_4683del (p.Glu1560fs)	CREBBP	Pathogenic	criteria provided, multiple submitters, no conflicts
1076909	NM_004380.3(CREBBP):c.4944dup (p.Ile1649fs)	CREBBP	Pathogenic	criteria provided, multiple submitters, no conflicts
1098286	NM_004380.3(CREBBP):c.3369+1del	CREBBP	Pathogenic	criteria provided, multiple submitters, no conflicts
1172536	NM_004380.3(CREBBP):c.3699-1469_3836+1579del	CREBBP	Pathogenic	criteria provided, single submitter
1299666	NM_004380.3(CREBBP):c.1676+2_1676+5del	CREBBP	Pathogenic	no assertion criteria provided
1308633	NM_004380.3(CREBBP):c.6324C>G (p.Tyr2108Ter)	CREBBP	Pathogenic	criteria provided, multiple submitters, no conflicts
1321977	NM_004380.3(CREBBP):c.4133G>A (p.Arg1378Gln)	CREBBP	Pathogenic	criteria provided, multiple submitters, no conflicts
158334	NM_004380.3(CREBBP):c.1063C>T (p.Gln355Ter)	CREBBP	Pathogenic	criteria provided, multiple submitters, no conflicts
158335	NM_004380.3(CREBBP):c.1156C>T (p.Arg386Ter)	CREBBP	Pathogenic	criteria provided, single submitter
158337	NM_004380.3(CREBBP):c.1257G>A (p.Trp419Ter)	CREBBP	Pathogenic	criteria provided, single submitter
158338	NM_004380.3(CREBBP):c.1270C>T (p.Arg424Ter)	CREBBP	Pathogenic	criteria provided, multiple submitters, no conflicts
158339	NM_004380.3(CREBBP):c.1590del (p.Asn530fs)	CREBBP	Pathogenic	criteria provided, single submitter
158341	NM_004380.3(CREBBP):c.1821del (p.Lys607fs)	CREBBP	Pathogenic	criteria provided, single submitter
158344	NM_004380.3(CREBBP):c.2026del (p.Gln676fs)	CREBBP	Pathogenic	criteria provided, single submitter
158345	NM_004380.3(CREBBP):c.2122_2123del (p.Leu708fs)	CREBBP	Pathogenic	criteria provided, single submitter
158346	NM_004380.3(CREBBP):c.2535C>A (p.Cys845Ter)	CREBBP	Pathogenic	criteria provided, single submitter
158348	NM_004380.3(CREBBP):c.2606_2607del (p.Leu869fs)	CREBBP	Pathogenic	criteria provided, single submitter
158351	NM_004380.3(CREBBP):c.2791C>T (p.Gln931Ter)	CREBBP	Pathogenic	criteria provided, single submitter
158352	NM_004380.3(CREBBP):c.286C>T (p.Gln96Ter)	CREBBP	Pathogenic	criteria provided, single submitter
158353	NM_004380.3(CREBBP):c.299del (p.Gly100fs)	CREBBP	Pathogenic	criteria provided, single submitter
158354	NM_004380.3(CREBBP):c.316C>T (p.Gln106Ter)	CREBBP	Pathogenic	criteria provided, single submitter
158355	NM_004380.3(CREBBP):c.3310C>T (p.Gln1104Ter)	CREBBP	Pathogenic	criteria provided, single submitter
158356	NM_004380.3(CREBBP):c.3369+1G>T	CREBBP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158358	NM_004380.3(CREBBP):c.3613G>T (p.Glu1205Ter)	CREBBP	Pathogenic	criteria provided, single submitter
158359	NM_004380.3(CREBBP):c.3779+1G>A	CREBBP	Pathogenic	criteria provided, multiple submitters, no conflicts
158361	NM_004380.3(CREBBP):c.3836+1G>A	CREBBP	Pathogenic	criteria provided, multiple submitters, no conflicts
158364	NM_004380.3(CREBBP):c.3983-2A>G	CREBBP	Pathogenic	criteria provided, single submitter
158367	NM_004380.3(CREBBP):c.4045C>T (p.Gln1349Ter)	CREBBP	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 5 · 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
CREBBP	Definitive	Autosomal dominant	Rubinstein-Taybi syndrome due to CREBBP mutations	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CREBBP	Orphanet:353277	Rubinstein-Taybi syndrome due to CREBBP mutations
CREBBP	Orphanet:353281	Rubinstein-Taybi syndrome due to 16p13.3 microdeletion
CREBBP	Orphanet:370026	Acute myeloid leukemia with t(8;16)(p11;p13) translocation
CREBBP	Orphanet:592574	Menke-Hennekam syndrome
EP300	Orphanet:353284	Rubinstein-Taybi syndrome due to EP300 haploinsufficiency

