isolated focal cortical dysplasia type II

Summary

isolated focal cortical dysplasia type II (MONDO:0011818) is a disease with 8 cohort genes. The dominant Reactome pathway is Energy dependent regulation of mTOR by LKB1-AMPK (4 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 8
• ClinVar variants: 1,407

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	isolated focal cortical dysplasia type II
Mondo ID	MONDO:0011818
MeSH	C537067
OMIM	607341
Orphanet	268994
UMLS	C1846385
MedGen	339510
GARD	0010190
Is cancer (heuristic)	no

Also known as: CDT · cortical dysplasia of Taylor · cortical dysplasia, Taylor type · FCD type II · FCDT · FCORD2 · focal cortical dysplasia of Taylor · focal cortical dysplasia type 2 · focal cortical dysplasia type II · focal cortical dysplasia, type II, somatic · isolated focal cortical dysplasia type 2

Data availability: 1,407 ClinVar variants · 6 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › cerebral cortical dysplasia › isolated focal cortical dysplasia › isolated focal cortical dysplasia type II

Related subtypes (1): isolated focal cortical dysplasia type I

Subtypes (2): isolated focal cortical dysplasia type IIa, isolated focal cortical dysplasia type IIb

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:

293 uncertain significance, 152 conflicting classifications of pathogenicity, 64 benign/likely benign, 36 benign, 20 likely benign, 17 pathogenic, 13 likely pathogenic, 5 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
156702	NM_004958.4(MTOR):c.5930C>A (p.Thr1977Lys)	MTOR	Pathogenic	reviewed by expert panel
156703	NM_004958.4(MTOR):c.6644C>T (p.Ser2215Phe)	MTOR	Pathogenic	reviewed by expert panel
217823	NM_004958.4(MTOR):c.5395G>A (p.Glu1799Lys)	MTOR	Pathogenic	criteria provided, multiple submitters, no conflicts
2672094	NM_004958.4(MTOR):c.4376C>A (p.Ala1459Asp)	MTOR	Pathogenic	criteria provided, single submitter
376129	NM_004958.4(MTOR):c.6644C>A (p.Ser2215Tyr)	MTOR	Pathogenic	reviewed by expert panel
3238630	NM_005614.4(RHEB):c.104_105delinsTA (p.Tyr35Leu)	RHEB	Pathogenic	criteria provided, single submitter
3382611	NM_000368.5(TSC1):c.741G>A (p.Trp247Ter)	TSC1	Pathogenic	criteria provided, single submitter
12393	NM_000548.5(TSC2):c.5024C>T (p.Pro1675Leu)	TSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
12396	NM_000548.5(TSC2):c.1513C>T (p.Arg505Ter)	TSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
12397	NM_000548.5(TSC2):c.1832G>A (p.Arg611Gln)	TSC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12401	NM_000548.5(TSC2):c.4508A>C (p.Gln1503Pro)	TSC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12403	NM_000548.5(TSC2):c.2714G>A (p.Arg905Gln)	TSC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12404	NM_000548.5(TSC2):c.2713C>T (p.Arg905Trp)	TSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1686279	NM_000548.5(TSC2):c.3376del (p.Asp1126fs)	TSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
2500105	NM_000548.5(TSC2):c.4582G>T (p.Glu1528Ter)	TSC2	Pathogenic	criteria provided, single submitter
280185	NM_000548.5(TSC2):c.2640-2A>G	TSC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280337	NM_000548.5(TSC2):c.2105_2108del (p.Asp702fs)	TSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
3381867	NM_000548.5(TSC2):c.716_719del (p.Phe239fs)	TSC2	Pathogenic	criteria provided, single submitter
3382198	NM_000548.5(TSC2):c.4138_4195del (p.Gln1380fs)	TSC2	Pathogenic	criteria provided, single submitter
3382768	NM_000548.5(TSC2):c.3003del (p.Ser1002fs)	TSC2	Pathogenic	criteria provided, single submitter
