Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome

Summary

Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome (MONDO:0014716) is a disease caused by MTOR (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MTOR (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 111
• Phenotypes (HPO): 45
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

45 HPO clinical features (Orphanet curated; top 45 by frequency):

HPO ID	Term	Frequency
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001355	Megalencephaly	Very frequent (80-99%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0001520	Large for gestational age	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002007	Frontal bossing	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002167	Abnormality of speech or vocalization	Frequent (30-79%)
HP:0002197	Generalized-onset seizure	Frequent (30-79%)
HP:0002212	Curly hair	Frequent (30-79%)
HP:0007359	Focal-onset seizure	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000154	Wide mouth	Occasional (5-29%)
HP:0000194	Open mouth	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000343	Long philtrum	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0000752	Hyperactivity	Occasional (5-29%)
HP:0000957	Cafe-au-lait spot	Occasional (5-29%)
HP:0001028	Hemangioma	Occasional (5-29%)
HP:0001053	Hypopigmented skin patches	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001273	Abnormal corpus callosum morphology	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0001538	Protuberant abdomen	Occasional (5-29%)
HP:0001540	Diastasis recti	Occasional (5-29%)
HP:0001763	Pes planus	Occasional (5-29%)
HP:0002099	Asthma	Occasional (5-29%)
HP:0002126	Polymicrogyria	Occasional (5-29%)
HP:0004789	Lactose intolerance	Occasional (5-29%)
HP:0005257	Thoracic hypoplasia	Occasional (5-29%)
HP:0011220	Prominent forehead	Occasional (5-29%)
HP:0025104	Capillary malformation	Occasional (5-29%)
HP:0000047	Hypospadias	Very rare (<1-4%)
HP:0000331	Short chin	Very rare (<1-4%)
HP:0000494	Downslanted palpebral fissures	Very rare (<1-4%)
HP:0001998	Neonatal hypoglycemia	Very rare (<1-4%)
HP:0002720	Decreased circulating IgA level	Very rare (<1-4%)
HP:0005266	Intestinal polyp	Very rare (<1-4%)
HP:0005280	Depressed nasal bridge	Very rare (<1-4%)
HP:0012393	Allergy	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome
Mondo ID	MONDO:0014716
OMIM	616638
Orphanet	457485
UMLS	C4225259
MedGen	899689
GARD	0013636
NORD	91167
Is cancer (heuristic)	no

Also known as: macrocephaly, seizures, mental retardation, umbilical hernia, and Facial Dysmorphism · MINDS syndrome · SKS · Smith-Kingsmore Syndrome · Smith-Kingsmore syndrome

Data availability: 111 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, SLC39A8-CDG, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

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

111 retrieved; paginated sample, class counts are floors:

44 uncertain significance, 22 conflicting classifications of pathogenicity, 13 likely pathogenic, 11 pathogenic, 8 benign/likely benign, 8 benign, 2 pathogenic/likely pathogenic, 2 not provided, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1339561	NM_004958.4(MTOR):c.257del (p.Gly86fs)	MTOR	Pathogenic	no assertion criteria provided
156702	NM_004958.4(MTOR):c.5930C>A (p.Thr1977Lys)	MTOR	Pathogenic	reviewed by expert panel
156709	NM_004958.4(MTOR):c.7255G>A (p.Glu2419Lys)	MTOR	Pathogenic	criteria provided, multiple submitters, no conflicts
190121	NM_004958.4(MTOR):c.4448G>T (p.Cys1483Phe)	MTOR	Pathogenic	criteria provided, single submitter
217823	NM_004958.4(MTOR):c.5395G>A (p.Glu1799Lys)	MTOR	Pathogenic	criteria provided, multiple submitters, no conflicts
224083	NM_004958.4(MTOR):c.5663T>G (p.Phe1888Cys)	MTOR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224088	NM_004958.4(MTOR):c.4785G>A (p.Met1595Ile)	MTOR	Pathogenic	criteria provided, single submitter
242349	NM_004958.4(MTOR):c.6981G>A (p.Met2327Ile)	MTOR	Pathogenic	criteria provided, multiple submitters, no conflicts
376453	NM_004958.4(MTOR):c.4448G>A (p.Cys1483Tyr)	MTOR	Pathogenic	reviewed by expert panel
4056380	NM_004958.4(MTOR):c.7289G>C (p.Arg2430Thr)	MTOR	Pathogenic	criteria provided, single submitter
520633	NM_004958.4(MTOR):c.7238G>T (p.Ser2413Ile)	MTOR	Pathogenic	criteria provided, multiple submitters, no conflicts
584432	NM_004958.4(MTOR):c.5930C>T (p.Thr1977Ile)	MTOR	Pathogenic	criteria provided, multiple submitters, no conflicts
626213	NM_004958.4(MTOR):c.7216G>A (p.Val2406Met)	MTOR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4814119	NM_017950.4(CCDC40):c.1159+1G>A	CCDC40	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065618	NM_004958.4(MTOR):c.6227G>A (p.Arg2076Gln)	MTOR	Likely pathogenic	no assertion criteria provided
1320130	NM_004958.4(MTOR):c.5912C>T (p.Ala1971Val)	MTOR	Likely pathogenic	criteria provided, single submitter
1339560	NM_004958.4(MTOR):c.6457A>G (p.Ile2153Val)	MTOR	Likely pathogenic	no assertion criteria provided
2444379	NM_004958.4(MTOR):c.3945-26_4016dup	MTOR	Likely pathogenic	criteria provided, single submitter
2672097	NM_004958.4(MTOR):c.5662T>C (p.Phe1888Leu)	MTOR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3731617	NM_004958.4(MTOR):c.5408A>C (p.His1803Pro)	MTOR	Likely pathogenic	criteria provided, single submitter
376455	NM_004958.4(MTOR):c.7500T>G (p.Ile2500Met)	MTOR	Likely pathogenic	criteria provided, single submitter
3765844	NM_004958.4(MTOR):c.7535A>G (p.Asp2512Gly)	MTOR	Likely pathogenic	criteria provided, single submitter
3775749	NM_004958.4(MTOR):c.4702A>G (p.Arg1568Gly)	MTOR	Likely pathogenic	criteria provided, single submitter
391346	NM_004958.4(MTOR):c.7292T>C (p.Leu2431Pro)	MTOR	Likely pathogenic	criteria provided, single submitter
4293751	NM_004958.4(MTOR):c.4961T>C (p.Leu1654Pro)	MTOR	Likely pathogenic	criteria provided, single submitter
4819712	NM_004958.4(MTOR):c.4388A>G (p.Tyr1463Cys)	MTOR	Likely pathogenic	criteria provided, single submitter
1047242	NM_004958.4(MTOR):c.2045G>A (p.Arg682His)	MTOR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1213694	NM_004958.4(MTOR):c.1816T>C (p.Cys606Arg)	MTOR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1315329	NM_004958.4(MTOR):c.2581T>C (p.Tyr861His)	MTOR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1325857	NM_004958.4(MTOR):c.7529G>T (p.Gly2510Val)	MTOR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

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
MTOR	Definitive	Autosomal dominant	macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome	6

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
CCDC40	Orphanet:244	Primary ciliary dyskinesia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MTOR	HGNC:3942	ENSG00000198793	P42345	Serine/threonine-protein kinase mTOR	gencc,clinvar
CCDC40	HGNC:26090	ENSG00000141519	Q4G0X9	Coiled-coil domain-containing protein 40	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
CCDC40	Coiled-coil domain-containing protein 40	Required for assembly of dynein regulatory complex (DRC) and inner dynein arm (IDA) complexes, which are responsible for ciliary beat regulation, thereby playing a central role in motility in cilia and flagella.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MTOR	Kinase	yes		PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
CCDC40	Other/Unknown	no		CCDC40

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	1
primordial germ cell in gonad	1
right hemisphere of cerebellum	1
bronchial epithelial cell	1
right uterine tube	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MTOR	207	ubiquitous	marker	primordial germ cell in gonad, right hemisphere of cerebellum, cerebellar hemisphere
CCDC40	184	ubiquitous	marker	right uterine tube, bronchial epithelial cell, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MTOR	9,490
CCDC40	1,527