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CREBBP	HGNC:2348	ENSG00000005339	Q92793	CREB-binding protein	gencc,clinvar
HSP90B2P	HGNC:12099	ENSG00000259706	Q58FF3	Putative endoplasmin-like protein	clinvar
TRAP1	HGNC:16264	ENSG00000126602	Q12931	Heat shock protein 75 kDa, mitochondrial	clinvar
ADCY9	HGNC:240	ENSG00000162104	O60503	Adenylate cyclase type 9	clinvar
EP300	HGNC:3373	ENSG00000100393	Q09472	Histone acetyltransferase p300	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CREBBP	CREB-binding protein	Acetylates histones, giving a specific tag for transcriptional activation.
HSP90B2P	Putative endoplasmin-like protein	Putative molecular chaperone.
TRAP1	Heat shock protein 75 kDa, mitochondrial	Chaperone that expresses an ATPase activity.
ADCY9	Adenylate cyclase type 9	Adenylyl cyclase that catalyzes the formation of the signaling molecule cAMP in response to activation of G protein-coupled receptors.
EP300	Histone acetyltransferase p300	Functions as a histone acetyltransferase and regulates transcription via chromatin remodeling.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 3 · Druggable fraction: 0.0

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	2	3.3×	0.229
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CREBBP	Transcription factor	no	2.3.1.48	Znf_TAZ, Znf_ZZ, Bromodomain
HSP90B2P	Other/Unknown	no		Hsp90_fam, Ribosomal_Su5_D2-typ_SF, HSP90_C
TRAP1	Other/Unknown	no		Hsp90_fam, HATPase_dom, Ribosomal_Su5_D2-typ_SF
ADCY9	Other/Unknown	no		A/G_cyclase, A/G_cyclase_CS, Nucleotide_cyclase
EP300	Transcription factor	no	2.3.1.48	Znf_TAZ, Znf_ZZ, Bromodomain

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	2
amniotic fluid	1
tibia	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
gastrocnemius	1
hindlimb stylopod muscle	1
right uterine tube	1
choroid plexus epithelium	1
secondary oocyte	1
vastus lateralis	1
adrenal tissue	1
bone marrow cell	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CREBBP	297	ubiquitous	marker	sural nerve, tibia, amniotic fluid
HSP90B2P	108	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, sural nerve
TRAP1	294	ubiquitous	marker	hindlimb stylopod muscle, right uterine tube, gastrocnemius
ADCY9	296	ubiquitous	marker	secondary oocyte, choroid plexus epithelium, vastus lateralis
EP300	292	ubiquitous	marker	colonic epithelium, adrenal tissue, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EP300	10,122
CREBBP	6,959
TRAP1	5,216
ADCY9	1,492
HSP90B2P	8