3578789	NM_000548.5(TSC2):c.1832G>C (p.Arg611Pro)	TSC2	Pathogenic	criteria provided, single submitter
3724267	NM_000548.5(TSC2):c.3796_3797del (p.Leu1266fs)	TSC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685378	NM_004958.4(MTOR):c.4298T>C (p.Leu1433Ser)	MTOR	Likely pathogenic	criteria provided, single submitter
2447866	NM_000368.5(TSC1):c.35_69del (p.Ala12fs)	TSC1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679313	NM_000368.5(TSC1):c.107-1G>C	TSC1	Likely pathogenic	criteria provided, single submitter
2679322	NM_000368.5(TSC1):c.1264-2A>G	TSC1	Likely pathogenic	criteria provided, single submitter
3596506	NM_000368.5(TSC1):c.2022dup (p.Asp675fs)	TSC1	Likely pathogenic	criteria provided, single submitter
3596515	NM_000368.5(TSC1):c.301_302dup (p.Ser102fs)	TSC1	Likely pathogenic	criteria provided, single submitter
1473495	NM_000548.5(TSC2):c.5237A>C (p.His1746Pro)	TSC2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679331	NM_000548.5(TSC2):c.4146del (p.Ser1383fs)	TSC2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 19 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TSC1	Orphanet:210159	Adult hepatocellular carcinoma
TSC1	Orphanet:269008	Isolated focal cortical dysplasia type IIb
TSC1	Orphanet:538	Lymphangioleiomyomatosis
TSC1	Orphanet:805	Tuberous sclerosis complex
TSC2	Orphanet:210159	Adult hepatocellular carcinoma
TSC2	Orphanet:269001	Isolated focal cortical dysplasia type IIa
TSC2	Orphanet:269008	Isolated focal cortical dysplasia type IIb
TSC2	Orphanet:538	Lymphangioleiomyomatosis
TSC2	Orphanet:805	Tuberous sclerosis complex
TSC2	Orphanet:88924	Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis
MTOR	Orphanet:269001	Isolated focal cortical dysplasia type IIa
MTOR	Orphanet:269008	Isolated focal cortical dysplasia type IIb
MTOR	Orphanet:457485	Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome
MTOR	Orphanet:99802	Hemimegalencephaly
NTHL1	Orphanet:454840	NTHL1-related polyposis
PKD1	Orphanet:730	Autosomal dominant polycystic kidney disease
PKD1	Orphanet:88924	Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis
PRKD1	Orphanet:276145	Malignant epithelial tumor of salivary glands
PRKD1	Orphanet:708019	Congenital heart defect-ectodermal dysplasia- brachydactyly-telangiectasia syndrome

Cohort genes → proteins

8 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RHEB	HGNC:10011	ENSG00000106615	Q15382	GTP-binding protein Rheb	clinvar
TSC1	HGNC:12362	ENSG00000165699	Q92574	Hamartin	clinvar
TSC2	HGNC:12363	ENSG00000103197	P49815	Tuberin	clinvar
MIR1225	HGNC:33931	ENSG00000221656		microRNA 1225	clinvar
MTOR	HGNC:3942	ENSG00000198793	P42345	Serine/threonine-protein kinase mTOR	clinvar
NTHL1	HGNC:8028	ENSG00000065057	P78549	Endonuclease III-like protein 1	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)
RHEB	GTP-binding protein Rheb	Small GTPase that acts as an allosteric activator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular biomass generation…
TSC1	Hamartin	Non-catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolec…
TSC2	Tuberin	Catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule…
MTOR	Serine/threonine-protein kinase mTOR	Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals.
NTHL1	Endonuclease III-like protein 1	Bifunctional DNA N-glycosylase with associated apurinic/apyrimidinic (AP) lyase function that catalyzes the first step in base excision repair (BER), the primary repair pathway for the repair of oxidative DNA damage.
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: 0 · Unknown: 3 · Druggable fraction: 0.62

