Overgrowth syndrome

Summary

Overgrowth syndrome (MONDO:0019716) is a disease (an umbrella term covering 31 Mondo subtypes) with 4 cohort genes and 2 clinical trials. The dominant Reactome pathway is CD28 dependent PI3K/Akt signaling (3 cohort genes).

At a glance

• Umbrella term: 31 Mondo subtypes
• Cohort genes: 4
• ClinVar variants: 5
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	overgrowth syndrome
Mondo ID	MONDO:0019716
Orphanet	93460
ICD-11	2113355045
NCIT	C94828
UMLS	C2986703
MedGen	458929
GARD	0019213
Is cancer (heuristic)	no

Data availability: 5 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 31 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › overgrowth syndrome

Related subtypes (189): precocious puberty, complex cortical dysplasia with other brain malformations, imperforate anus, microcephaly, demyelinating disease, hypospadias, bone development disease, primary basilar invagination, familial bicuspid aortic valve, camptodactyly of fingers, isolated congenital digital clubbing, aorta coarctation, gingival fibromatosis-progressive deafness syndrome, Eng-Strom syndrome, Morgagni-Stewart-Morel syndrome, familial partial lipodystrophy, Dunnigan type, megalodactyly, odontomatosis-aortae esophagus stenosis syndrome, otodental syndrome, oculodental syndrome, Rutherfurd type, spina bifida, steatocystoma multiplex-natal teeth syndrome, distal symphalangism, thumb deformity-alopecia-pigmentation anomaly syndrome, double uterus-hemivagina-renal agenesis syndrome, amelogenesis imperfecta type 1G, Bloom syndrome, cardiac valvular defect, developmental, isolated cerebellar hypoplasia/agenesis, cleft palate-stapes fixation-oligodontia syndrome, Jalili syndrome, craniodiaphyseal dysplasia, craniofacial dyssynostosis, deafness-oligodontia syndrome, duodenal atresia, Fowler syndrome, multiple intestinal atresia, natal teeth-intestinal pseudoobstruction-patent ductus syndrome, atresia of small intestine, mulibrey nanism, oculocerebral hypopigmentation syndrome, Cross type, familial osteodysplasia, Anderson type, pancreatic agenesis, postaxial polydactyly-dental and vertebral anomalies syndrome, familial primary pulmonary hypoplasia, renal tubular dysgenesis of genetic origin, Rothmund-Thomson syndrome, familial isolated congenital asplenia, subaortic stenosis, membranous, non-eruption of teeth-maxillary hypoplasia-genu valgum syndrome, corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome, CK syndrome, Ogden syndrome, Nance-Horan syndrome, colonic atresia, Aicardi syndrome, torticollis-keloids-cryptorchidism-renal dysplasia syndrome, 46,XY complete gonadal dysgenesis, loose anagen syndrome, lung agenesis-heart defect-thumb anomalies syndrome, Chudley-McCullough syndrome, macrocephaly-autism syndrome, DNA ligase IV deficiency, horizontal gaze palsy with progressive scoliosis, cataract - congenital heart disease - neural tube defect syndrome, autosomal recessive frontotemporal pachygyria, craniofacial dysplasia - osteopenia syndrome, porencephaly-microcephaly-bilateral congenital cataract syndrome, congenital short bowel syndrome, familial median cleft of the upper and lower lips, progeroid features-hepatocellular carcinoma predisposition syndrome, progressive microcephaly-seizures-cortical blindness-developmental delay syndrome, aneurysm of sinus of Valsalva, blepharoptosis-cleft palate-ectrodactyly-dental anomalies syndrome, medullary sponge kidney, isolated congenital syngnathia, cleft lip and alveolus, diprosopus, T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency, high