Intra-cohort edges

A	B	Sources
CREBBP	EP300	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CREBBP	Q92793	144
EP300	Q09472	60
TRAP1	Q12931	24
ADCY9	O60503	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HSP90B2P	Q58FF3	82.17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 187. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production	2	1142.0×	6e-05	CREBBP, EP300
NFE2L2 regulating inflammation associated genes	2	1142.0×	6e-05	CREBBP, EP300
NFE2L2 regulating ER-stress associated genes	2	1142.0×	6e-05	CREBBP, EP300
NFE2L2 regulates pentose phosphate pathway genes	2	713.8×	8e-05	CREBBP, EP300
NFE2L2 regulating MDR associated enzymes	2	713.8×	8e-05	CREBBP, EP300
Regulation of NFE2L2 gene expression	2	713.8×	8e-05	CREBBP, EP300
Regulation of FOXO transcriptional activity by acetylation	2	571.0×	1e-04	CREBBP, EP300
Regulation of gene expression by Hypoxia-inducible Factor	2	475.8×	1e-04	CREBBP, EP300
Activation of the TFAP2 (AP-2) family of transcription factors	2	475.8×	1e-04	CREBBP, EP300
NFE2L2 regulating tumorigenic genes	2	475.8×	1e-04	CREBBP, EP300
RUNX3 regulates NOTCH signaling	2	407.9×	1e-04	CREBBP, EP300
TRAF3-dependent IRF activation pathway	2	380.7×	1e-04	CREBBP, EP300
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	2	356.9×	1e-04	CREBBP, EP300
FOXO-mediated transcription of cell death genes	2	356.9×	1e-04	CREBBP, EP300
Zygotic genome activation (ZGA)	2	335.9×	2e-04	CREBBP, EP300
NOTCH4 Intracellular Domain Regulates Transcription	2	285.5×	2e-04	CREBBP, EP300
NFE2L2 regulating anti-oxidant/detoxification enzymes	2	271.9×	2e-04	CREBBP, EP300
CD209 (DC-SIGN) signaling	2	259.6×	2e-04	CREBBP, EP300
NOTCH3 Intracellular Domain Regulates Transcription	2	219.6×	3e-04	CREBBP, EP300
Attenuation phase	2	203.9×	3e-04	CREBBP, EP300
Formation of paraxial mesoderm	2	203.9×	3e-04	CREBBP, EP300
RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression	2	203.9×	3e-04	CREBBP, EP300
TRAF6 mediated IRF7 activation	2	190.3×	3e-04	CREBBP, EP300
Nuclear events mediated by NFE2L2	2	167.9×	4e-04	CREBBP, EP300
Evasion by RSV of host interferon responses	2	163.1×	4e-04	CREBBP, EP300
Expression of BMAL (ARNTL), CLOCK, and NPAS2	2	146.4×	5e-04	CREBBP, EP300
SUMOylation of transcription cofactors	2	121.5×	7e-04	CREBBP, EP300
NOTCH1 Intracellular Domain Regulates Transcription	2	119.0×	7e-04	CREBBP, EP300
Heme signaling	2	107.7×	8e-04	CREBBP, EP300
Constitutive Signaling by NOTCH1 PEST Domain Mutants	2	98.5×	9e-04	CREBBP, EP300

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
N-terminal peptidyl-lysine acetylation	2	2246.9×	2e-05	CREBBP, EP300
protein acetylation	2	561.7×	2e-04	CREBBP, EP300
regulation of cellular response to heat	2	421.3×	2e-04	CREBBP, EP300
stimulatory C-type lectin receptor signaling pathway	2	293.1×	4e-04	CREBBP, EP300
positive regulation of transforming growth factor beta receptor signaling pathway	2	210.7×	6e-04	CREBBP, EP300
cellular response to nutrient levels	2	187.2×	6e-04	CREBBP, EP300
canonical NF-kappaB signal transduction	2	146.5×	9e-04	CREBBP, EP300
cellular response to UV	2	118.3×	0.001	CREBBP, EP300
protein destabilization	2	116.2×	0.001	CREBBP, EP300
behavioral defense response	1	3370.4×	0.002	EP300
negative regulation of protein oligomerization	1	3370.4×	0.002	EP300
swimming	1	3370.4×	0.002	EP300
peptidyl-lysine propionylation	1	3370.4×	0.002	EP300
regulation of tubulin deacetylation	1	3370.4×	0.002	EP300
peptidyl-lysine crotonylation	1	3370.4×	0.002	EP300
peptidyl-lysine butyrylation	1	3370.4×	0.002	EP300
internal protein amino acid acetylation	1	1685.2×	0.003	EP300
translational attenuation	1	1685.2×	0.003	TRAP1
negative regulation of cellular respiration	1	1685.2×	0.003	TRAP1
protein folding	2	41.4×	0.004	HSP90B2P, TRAP1
response to hypoxia	2	38.3×	0.004	CREBBP, EP300
thigmotaxis	1	842.6×	0.004	EP300
negative regulation of chromosome condensation	1	842.6×	0.004	EP300
internal peptidyl-lysine acetylation	1	674.1×	0.005	EP300
negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide	1	674.1×	0.005	TRAP1
negative regulation of brown fat cell differentiation	1	561.7×	0.006	EP300
negative regulation of transcription by RNA polymerase I	1	481.5×	0.007	CREBBP
positive regulation of TORC2 signaling	1	421.3×	0.007	EP300
positive regulation of T-helper 17 cell lineage commitment	1	421.3×	0.007	EP300
homeostatic process	1	337.0×	0.009	CREBBP