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	6.9×	0.126
Enzyme (other)	2	3.0×	0.278
Antibody/Immunoglobulin	1	3.6×	0.325
Other/Unknown	3	0.7×	0.919

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RHEB	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
TSC1	Other/Unknown	no		Hamartin
TSC2	Other/Unknown	no		Rap/Ran_GAP_dom, Tuberin, ARM-like
MIR1225	Other/Unknown	no
MTOR	Kinase	yes		PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
NTHL1	Enzyme (other)	yes	4.2.99.18	HhH_motif, HhH-GPD_domain, Endonuclease3_FeS-loop_motif
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.

7 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	3
right hemisphere of cerebellum	3
ventricular zone	2
cerebellar cortex	2
embryo	1
ganglionic eminence	1
gluteal muscle	1
lateral globus pallidus	1
substantia nigra pars compacta	1
Brodmann (1909) area 9	1
skeletal muscle tissue	1
sural nerve	1
primordial germ cell in gonad	1
apex of heart	1
mucosa of transverse colon	1
right lobe of liver	1
seminal vesicle	1
thoracic aorta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RHEB	218	ubiquitous	marker	ventricular zone, embryo, ganglionic eminence
TSC1	297	ubiquitous	marker	substantia nigra pars compacta, gluteal muscle, lateral globus pallidus
TSC2	282	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
MIR1225	77		yes	sural nerve, skeletal muscle tissue, Brodmann (1909) area 9
MTOR	207	ubiquitous	marker	primordial germ cell in gonad, right hemisphere of cerebellum, cerebellar hemisphere
NTHL1	211	ubiquitous	marker	right lobe of liver, apex of heart, mucosa of transverse colon
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: 9.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MTOR	9,490
TSC1	5,445
TSC2	4,135
RHEB	3,739
PRKD1	2,131
NTHL1	1,994
PKD1	1,370
MIR1225	0

Intra-cohort edges

A	B	Sources
MTOR	RHEB	biogrid_interaction, intact, string_interaction
MTOR	TSC1	string_interaction
MTOR	TSC2	string_interaction
PKD1	PRKD1	string_interaction
PKD1	TSC1	string_interaction
PKD1	TSC2	string_interaction
RHEB	TSC1	string_interaction
RHEB	TSC2	string_interaction
TSC1	TSC2	biogrid_interaction, intact, string_interaction

