overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

Summary

overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes (MONDO:0100283) is a disease (an umbrella term covering 5 Mondo subtypes) caused by variants in AKT3, MTOR, PIK3CA, and 1 other genes, with 4 cohort genes. The dominant Reactome pathway is CD28 dependent PI3K/Akt signaling (4 cohort genes).

At a glance

• Causal genes: AKT3 (GenCC Definitive), MTOR (GenCC Definitive), PIK3CA (GenCC Definitive), PIK3R2 (GenCC Definitive)
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 4
• ClinVar variants: 50

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
Mondo ID	MONDO:0100283
GARD	0026123
Is cancer (heuristic)	no

Also known as: overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

Data availability: 50 ClinVar variants · 43 ClinGen variant curations · 6 GenCC gene-disease records.

Disease family

An umbrella term covering 5 Mondo subtypes.

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

Related subtypes (53): craniosynostosis-Dandy-Walker malformation-hydrocephalus syndrome, Aase-Smith syndrome, arachnoid cyst, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, Dandy-Walker malformation-postaxial polydactyly syndrome, cervical hypertrichosis-peripheral neuropathy syndrome, Joubert syndrome with oculorenal defect, NPHP3-related Meckel-like syndrome, orofaciodigital syndrome type 6, X-linked intellectual disability-cerebellar hypoplasia syndrome, syndromic X-linked intellectual disability Najm type, X-linked cerebral-cerebellar-coloboma syndrome syndrome, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, aprosencephaly cerebellar dysgenesis, Gomez-Lopez-Hernandez syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome, hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism, pontine tegmental cap dysplasia, ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome, cerebellar-facial-dental syndrome, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal recessive spinocerebellar ataxia 20, SLC39A8-CDG, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, TELO2-related intellectual disability-neurodevelopmental disorder, isolated cerebellar vermis hypoplasia, cerebral gigantism-jaw cysts syndrome, holoprosencephaly-caudal dysgenesis syndrome, Joubert syndrome with ocular defect, macrocephaly-short stature-paraplegia syndrome, glioependymal/ependymal cyst, isolated cerebellar vermis agenesis, isolated unilateral hemispheric cerebellar hypoplasia, isolated bilateral hemispheric cerebellar hypoplasia, Hoyeraal-Hreidarsson syndrome, neural tube defect, partial corpus callosum agenesis-cerebellar vermis hypoplasia with posterior fossa cysts syndrome, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, tubulinopathy-associated dysgyria, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, rhombencephalosynapsis, Lhermitte-Duclos disease, Ritscher-Schinzel syndrome, spinal muscular atrophy-Dandy-Walker malformation-cataracts syndrome, cystic malformation of the posterior fossa, pontocerebellar hypoplasia, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, hereditary cerebral malformation, isolated arhinencephaly

Subtypes (5): megalencephaly-capillary malformation-polymicrogyria syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, isolated focal cortical dysplasia, megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome, hemimegalencephaly

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

50 retrieved; paginated sample, class counts are floors:

16 pathogenic, 12 likely benign, 12 uncertain significance, 4 benign, 4 likely pathogenic, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
39816	NM_005465.7(AKT3):c.49G>A (p.Glu17Lys)	AKT3	Pathogenic	reviewed by expert panel
1296989	NM_004958.4(MTOR):c.5930C>G (p.Thr1977Arg)	MTOR	Pathogenic	reviewed by expert panel
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
156709	NM_004958.4(MTOR):c.7255G>A (p.Glu2419Lys)	MTOR	Pathogenic	criteria provided, multiple submitters, no conflicts
217823	NM_004958.4(MTOR):c.5395G>A (p.Glu1799Lys)	MTOR	Pathogenic	criteria provided, multiple submitters, no conflicts
374796	NM_004958.4(MTOR):c.4447T>C (p.Cys1483Arg)	MTOR	Pathogenic	reviewed by expert panel
376129	NM_004958.4(MTOR):c.6644C>A (p.Ser2215Tyr)	MTOR	Pathogenic	reviewed by expert panel
376130	NM_004958.4(MTOR):c.4379T>C (p.Leu1460Pro)	MTOR	Pathogenic	reviewed by expert panel
376453	NM_004958.4(MTOR):c.4448G>A (p.Cys1483Tyr)	MTOR	Pathogenic	reviewed by expert panel
417723	NM_004958.4(MTOR):c.7280T>C (p.Leu2427Pro)	MTOR	Pathogenic	reviewed by expert panel
1198826	NM_006218.4(PIK3CA):c.277C>T (p.Arg93Trp)	PIK3CA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13652	NM_006218.4(PIK3CA):c.3140A>G (p.His1047Arg)	PIK3CA	Pathogenic	reviewed by expert panel
31944	NM_006218.4(PIK3CA):c.1624G>A (p.Glu542Lys)	PIK3CA	Pathogenic	reviewed by expert panel
376476	NM_006218.4(PIK3CA):c.2176G>A (p.Glu726Lys)	PIK3CA	Pathogenic	reviewed by expert panel
39703	NM_006218.4(PIK3CA):c.2740G>A (p.Gly914Arg)	PIK3CA	Pathogenic	reviewed by expert panel
39808	NM_005027.4(PIK3R2):c.1117G>A (p.Gly373Arg)	PIK3R2	Pathogenic	reviewed by expert panel
1296993	NM_004958.4(MTOR):c.4468T>C (p.Trp1490Arg)	MTOR	Likely pathogenic	reviewed by expert panel
1296997	NM_004958.4(MTOR):c.5005G>T (p.Ala1669Ser)	MTOR	Likely pathogenic	reviewed by expert panel
376492	NM_006218.4(PIK3CA):c.113G>A (p.Arg38His)	PIK3CA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
995382	NM_006218.4(PIK3CA):c.325GAA[1] (p.Glu110del)	PIK3CA	Likely pathogenic	reviewed by expert panel
1112740	NM_004958.4(MTOR):c.2857G>A (p.Val953Met)	MTOR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1296991	NM_004958.4(MTOR):c.997C>T (p.Leu333=)	MTOR	Uncertain significance	reviewed by expert panel
1296994	NM_004958.4(MTOR):c.4375G>T (p.Ala1459Ser)	MTOR	Uncertain significance	reviewed by expert panel
1296995	NM_004958.4(MTOR):c.3004C>T (p.Arg1002Ter)	MTOR	Uncertain significance	reviewed by expert panel
1296996	NM_004958.4(MTOR):c.1249A>G (p.Met417Val)	MTOR	Uncertain significance	reviewed by expert panel
1505200	NM_004958.4(MTOR):c.1509G>C (p.Glu503Asp)	MTOR	Uncertain significance	criteria provided, multiple submitters, no conflicts
1699346	NM_004958.4(MTOR):c.5062C>T (p.Pro1688Ser)	MTOR	Uncertain significance	criteria provided, single submitter
659938	NM_004958.4(MTOR):c.4382T>C (p.Val1461Ala)	MTOR	Uncertain significance	reviewed by expert panel
664963	NM_004958.4(MTOR):c.5432G>T (p.Arg1811Leu)	MTOR	Uncertain significance	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 30 · Orphanet: 22 · 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
AKT3	Definitive	Autosomal dominant	overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes	8
MTOR	Definitive	Autosomal dominant	overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes	6
PIK3CA	Definitive	Autosomal dominant	overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes	9
PIK3R2	Definitive	Autosomal dominant	overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AKT3	Orphanet:83473	Megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome
AKT3	Orphanet:99802	Hemimegalencephaly
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
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
PIK3R2	Orphanet:83473	Megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AKT3	HGNC:393	ENSG00000117020	Q9Y243	RAC-gamma serine/threonine-protein kinase	gencc,clinvar
MTOR	HGNC:3942	ENSG00000198793	P42345	Serine/threonine-protein kinase mTOR	gencc,clinvar
PIK3CA	HGNC:8975	ENSG00000121879	P42336	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	gencc,clinvar
PIK3R2	HGNC:8980	ENSG00000105647	O00459	Phosphatidylinositol 3-kinase regulatory subunit beta	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AKT3	RAC-gamma serine/threonine-protein kinase	AKT3 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis.
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.
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.
PIK3R2	Phosphatidylinositol 3-kinase regulatory subunit beta	Regulatory subunit of phosphoinositide-3-kinase (PI3K), a kinase that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3).