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 3 · Phased (≥1): 3 · Undrugged: 2

Druggability breadth: 4 of 5 evidence-associated genes (80%) 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
CREBBP	COLCHICINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CREBBP	13	4
TRAP1	9	3
EP300	9	3
HSP90B2P	0	0
ADCY9	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COLCHICINE	4	CREBBP
ALTRETAMINE	4	CREBBP
CURCUMIN	3	CREBBP, EP300
PAPAVERINE	3	CREBBP
EPIGALOCATECHIN GALLATE	3	CREBBP, EP300
TANESPIMYCIN	3	TRAP1
GANETESPIB	3	TRAP1
COENZYME_A	3	EP300
MOLIBRESIB	2	CREBBP, EP300
FISETIN	2	CREBBP
ETAZOLATE	2	CREBBP
LUNRESERTIB	2	CREBBP
TRACAZOLATE	2	CREBBP
NOCODAZOLE	2	CREBBP
MITOQUINONE CATION	2	TRAP1
ADENOSINE TRIPHOSPHATE	2	TRAP1
PU-H71	2	TRAP1
LUMINESPIB	2	TRAP1
GELDANAMYCIN	2	TRAP1
BIIB021	2	TRAP1
MIVEBRESIB	2	EP300
STREPTONIGRIN	2	EP300
INOBRODIB	1	CREBBP, EP300
AZD-5153	1	CREBBP
CUDC-305	1	TRAP1
BERBERINE CHLORIDE	1	EP300
PLUMBAGIN	1	EP300

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
EP300	767	Binding:763, Functional:3, ADMET:1
CREBBP	687	Binding:644, Functional:43
TRAP1	94	Binding:94
ADCY9	18	Binding:16, Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CREBBP	2.3.1.48	histone acetyltransferase
EP300	2.3.1.48	histone acetyltransferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CREBBP	687
EP300	767

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

27 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)
COLCHICINE	4	CREBBP
ALTRETAMINE	4	CREBBP
CURCUMIN	3	CREBBP, EP300
PAPAVERINE	3	CREBBP
EPIGALOCATECHIN GALLATE	3	CREBBP, EP300
TANESPIMYCIN	3	TRAP1
GANETESPIB	3	TRAP1
COENZYME_A	3	EP300
MOLIBRESIB	2	CREBBP, EP300
FISETIN	2	CREBBP
ETAZOLATE	2	CREBBP
LUNRESERTIB	2	CREBBP
TRACAZOLATE	2	CREBBP
NOCODAZOLE	2	CREBBP
MITOQUINONE CATION	2	TRAP1
ADENOSINE TRIPHOSPHATE	2	TRAP1
PU-H71	2	TRAP1
LUMINESPIB	2	TRAP1
GELDANAMYCIN	2	TRAP1
BIIB021	2	TRAP1
MIVEBRESIB	2	EP300
STREPTONIGRIN	2	EP300
INOBRODIB	1	CREBBP, EP300
AZD-5153	1	CREBBP
CUDC-305	1	TRAP1
BERBERINE CHLORIDE	1	EP300
PLUMBAGIN	1	EP300

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CREBBP
B	Phased (≥1) drug, not yet approved	2	TRAP1, EP300
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	HSP90B2P, ADCY9

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HSP90B2P	0	—
ADCY9	18	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.