Structural data

PDB: 6 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MTOR	P42345	70
RHEB	Q15382	15
PKD1	P98161	13
TSC1	Q92574	5
TSC2	P49815	2
NTHL1	P78549	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PRKD1	Q15139	68.99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 54. Enrichment computed across 8 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Energy dependent regulation of mTOR by LKB1-AMPK	4	225.0×	6e-08	RHEB, TSC1, TSC2, MTOR
TP53 Regulates Metabolic Genes	4	74.2×	3e-06	RHEB, TSC1, TSC2, MTOR
Macroautophagy	4	65.9×	3e-06	RHEB, TSC1, TSC2, MTOR
Inhibition of TSC complex formation by AKT (PKB)	2	652.6×	4e-05	TSC1, TSC2
mTORC1-mediated signalling	2	135.9×	1e-03	RHEB, MTOR
Constitutive Signaling by AKT1 E17K in Cancer	2	120.8×	0.001	TSC2, MTOR
MTOR signalling	2	75.9×	0.002	RHEB, MTOR
TBC/RABGAPs	2	74.2×	0.002	TSC1, TSC2
Defective NTHL1 substrate processing	1	1631.4×	0.003	NTHL1
Defective NTHL1 substrate binding	1	1631.4×	0.003	NTHL1
Amino acids regulate mTORC1	2	57.2×	0.003	RHEB, MTOR
Regulation of PTEN gene transcription	2	51.0×	0.003	RHEB, MTOR
Displacement of DNA glycosylase by APEX1	1	148.3×	0.028	NTHL1
AKT phosphorylates targets in the cytosol	1	116.5×	0.033	TSC2
Dengue virus modulates apoptosis	1	102.0×	0.035	MTOR
VxPx cargo-targeting to cilium	1	74.2×	0.043	PKD1
Regulation of TP53 Expression and Degradation	1	74.2×	0.043	MTOR
Regulation of T cell activation by CD28 family	1	60.4×	0.044	MTOR
VEGFR2 mediated vascular permeability	1	58.3×	0.044	MTOR
Cellular response to heat stress	1	56.3×	0.044	MTOR
CD28 dependent PI3K/Akt signaling	1	56.3×	0.044	MTOR
Co-stimulation by CD28	1	54.4×	0.044	MTOR
PI3K/AKT Signaling in Cancer	1	52.6×	0.044	MTOR
HSF1-dependent transactivation	1	45.3×	0.049	MTOR
Response of endothelial cells to shear stress	1	42.9×	0.049	MTOR
Regulation of TP53 Degradation	1	41.8×	0.049	MTOR
Sphingolipid de novo biosynthesis	1	40.8×	0.049	PRKD1
Cellular responses to mechanical stimuli	1	37.1×	0.051	MTOR
PTEN Regulation	1	32.6×	0.056	MTOR
Signaling by VEGF	1	31.4×	0.057	MTOR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of cell cycle	4	42.6×	2e-04	RHEB, TSC1, TSC2, PKD1
negative regulation of cell size	2	481.5×	5e-04	TSC1, MTOR
cellular response to starvation	3	83.0×	5e-04	TSC1, TSC2, MTOR
anoikis	2	370.4×	6e-04	TSC2, MTOR
negative regulation of macroautophagy	2	321.0×	7e-04	TSC1, MTOR
positive regulation of oligodendrocyte differentiation	2	192.6×	0.002	RHEB, MTOR
negative regulation of TOR signaling	2	160.5×	0.002	TSC1, TSC2
cellular response to nutrient levels	2	133.8×	0.003	RHEB, MTOR
oligodendrocyte differentiation	2	120.4×	0.003	RHEB, MTOR
cell projection organization	2	107.0×	0.003	TSC1, MTOR
negative regulation of insulin receptor signaling pathway	2	107.0×	0.003	TSC2, MTOR
negative regulation of TORC1 signaling	2	92.6×	0.003	TSC1, TSC2
cellular response to amino acid starvation	2	90.8×	0.003	MTOR, PRKD1
regulation of macroautophagy	2	84.5×	0.004	RHEB, MTOR
positive regulation of SCF-dependent proteasomal ubiquitin-dependent catabolic process	1	2407.4×	0.006	MTOR
metanephric distal tubule morphogenesis	1	2407.4×	0.006	PKD1
neural tube closure	2	53.5×	0.007	TSC1, TSC2
regulation of skeletal muscle contraction by modulation of calcium ion sensitivity of myofibril	1	1203.7×	0.008	PRKD1
nitrogen cycle metabolic process	1	1203.7×	0.008	PKD1
mesonephric tubule development	1	1203.7×	0.008	PKD1
regulation of locomotor rhythm	1	1203.7×	0.008	MTOR
positive regulation of cytoplasmic translational initiation	1	1203.7×	0.008	MTOR
cell-matrix adhesion	2	46.8×	0.008	TSC1, PKD1
response to virus	2	41.1×	0.009	RHEB, MTOR
kidney development	2	40.1×	0.009	TSC1, PKD1
lymph vessel morphogenesis	1	802.5×	0.010	PKD1
memory T cell differentiation	1	802.5×	0.010	TSC1
metanephric proximal tubule development	1	802.5×	0.010	PKD1
T-helper 1 cell lineage commitment	1	601.9×	0.010	MTOR
calcium-independent cell-matrix adhesion	1	601.9×	0.010	PKD1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 6