Protein-family classification

Druggable: 4 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	4	27.7×	2e-06

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AKT3	Kinase	yes	2.7.11.1	Prot_kinase_dom, AGC-kinase_C, PH_domain
MTOR	Kinase	yes		PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
PIK3CA	Kinase	yes	2.7.1.137	PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom, PI3K_accessory_dom
PIK3R2	Kinase	yes	2.7.1.137	RhoGAP_dom, SH2, SH3_domain

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	2
cortical plate	2
embryo	1
cerebellar hemisphere	1
primordial germ cell in gonad	1
right hemisphere of cerebellum	1
adrenal tissue	1
tendon	1
ganglionic eminence	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AKT3	231	ubiquitous	marker	cortical plate, calcaneal tendon, embryo
MTOR	207	ubiquitous	marker	primordial germ cell in gonad, right hemisphere of cerebellum, cerebellar hemisphere
PIK3CA	284	ubiquitous	marker	calcaneal tendon, adrenal tissue, tendon
PIK3R2	138	ubiquitous	marker	cortical plate, ganglionic eminence, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MTOR	9,490
PIK3CA	5,157
AKT3	3,392
PIK3R2	2,751

Intra-cohort edges

A	B	Sources
AKT3	PIK3CA	string_interaction
AKT3	PIK3R2	string_interaction
PIK3CA	PIK3R2	biogrid_interaction, intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIK3CA	P42336	135
MTOR	P42345	70
PIK3R2	O00459	8
AKT3	Q9Y243	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 162. Enrichment computed across 4 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
CD28 dependent PI3K/Akt signaling	4	393.8×	5e-09	AKT3, MTOR, PIK3CA, PIK3R2
VEGFA-VEGFR2 Pathway	4	139.3×	2e-07	AKT3, MTOR, PIK3CA, PIK3R2
PIP3 activates AKT signaling	4	66.8×	3e-06	AKT3, MTOR, PIK3CA, PIK3R2
Extra-nuclear estrogen signaling	3	127.8×	3e-05	AKT3, PIK3CA, PIK3R2
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	3	120.6×	3e-05	MTOR, PIK3CA, PIK3R2
Signaling by LTK in cancer	2	815.7×	5e-05	PIK3CA, PIK3R2
PI3K/AKT activation	2	634.4×	8e-05	PIK3CA, PIK3R2
IRS-mediated signalling	2	519.1×	9e-05	PIK3CA, PIK3R2
Co-stimulation by ICOS	2	519.1×	9e-05	PIK3CA, PIK3R2
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	2	439.2×	1e-04	PIK3CA, PIK3R2
Signaling by PDGFRA extracellular domain mutants	2	439.2×	1e-04	PIK3CA, PIK3R2
Signaling by LTK	2	439.2×	1e-04	PIK3CA, PIK3R2
Tie2 Signaling	2	300.5×	2e-04	PIK3CA, PIK3R2
Role of LAT2/NTAL/LAB on calcium mobilization	2	300.5×	2e-04	PIK3CA, PIK3R2
Signaling by ALK	2	285.5×	2e-04	PIK3CA, PIK3R2
Regulation of TP53 Expression and Degradation	2	259.6×	2e-04	AKT3, MTOR
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	2	259.6×	2e-04	PIK3CA, PIK3R2
Regulation of signaling by CBL	2	248.3×	2e-04	PIK3CA, PIK3R2
Nephrin family interactions	2	237.9×	2e-04	PIK3CA, PIK3R2
Role of phospholipids in phagocytosis	2	228.4×	2e-04	PIK3CA, PIK3R2
Regulation of T cell activation by CD28 family	2	211.5×	2e-04	AKT3, MTOR
Constitutive Signaling by AKT1 E17K in Cancer	2	211.5×	2e-04	AKT3, MTOR
VEGFR2 mediated vascular permeability	2	203.9×	2e-04	AKT3, MTOR
Interleukin receptor SHC signaling	2	203.9×	2e-04	PIK3CA, PIK3R2
Downstream signal transduction	2	190.3×	2e-04	PIK3CA, PIK3R2
Co-stimulation by CD28	2	190.3×	2e-04	AKT3, MTOR
PI3K/AKT Signaling in Cancer	2	184.2×	2e-04	AKT3, MTOR
DAP12 signaling	2	184.2×	2e-04	PIK3CA, PIK3R2
FLT3 Signaling	2	173.0×	3e-04	AKT3, PIK3CA
Interleukin-3, Interleukin-5 and GM-CSF signaling	2	158.6×	3e-04	PIK3CA, PIK3R2

