Hemimegalencephaly

Summary

Hemimegalencephaly (MONDO:0020492) is a disease with 7 cohort genes and 2 clinical trials. The dominant Reactome pathway is mTORC1-mediated signalling (3 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 7
• ClinVar variants: 8
• Phenotypes (HPO): 33
• Clinical trials: 2

Clinical features

Signs & symptoms

Clinical features (HPO)

33 HPO clinical features (Orphanet curated; top 33 by frequency):

HPO ID	Term	Frequency
HP:0001250	Seizure	Very frequent (80-99%)
HP:0025373	Interictal EEG abnormality	Very frequent (80-99%)
HP:0030890	Hyperintensity of cerebral white matter on MRI	Very frequent (80-99%)
HP:0000267	Cranial asymmetry	Frequent (30-79%)
HP:0000929	Abnormal skull morphology	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002126	Polymicrogyria	Frequent (30-79%)
HP:0002392	EEG with polyspike wave complexes	Frequent (30-79%)
HP:0007206	Hemimegalencephaly	Frequent (30-79%)
HP:0010851	EEG with burst suppression	Frequent (30-79%)
HP:0011153	Focal motor seizure	Frequent (30-79%)
HP:0011193	EEG with focal spikes	Frequent (30-79%)
HP:0011195	EEG with focal sharp slow waves	Frequent (30-79%)
HP:0011215	Hemihypsarrhythmia	Frequent (30-79%)
HP:0032046	Focal cortical dysplasia	Frequent (30-79%)
HP:0000256	Macrocephaly	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0001269	Hemiparesis	Occasional (5-29%)
HP:0001302	Pachygyria	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0002133	Status epilepticus	Occasional (5-29%)
HP:0002171	Gliosis	Occasional (5-29%)
HP:0002282	Gray matter heterotopia	Occasional (5-29%)
HP:0004302	Functional motor deficit	Occasional (5-29%)
HP:0006824	Cranial nerve paralysis	Occasional (5-29%)
HP:0010819	Atonic seizure	Occasional (5-29%)
HP:0010864	Intellectual disability, severe	Occasional (5-29%)
HP:0011097	Epileptic spasm	Occasional (5-29%)
HP:0011167	Focal tonic seizure	Occasional (5-29%)
HP:0012246	Oculomotor nerve palsy	Occasional (5-29%)
HP:0012377	Hemianopia	Occasional (5-29%)
HP:0012757	Abnormal neuron morphology	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hemimegalencephaly
Mondo ID	MONDO:0020492
MeSH	D065705
Orphanet	99802
ICD-11	961229160
NCIT	C177779
SNOMED CT	253170008
UMLS	C0431391
MedGen	140910
GARD	0002637
NORD	1220
Is cancer (heuristic)	no

Also known as: macrencephaly · unilateral megalencephaly

Data availability: 8 ClinVar variants · 8 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system malformation › overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes › hemimegalencephaly

Related subtypes (4): megalencephaly-capillary malformation-polymicrogyria syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, isolated focal cortical dysplasia, megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus 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

8 retrieved; paginated sample, class counts are floors:

4 pathogenic, 2 uncertain significance, 1 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
375693	maternal UPD(16p)	ACSM2A	Pathogenic	no assertion criteria provided
374796	NM_004958.4(MTOR):c.4447T>C (p.Cys1483Arg)	MTOR	Pathogenic	reviewed by expert panel
1048543	NM_000314.8(PTEN):c.255_262delinsC (p.Ala86fs)	PTEN	Pathogenic	criteria provided, single submitter
1048544	NM_000314.8(PTEN):c.1110_1111dup (p.Asp371fs)	PTEN	Pathogenic	criteria provided, single submitter
545666	NM_005614.4(RHEB):c.119A>T (p.Glu40Val)	RHEB	Likely pathogenic	criteria provided, single submitter
374062	NM_006218.4(PIK3CA):c.1059+12T>A	PIK3CA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
523497	NM_007327.4(GRIN1):c.1198-19G>C	GRIN1	Uncertain significance	criteria provided, single submitter
631553	NM_001010.3(RPS6):c.695G>A (p.Arg232His)	RPS6	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 37 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
GRIN1	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
GRIN1	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
GRIN1	Orphanet:208447	Bilateral generalized polymicrogyria
GRIN1	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
PIK3CA	Orphanet:140944	CLOVES syndrome
PIK3CA	Orphanet:144	Lynch syndrome
PIK3CA	Orphanet:168984	CLAPO syndrome
PIK3CA	Orphanet:201	Cowden syndrome
PIK3CA	Orphanet:210159	Adult hepatocellular carcinoma
PIK3CA	Orphanet:221061	Familial cerebral cavernous malformation
PIK3CA	Orphanet:2495	Meningioma
PIK3CA	Orphanet:276280	Hemihyperplasia-multiple lipomatosis syndrome
PIK3CA	Orphanet:295239	Macrodactyly of fingers, unilateral
PIK3CA	Orphanet:295243	Macrodactyly of toes, unilateral
PIK3CA	Orphanet:314662	Segmental progressive overgrowth syndrome with fibroadipose hyperplasia
PIK3CA	Orphanet:60040	Megalencephaly-capillary malformation-polymicrogyria syndrome
PIK3CA	Orphanet:714737	Diffuse capillary malformation with overgrowth
PIK3CA	Orphanet:90308	Capillary-lymphatic-venous malformation with segmental distribution
PIK3CA	Orphanet:99802	Hemimegalencephaly
PTEN	Orphanet:109	Bannayan-Riley-Ruvalcaba syndrome
PTEN	Orphanet:137608	Segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome
PTEN	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
PTEN	Orphanet:201	Cowden syndrome
PTEN	Orphanet:210548	Macrocephaly-intellectual disability-autism syndrome
PTEN	Orphanet:2969	Proteus-like syndrome
PTEN	Orphanet:494547	Squamous cell carcinoma of the hypopharynx
PTEN	Orphanet:494550	Squamous cell carcinoma of the larynx
PTEN	Orphanet:500464	Squamous cell carcinoma of the nasal cavity and paranasal sinuses
PTEN	Orphanet:500478	Squamous cell carcinoma of the oropharynx
PTEN	Orphanet:502363	Squamous cell carcinoma of the oral cavity
PTEN	Orphanet:502366	Squamous cell carcinoma of the lip
PTEN	Orphanet:65285	Lhermitte-Duclos disease
PTEN	Orphanet:79076	Juvenile polyposis of infancy

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RHEB	HGNC:10011	ENSG00000106615	Q15382	GTP-binding protein Rheb	clinvar
RPS6	HGNC:10429	ENSG00000137154	P62753	Small ribosomal subunit protein eS6	clinvar
ACSM2A	HGNC:32017	ENSG00000183747	Q08AH3	Acyl-coenzyme A synthetase ACSM2A, mitochondrial	clinvar
MTOR	HGNC:3942	ENSG00000198793	P42345	Serine/threonine-protein kinase mTOR	clinvar
GRIN1	HGNC:4584	ENSG00000176884	Q05586	Glutamate receptor ionotropic, NMDA 1	clinvar
PIK3CA	HGNC:8975	ENSG00000121879	P42336	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	clinvar
PTEN	HGNC:9588	ENSG00000171862	P60484	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	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…
RPS6	Small ribosomal subunit protein eS6	Component of the 40S small ribosomal subunit.
ACSM2A	Acyl-coenzyme A synthetase ACSM2A, mitochondrial	Catalyzes the activation of fatty acids by CoA to produce an acyl-CoA, the first step in fatty acid metabolism.
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.
GRIN1	Glutamate receptor ionotropic, NMDA 1	Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+).
PIK3CA	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides.
PTEN	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	Dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins.

Protein-family classification

Druggable: 4 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.57

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	7.9×	0.097
Phosphatase	1	12.0×	0.161
Enzyme (other)	1	1.7×	0.609
Other/Unknown	3	0.8×	0.858

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
RPS6	Other/Unknown	no		Ribosomal_eS6, Ribosomal_eS6-like, Ribosomal_eS6_CS
ACSM2A	Other/Unknown	no		AMP-dep_synth/lig_dom, AMP-binding_CS, AMP-bd_C
MTOR	Kinase	yes		PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
GRIN1	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
PIK3CA	Kinase	yes	2.7.1.137	PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom, PI3K_accessory_dom
PTEN	Phosphatase	yes	3.1.3.16	Tyr_Pase_dom, Tyr_Pase_cat, Tensin_C2-dom