Druggability breadth: 6 of 8 evidence-associated genes (75%) 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
MTOR	SALMETEROL XINAFOATE
PRKD1	INGENOL MEBUTATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MTOR	164	4
PRKD1	26	4
RHEB	0	0
TSC1	0	0
TSC2	0	0
MIR1225	0	0
NTHL1	0	0
PKD1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SALMETEROL XINAFOATE	4	MTOR
IMIPRAMINE	4	MTOR
AMOXAPINE	4	MTOR
IDARUBICIN	4	MTOR
TETRABENAZINE	4	MTOR
TEMSIROLIMUS	4	MTOR
MIFEPRISTONE	4	MTOR
ZIPRASIDONE HYDROCHLORIDE	4	MTOR
PIMOZIDE	4	MTOR
NAFTOPIDIL	4	MTOR
NICLOSAMIDE	4	MTOR
FELODIPINE	4	MTOR
NICARDIPINE	4	MTOR
AZACITIDINE	4	MTOR
TRIFLUPERIDOL	4	MTOR
CYCLOSPORINE	4	MTOR
CLEMASTINE	4	MTOR
TERFENADINE	4	MTOR
FLUOROURACIL	4	MTOR
PANCURONIUM	4	MTOR
EVEROLIMUS	4	MTOR
NIFEDIPINE	4	MTOR
PRAZOSIN	4	MTOR
MAPROTILINE	4	MTOR
DOMPERIDONE	4	MTOR
ALPELISIB	4	MTOR
TACROLIMUS ANHYDROUS	4	MTOR
EBASTINE	4	MTOR
MASOPROCOL	4	MTOR
COPANLISIB	4	MTOR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
MTOR	1,375	Binding:1335, Functional:37, ADMET:2, Toxicity:1
PRKD1	660	Binding:650, Functional:10
PKD1	27	Binding:27
NTHL1	8	Binding:7, Functional:1
RHEB	4	Binding:4
TSC2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RHEB	3.6.5.2	small monomeric GTPase
NTHL1	4.2.99.18	DNA-(apurinic or apyrimidinic site) lyase
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
MTOR	1,375
PRKD1	660

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; 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)
SALMETEROL XINAFOATE	4	MTOR
IMIPRAMINE	4	MTOR
AMOXAPINE	4	MTOR
IDARUBICIN	4	MTOR
TETRABENAZINE	4	MTOR
TEMSIROLIMUS	4	MTOR
MIFEPRISTONE	4	MTOR
ZIPRASIDONE HYDROCHLORIDE	4	MTOR
PIMOZIDE	4	MTOR
NAFTOPIDIL	4	MTOR
NICLOSAMIDE	4	MTOR
FELODIPINE	4	MTOR
NICARDIPINE	4	MTOR
AZACITIDINE	4	MTOR
TRIFLUPERIDOL	4	MTOR
CYCLOSPORINE	4	MTOR
CLEMASTINE	4	MTOR
TERFENADINE	4	MTOR
FLUOROURACIL	4	MTOR
PANCURONIUM	4	MTOR
EVEROLIMUS	4	MTOR
NIFEDIPINE	4	MTOR
PRAZOSIN	4	MTOR
MAPROTILINE	4	MTOR
DOMPERIDONE	4	MTOR
ALPELISIB	4	MTOR
TACROLIMUS ANHYDROUS	4	MTOR
EBASTINE	4	MTOR
MASOPROCOL	4	MTOR
COPANLISIB	4	MTOR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	MTOR, PRKD1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	3	RHEB, NTHL1, PKD1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	TSC1, TSC2, MIR1225

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)
RHEB	4	MTOR
TSC1	0	MTOR
TSC2	1	MTOR
PKD1	27	PRKD1
MIR1225	0	—
NTHL1	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.