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
insulin receptor signaling pathway	3	166.3×	5e-05	AKT3, PIK3CA, PIK3R2
cellular response to insulin stimulus	3	127.7×	6e-05	MTOR, PIK3CA, PIK3R2
TORC2 signaling	2	766.0×	1e-04	MTOR, PIK3CA
anoikis	2	648.1×	1e-04	MTOR, PIK3CA
negative regulation of macroautophagy	2	561.7×	1e-04	MTOR, PIK3CA
positive regulation of lamellipodium assembly	2	300.9×	4e-04	MTOR, PIK3CA
positive regulation of TOR signaling	2	247.8×	5e-04	AKT3, PIK3CA
cardiac muscle contraction	2	200.6×	7e-04	MTOR, PIK3CA
phosphatidylinositol 3-kinase/protein kinase B signal transduction	2	105.3×	0.002	PIK3CA, PIK3R2
response to muscle inactivity	1	4213.0×	0.003	PIK3CA
positive regulation of SCF-dependent proteasomal ubiquitin-dependent catabolic process	1	4213.0×	0.003	MTOR
response to butyrate	1	4213.0×	0.003	PIK3CA
regulation of locomotor rhythm	1	2106.5×	0.005	MTOR
positive regulation of cytoplasmic translational initiation	1	2106.5×	0.005	MTOR
response to L-leucine	1	1404.3×	0.007	PIK3CA
cellular response to hydrostatic pressure	1	1404.3×	0.007	PIK3CA
T-helper 1 cell lineage commitment	1	1053.2×	0.007	MTOR
negative regulation of lysosome organization	1	1053.2×	0.007	MTOR
positive regulation of pentose-phosphate shunt	1	1053.2×	0.007	MTOR
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	2	39.2×	0.007	MTOR, PIK3CA
cellular response to methionine	1	842.6×	0.008	MTOR
positive regulation of wound healing, spreading of epidermal cells	1	842.6×	0.008	MTOR
positive regulation of artery morphogenesis	1	842.6×	0.008	AKT3
‘de novo’ pyrimidine nucleobase biosynthetic process	1	702.2×	0.008	MTOR
negative regulation of actin filament depolymerization	1	702.2×	0.008	PIK3CA
regulation of cellular respiration	1	702.2×	0.008	PIK3CA
voluntary musculoskeletal movement	1	702.2×	0.008	MTOR
regulation of lysosome organization	1	702.2×	0.008	MTOR
regulation of membrane permeability	1	601.9×	0.008	MTOR
regulation of actin filament organization	1	601.9×	0.008	PIK3CA

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 4 evidence-associated genes (100%) 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
AKT3	CAPIVASERTIB
MTOR	SALMETEROL XINAFOATE
PIK3CA	IDELALISIB
PIK3R2	IDELALISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MTOR	164	4
PIK3CA	67	4
AKT3	18	4
PIK3R2	6	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CAPIVASERTIB	4	AKT3
MIDOSTAURIN	4	AKT3, PIK3CA
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

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
AKT3	660	Binding:644, Functional:16
PIK3R2	27	Binding:27

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AKT3	2.7.11.1	non-specific serine/threonine protein kinase
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
PIK3R2	2.7.1.137	phosphatidylinositol 3-kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
AKT3	660
MTOR	1,375
PIK3CA	2,034

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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)
CAPIVASERTIB	4	AKT3
MIDOSTAURIN	4	AKT3, PIK3CA
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

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	AKT3, MTOR, PIK3CA, PIK3R2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.