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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	2
right hemisphere of cerebellum	2
calcaneal tendon	2
embryo	1
ganglionic eminence	1
ventricular zone	1
mammary duct	1
skin of hip	1
upper leg skin	1
adult mammalian kidney	1
liver	1
right lobe of liver	1
primordial germ cell in gonad	1
right frontal lobe	1
adrenal tissue	1
tendon	1
endothelial cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RHEB	218	ubiquitous	marker	ventricular zone, embryo, ganglionic eminence
RPS6	311	ubiquitous	marker	skin of hip, upper leg skin, mammary duct
ACSM2A	128	tissue_specific	marker	right lobe of liver, liver, adult mammalian kidney
MTOR	207	ubiquitous	marker	primordial germ cell in gonad, right hemisphere of cerebellum, cerebellar hemisphere
GRIN1	215	tissue_specific	marker	right hemisphere of cerebellum, right frontal lobe, cerebellar hemisphere
PIK3CA	284	ubiquitous	marker	calcaneal tendon, adrenal tissue, tendon
PTEN	256	ubiquitous	marker	sperm, endothelial cell, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTEN	11,626
MTOR	9,490
PIK3CA	5,157
RHEB	3,739
RPS6	1,925
ACSM2A	1,657
GRIN1	118

Intra-cohort edges

A	B	Sources
MTOR	PTEN	string_interaction
MTOR	RHEB	biogrid_interaction, intact, string_interaction
PIK3CA	PTEN	string_interaction

Structural data

PDB: 7 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RPS6	P62753	218
PIK3CA	P42336	135
GRIN1	Q05586	85
MTOR	P42345	70
RHEB	Q15382	15
PTEN	P60484	12
ACSM2A	Q08AH3	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 173. Enrichment computed across 7 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
mTORC1-mediated signalling	3	203.9×	5e-05	RHEB, RPS6, MTOR
MTOR signalling	3	113.8×	1e-04	RHEB, RPS6, MTOR
Regulation of PTEN gene transcription	3	76.5×	3e-04	RHEB, MTOR, PTEN
TP53 Regulates Metabolic Genes	3	55.6×	7e-04	RHEB, MTOR, PTEN
Energy dependent regulation of mTOR by LKB1-AMPK	2	112.5×	0.004	RHEB, MTOR
CD28 dependent PI3K/Akt signaling	2	112.5×	0.004	MTOR, PIK3CA
Synthesis of PIPs at the plasma membrane	2	60.4×	0.011	PIK3CA, PTEN
Amino acids regulate mTORC1	2	57.2×	0.011	RHEB, MTOR
Cellular response to starvation	2	47.3×	0.014	RPS6, MTOR
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	2	46.0×	0.014	MTOR, PIK3CA
Signaling by ALK fusions and activated point mutants	2	42.9×	0.014	RPS6, PIK3CA
VEGFA-VEGFR2 Pathway	2	39.8×	0.015	MTOR, PIK3CA
PTEN Loss of Function in Cancer	1	815.7×	0.015	PTEN
Downstream TCR signaling	2	36.7×	0.015	PIK3CA, PTEN
Macroautophagy	2	33.0×	0.018	RHEB, MTOR
Amino Acid conjugation	1	326.3×	0.033	ACSM2A
MET activates PI3K/AKT signaling	1	271.9×	0.035	PIK3CA
Activated NTRK3 signals through PI3K	1	271.9×	0.035	PIK3CA
Activated NTRK2 signals through PI3K	1	233.1×	0.037	PIK3CA
Signaling by LTK in cancer	1	233.1×	0.037	PIK3CA
PIP3 activates AKT signaling	2	19.1×	0.037	MTOR, PIK3CA
Conjugation of salicylate with glycine	1	203.9×	0.038	ACSM2A
Conjugation of carboxylic acids	1	181.3×	0.038	ACSM2A
PI3K/AKT activation	1	181.3×	0.038	PIK3CA
Regulation of PTEN mRNA translation	1	163.1×	0.038	PTEN
IRS-mediated signalling	1	148.3×	0.038	PIK3CA
PI3K events in ERBB4 signaling	1	148.3×	0.038	PIK3CA
Regulation of PTEN localization	1	148.3×	0.038	PTEN
Co-stimulation by ICOS	1	148.3×	0.038	PIK3CA
RAF/MAP kinase cascade	2	17.4×	0.038	GRIN1, PIK3CA