anorectal malformation, intermediate anorectal malformation, low anorectal malformation, microcephaly-polymicrogyria-corpus callosum agenesis syndrome, cordiform uterus, septate uterus, bicornuate uterus, uterine hypoplasia, agenesis and aplasia of uterine body, uterine cervical aplasia and agenesis, longitudinal vaginal septum, transverse vaginal septum, axial mesodermal dysplasia spectrum, multicystic dysplastic kidney, diabetic embryopathy, congenital microgastria, isolated cleft lip, cleft lip/palate, hereditary gingival fibromatosis, congenital bronchobiliary fistula, congenital hydrocephalus, maternal hyperthermia induced birth defects, diphallia, epibulbar lipodermoid-preauricular appendage-polythelia syndrome, bronchogenic cyst, duplication of urethra, hypohidrotic ectodermal dysplasia, Lowe-Kohn-Cohen syndrome, biliary atresia with splenic malformation syndrome, congenital pulmonary airway malformation, familial intestinal malrotation-facial anomalies syndrome, megalencephaly, cephalocele, cerebral cortical dysplasia, L1 syndrome, familial omphalocele syndrome with facial dysmorphism, penoscrotal transposition, pericardial and diaphragmatic defect, hypogonadotropic hypogonadism-severe microcephaly-sensorineural hearing loss-dysmorphism syndrome, congenital deformities of limbs, familial isolated clinodactyly of fingers, congenital shoulder dislocation, congenital elbow dislocation, congenital knee dislocation, congenital patella dislocation, macrodactyly of fingers, macrodactyly of toes, upper limb hypertrophy, lower limb hypertrophy, duplication of the pituitary gland, diencephalic-mesencephalic junction dysplasia, steroid dehydrogenase deficiency-dental anomalies syndrome, congenital achiasma, tracheal agenesis, renal agenesis, hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome, isolated splenogonadal fusion, Joubert syndrome, congenital generalized hypercontractile muscle stiffness syndrome, congenital bilateral absence of vas deferens, congenital portosystemic shunt, lissencephaly spectrum disorders, Berardinelli-Seip congenital lipodystrophy, congenital primary megaureter, craniorachischisis, vaginal atresia, bronchopulmonary dysplasia, dentinogenesis imperfecta-short stature-hearing loss-intellectual disability syndrome, aniridia, atypical Werner syndrome, X-linked intellectual disability-corpus callosum agenesis-spastic quadriparesis syndrome, anterior segment dysgenesis, congenital esophageal diverticulum, renal hypoplasia, renal dysplasia, developmental defect during embryogenesis, acalvaria, congenital aortic valve insufficiency, congenital anomaly of superior vena cava, congenital anomaly of hepatic vein, posterior hypospadias, isolated micropenis, isolated partial vaginal agenesis, anorectal malformation, pulmonary agenesis, congenital tricuspid malformation, Noonan syndrome and Noonan-related syndrome, coronary sinus stenosis, coronary sinus atresia, cartilage development disorder, syndactyly, polydactyly, brachydactyly, neurocristopathy, congenital absence of septum pellucidum, branchial arch disease, congenital anomaly of cardiovascular system, atelencephaly, aprosencephaly, aortic valve stenosis, hereditary lethal multiple congenital anomalies/dysmorphic syndrome, congenital agenesis of the scrotum, keratinization disease, lactation disease, COACH syndrome, constitutional delay of growth and puberty, isolated congenital femoral bifurcation, congenital peritoneal encapsulation, isolated short stature, congenital high airway obstruction syndrome