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
negative regulation of cell size	2	481.5×	9e-04	MTOR, PTEN
TORC2 signaling	2	437.7×	9e-04	MTOR, PIK3CA
anoikis	2	370.4×	9e-04	MTOR, PIK3CA
negative regulation of macroautophagy	2	321.0×	9e-04	MTOR, PIK3CA
TOR signaling	2	218.9×	0.002	RPS6, MTOR
positive regulation of oligodendrocyte differentiation	2	192.6×	0.002	RHEB, MTOR
positive regulation of lamellipodium assembly	2	172.0×	0.002	MTOR, PIK3CA
positive regulation of ubiquitin-dependent protein catabolic process	2	160.5×	0.002	MTOR, PTEN
positive regulation of excitatory postsynaptic potential	2	150.5×	0.002	GRIN1, PTEN
positive regulation of TOR signaling	2	141.6×	0.002	RHEB, PIK3CA
cellular response to nutrient levels	2	133.8×	0.002	RHEB, MTOR
oligodendrocyte differentiation	2	120.4×	0.002	RHEB, MTOR
cardiac muscle contraction	2	114.6×	0.002	MTOR, PIK3CA
regulation of macroautophagy	2	84.5×	0.004	RHEB, MTOR
response to muscle inactivity	1	2407.4×	0.005	PIK3CA
propylene metabolic process	1	2407.4×	0.005	GRIN1
positive regulation of SCF-dependent proteasomal ubiquitin-dependent catabolic process	1	2407.4×	0.005	MTOR
response to butyrate	1	2407.4×	0.005	PIK3CA
response to glycine	1	2407.4×	0.005	GRIN1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	2	60.2×	0.005	PIK3CA, PTEN
cellular response to insulin stimulus	2	48.6×	0.007	MTOR, PIK3CA
regulation of locomotor rhythm	1	1203.7×	0.008	MTOR
positive regulation of cytoplasmic translational initiation	1	1203.7×	0.008	MTOR
negative regulation of synaptic vesicle clustering	1	1203.7×	0.008	PTEN
response to virus	2	41.1×	0.009	RHEB, MTOR
medium-chain fatty-acyl-CoA metabolic process	1	802.5×	0.009	ACSM2A
response to L-leucine	1	802.5×	0.009	PIK3CA
negative regulation of keratinocyte migration	1	802.5×	0.009	PTEN
cellular response to hydrostatic pressure	1	802.5×	0.009	PIK3CA
glucose homeostasis	2	37.3×	0.009	RPS6, ACSM2A

Therapeutics

Drug target analysis

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

Druggability breadth: 6 of 7 evidence-associated genes (86%) 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
RPS6	GENTAMICIN SULFATE
MTOR	SALMETEROL XINAFOATE
GRIN1	DEXTROMETHORPHAN
PIK3CA	IDELALISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MTOR	164	4
PIK3CA	67	4
GRIN1	39	4
RPS6	1	4
RHEB	0	0
ACSM2A	0	0
PTEN	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
GENTAMICIN SULFATE	4	RPS6
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, PIK3CA
TACROLIMUS ANHYDROUS	4	MTOR
EBASTINE	4	MTOR
MASOPROCOL	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
PIK3CA	2,034	Binding:2009, ADMET:19, Toxicity:4, Functional:2
MTOR	1,375	Binding:1335, Functional:37, ADMET:2, Toxicity:1
GRIN1	481	Binding:435, Functional:40, ADMET:5, Toxicity:1
RPS6	108	Binding:108
PTEN	8	Binding:8
RHEB	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RHEB	3.6.5.2	small monomeric GTPase
PIK3CA	2.7.1.137, 2.7.1.153, 2.7.11.1	phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
PTEN	3.1.3.16, 3.1.3.67	protein-serine/threonine phosphatase, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
RPS6	108
MTOR	1,375
GRIN1	481
PIK3CA	2,034

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; 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)
GENTAMICIN SULFATE	4	RPS6
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, PIK3CA
TACROLIMUS ANHYDROUS	4	MTOR
EBASTINE	4	MTOR
MASOPROCOL	4	MTOR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	RPS6, MTOR, GRIN1, PIK3CA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	RHEB, PTEN
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ACSM2A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RHEB	4	MTOR
ACSM2A	0	—
PTEN	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07287202	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety, Tolerability, and Pharmacokinetics of SVG103 (Paxalisib) in Focal Cortical Dysplasia Type II (FCD-II), Tuberous Sclerosis Complex (TSC) or Hemimegalencephaly (HME)
NCT04344626	Not specified	WITHDRAWN	Use of a Tonometer to Identify Epileptogenic Lesions During Pediatric Epilepsy Surgery