Subtypes (31): Beckwith-Wiedemann syndrome, hemifacial hypertrophy, angioosteohypertrophic syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, isolated hemihyperplasia, hypoinsulinemic hypoglycemia and body hemihypertrophy, Perlman syndrome, Weaver syndrome, Simpson-Golabi-Behmel syndrome, tetrasomy 12p, Marshall-Smith syndrome, hemifacial myohyperplasia, CLAPO syndrome, Maffucci syndrome, Malan overgrowth syndrome, segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome, trisomy 5p, hemihyperplasia-multiple lipomatosis syndrome, 11p15.4 microduplication syndrome, 15q overgrowth syndrome, global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome, megalencephaly-severe kyphoscoliosis-overgrowth syndrome, congenital isolated hyperinsulinism, 4p16.3 microduplication syndrome, overgrowth syndrome with 2q37 translocation, MTOR-related overgrowth spectrum, AKT3-related overgrowth spectrum, PRC-2 complex-related overgrowth spectrum, PIK3CA-related overgrowth spectrum, PIK3R2-related overgrowth spectrum

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

5 retrieved; paginated sample, class counts are floors:

2 uncertain significance, 2 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2691258	NM_181523.3(PIK3R1):c.1718T>C (p.Leu573Pro)	PIK3R1	Pathogenic	no assertion criteria provided
2672097	NM_004958.4(MTOR):c.5662T>C (p.Phe1888Leu)	MTOR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
996074	NM_181523.3(PIK3R1):c.1392_1403del (p.Asp464_Tyr467del)	PIK3R1	Likely pathogenic	criteria provided, single submitter
3238636	NM_004958.4(MTOR):c.784C>T (p.His262Tyr)	MTOR	Uncertain significance	criteria provided, single submitter
2672095	NM_005027.4(PIK3R2):c.1675C>T (p.Arg559Cys)	PIK3R2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 9 · 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
RNF135	Supportive	Autosomal dominant	overgrowth-macrocephaly-facial dysmorphism syndrome	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RNF135	Orphanet:137634	Overgrowth-macrocephaly-facial dysmorphism syndrome
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
PIK3R1	Orphanet:3163	SHORT syndrome
PIK3R1	Orphanet:33110	Autosomal non-syndromic agammaglobulinemia
PIK3R1	Orphanet:693681	Activated PI3K-delta syndrome 2
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
RNF135	HGNC:21158	ENSG00000181481	Q8IUD6	E3 ubiquitin-protein ligase RNF135	gencc
MTOR	HGNC:3942	ENSG00000198793	P42345	Serine/threonine-protein kinase mTOR	clinvar
PIK3R1	HGNC:8979	ENSG00000145675	P27986	Phosphatidylinositol 3-kinase regulatory subunit alpha	clinvar
PIK3R2	HGNC:8980	ENSG00000105647	O00459	Phosphatidylinositol 3-kinase regulatory subunit beta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RNF135	E3 ubiquitin-protein ligase RNF135	E2-dependent E3 ubiquitin-protein ligase that functions as a RIGI coreceptor in the sensing of viral RNAs in cell cytoplasm and the activation of the antiviral innate immune response.
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.
PIK3R1	Phosphatidylinositol 3-kinase regulatory subunit alpha	Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane.
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: 3 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.75

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	3	20.8×	4e-04
Transcription factor	1	2.1×	0.403

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNF135	Transcription factor	no		Znf_RING, B30.2/SPRY, SPRY_dom
MTOR	Kinase	yes		PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
PIK3R1	Kinase	yes	2.7.1.153	RhoGAP_dom, SH2, SH3_domain
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
layer of synovial tissue	1
pancreatic ductal cell	1
parietal pleura	1
cerebellar hemisphere	1
primordial germ cell in gonad	1
right hemisphere of cerebellum	1
calcaneal tendon	1
caput epididymis	1
corpus epididymis	1
cortical plate	1
ganglionic eminence	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNF135	253	ubiquitous	marker	pancreatic ductal cell, parietal pleura, layer of synovial tissue
MTOR	207	ubiquitous	marker	primordial germ cell in gonad, right hemisphere of cerebellum, cerebellar hemisphere
PIK3R1	294	ubiquitous	marker	calcaneal tendon, caput epididymis, corpus epididymis
PIK3R2	138	ubiquitous	marker	cortical plate, ganglionic eminence, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MTOR	9,490
PIK3R1	5,168
PIK3R2	2,751
RNF135	1,083

Intra-cohort edges

A	B	Sources
PIK3R1	PIK3R2	biogrid_interaction, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIK3R1	P27986	105
MTOR	P42345	70
PIK3R2	O00459	8
RNF135	Q8IUD6	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 133. 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	3	295.3×	8e-06	MTOR, PIK3R1, PIK3R2
Signaling by LTK in cancer	2	815.7×	9e-05	PIK3R1, PIK3R2
VEGFA-VEGFR2 Pathway	3	104.5×	9e-05	MTOR, PIK3R1, PIK3R2
PI3K/AKT activation	2	634.4×	1e-04	PIK3R1, PIK3R2
IRS-mediated signalling	2	519.1×	1e-04	PIK3R1, PIK3R2
Co-stimulation by ICOS	2	519.1×	1e-04	PIK3R1, PIK3R2
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	2	439.2×	1e-04	PIK3R1, PIK3R2
Signaling by PDGFRA extracellular domain mutants	2	439.2×	1e-04	PIK3R1, PIK3R2
Signaling by LTK	2	439.2×	1e-04	PIK3R1, PIK3R2
PIP3 activates AKT signaling	3	50.1×	2e-04	MTOR, PIK3R1, PIK3R2
Tie2 Signaling	2	300.5×	2e-04	PIK3R1, PIK3R2
Role of LAT2/NTAL/LAB on calcium mobilization	2	300.5×	2e-04	PIK3R1, PIK3R2
Signaling by ALK	2	285.5×	2e-04	PIK3R1, PIK3R2
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	2	259.6×	2e-04	PIK3R1, PIK3R2
Regulation of signaling by CBL	2	248.3×	2e-04	PIK3R1, PIK3R2
Nephrin family interactions	2	237.9×	2e-04	PIK3R1, PIK3R2
Role of phospholipids in phagocytosis	2	228.4×	2e-04	PIK3R1, PIK3R2
Interleukin receptor SHC signaling	2	203.9×	3e-04	PIK3R1, PIK3R2
Downstream signal transduction	2	190.3×	3e-04	PIK3R1, PIK3R2
DAP12 signaling	2	184.2×	3e-04	PIK3R1, PIK3R2
Interleukin-7 signaling	2	158.6×	3e-04	PIK3R1, PIK3R2
Interleukin-3, Interleukin-5 and GM-CSF signaling	2	158.6×	3e-04	PIK3R1, PIK3R2
GPVI-mediated activation cascade	2	154.3×	4e-04	PIK3R1, PIK3R2
RHOU GTPase cycle	2	139.3×	4e-04	PIK3R1, PIK3R2
PI3K Cascade	2	135.9×	4e-04	PIK3R1, PIK3R2
RND1 GTPase cycle	2	132.8×	4e-04	PIK3R1, PIK3R2
RET signaling	2	129.8×	4e-04	PIK3R1, PIK3R2
RHOF GTPase cycle	2	129.8×	4e-04	PIK3R1, PIK3R2
RND3 GTPase cycle	2	129.8×	4e-04	PIK3R1, PIK3R2
RND2 GTPase cycle	2	129.8×	4e-04	PIK3R1, 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
cellular response to insulin stimulus	3	127.7×	1e-04	MTOR, PIK3R1, PIK3R2
positive regulation of lamellipodium assembly	2	300.9×	8e-04	MTOR, PIK3R1
intracellular glucose homeostasis	2	290.6×	8e-04	PIK3R1, PIK3R2
positive regulation of protein import into nucleus	2	210.7×	0.001	PIK3R1, PIK3R2
T cell differentiation	2	191.5×	0.001	PIK3R1, PIK3R2
insulin receptor signaling pathway	2	110.9×	0.002	PIK3R1, PIK3R2
B cell differentiation	2	109.4×	0.002	PIK3R1, PIK3R2
phosphatidylinositol 3-kinase/protein kinase B signal transduction	2	105.3×	0.002	PIK3R1, PIK3R2
response to endoplasmic reticulum stress	2	83.4×	0.003	PIK3R1, PIK3R2
positive regulation of SCF-dependent proteasomal ubiquitin-dependent catabolic process	1	4213.0×	0.003	MTOR
regulation of locomotor rhythm	1	2106.5×	0.005	MTOR
positive regulation of cytoplasmic translational initiation	1	2106.5×	0.005	MTOR
protein polyubiquitination	2	57.7×	0.005	RNF135, PIK3R1
regulation of toll-like receptor 4 signaling pathway	1	1404.3×	0.007	PIK3R1
positive regulation of endoplasmic reticulum unfolded protein response	1	1404.3×	0.007	PIK3R1
T-helper 1 cell lineage commitment	1	1053.2×	0.007	MTOR
myeloid leukocyte migration	1	1053.2×	0.007	PIK3R1
negative regulation of lysosome organization	1	1053.2×	0.007	MTOR
positive regulation of pentose-phosphate shunt	1	1053.2×	0.007	MTOR
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
‘de novo’ pyrimidine nucleobase biosynthetic process	1	702.2×	0.008	MTOR
interleukin-18-mediated signaling pathway	1	702.2×	0.008	PIK3R1
voluntary musculoskeletal movement	1	702.2×	0.008	MTOR
regulation of lysosome organization	1	702.2×	0.008	MTOR
protein stabilization	2	33.4×	0.008	MTOR, PIK3R1
free ubiquitin chain polymerization	1	601.9×	0.008	RNF135
RIG-I signaling pathway	1	601.9×	0.008	RNF135
regulation of membrane permeability	1	601.9×	0.008	MTOR
cellular response to nutrient	1	526.6×	0.009	MTOR

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 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
PIK3R1	IDELALISIB
PIK3R2	IDELALISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MTOR	164	4
PIK3R1	26	4
PIK3R2	6	4
RNF135	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, PIK3R1
TACROLIMUS ANHYDROUS	4	MTOR
EBASTINE	4	MTOR
MASOPROCOL	4	MTOR
COPANLISIB	4	MTOR, PIK3R1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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
PIK3R1	493	Binding:470, ADMET:23
PIK3R2	27	Binding:27

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PIK3R1	2.7.1.153	phosphatidylinositol-4,5-bisphosphate 3-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
MTOR	1,375
PIK3R1	493

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)
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, PIK3R1
TACROLIMUS ANHYDROUS	4	MTOR
EBASTINE	4	MTOR
MASOPROCOL	4	MTOR
COPANLISIB	4	MTOR, PIK3R1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	MTOR, PIK3R1, 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	1	RNF135

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RNF135	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT04993235	Not specified	UNKNOWN	Body Perception and Representation in Overgrowth Syndromes, Behavioral Assessment and Neuropsychological Development