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MTOR	P42345	70
CCDC40	Q4G0X9	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 41. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Dengue virus modulates apoptosis	1	713.8×	0.010	MTOR
Regulation of TP53 Expression and Degradation	1	519.1×	0.010	MTOR
mTORC1-mediated signalling	1	475.8×	0.010	MTOR
Regulation of T cell activation by CD28 family	1	423.0×	0.010	MTOR
Constitutive Signaling by AKT1 E17K in Cancer	1	423.0×	0.010	MTOR
VEGFR2 mediated vascular permeability	1	407.9×	0.010	MTOR
Cellular response to heat stress	1	393.8×	0.010	MTOR
Energy dependent regulation of mTOR by LKB1-AMPK	1	393.8×	0.010	MTOR
CD28 dependent PI3K/Akt signaling	1	393.8×	0.010	MTOR
Co-stimulation by CD28	1	380.7×	0.010	MTOR
PI3K/AKT Signaling in Cancer	1	368.4×	0.010	MTOR
HSF1-dependent transactivation	1	317.2×	0.010	MTOR
Response of endothelial cells to shear stress	1	300.5×	0.010	MTOR
Regulation of TP53 Degradation	1	292.8×	0.010	MTOR
MTOR signalling	1	265.6×	0.010	MTOR
Cellular responses to mechanical stimuli	1	259.6×	0.010	MTOR
PTEN Regulation	1	228.4×	0.010	MTOR
Signaling by VEGF	1	219.6×	0.010	MTOR
Amino acids regulate mTORC1	1	200.3×	0.011	MTOR
Regulation of PTEN gene transcription	1	178.4×	0.011	MTOR
Cellular response to starvation	1	165.5×	0.012	MTOR
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	160.8×	0.012	MTOR
Autophagy	1	148.3×	0.012	MTOR
VEGFA-VEGFR2 Pathway	1	139.3×	0.012	MTOR
Regulation of TP53 Activity	1	132.8×	0.012	MTOR
TP53 Regulates Metabolic Genes	1	129.8×	0.012	MTOR
Macroautophagy	1	115.3×	0.013	MTOR
Intracellular signaling by second messengers	1	91.4×	0.016	MTOR
PIP3 activates AKT signaling	1	66.8×	0.021	MTOR
Transcriptional Regulation by TP53	1	62.1×	0.022	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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of SCF-dependent proteasomal ubiquitin-dependent catabolic process	1	8426.0×	0.005	MTOR
regulation of locomotor rhythm	1	4213.0×	0.005	MTOR
positive regulation of cytoplasmic translational initiation	1	4213.0×	0.005	MTOR
T-helper 1 cell lineage commitment	1	2106.5×	0.005	MTOR
negative regulation of lysosome organization	1	2106.5×	0.005	MTOR
positive regulation of pentose-phosphate shunt	1	2106.5×	0.005	MTOR
determination of pancreatic left/right asymmetry	1	1685.2×	0.005	CCDC40
cellular response to methionine	1	1685.2×	0.005	MTOR
positive regulation of wound healing, spreading of epidermal cells	1	1685.2×	0.005	MTOR
‘de novo’ pyrimidine nucleobase biosynthetic process	1	1404.3×	0.005	MTOR
voluntary musculoskeletal movement	1	1404.3×	0.005	MTOR
determination of digestive tract left/right asymmetry	1	1404.3×	0.005	CCDC40
determination of liver left/right asymmetry	1	1404.3×	0.005	CCDC40
regulation of lysosome organization	1	1404.3×	0.005	MTOR
regulation of membrane permeability	1	1203.7×	0.005	MTOR
regulation of cilium beat frequency	1	1053.2×	0.005	CCDC40
cellular response to nutrient	1	1053.2×	0.005	MTOR
heart valve morphogenesis	1	936.2×	0.005	MTOR
negative regulation of cell size	1	842.6×	0.005	MTOR
positive regulation of myotube differentiation	1	766.0×	0.005	MTOR
TORC2 signaling	1	766.0×	0.005	MTOR
regulation of osteoclast differentiation	1	766.0×	0.005	MTOR
positive regulation of transcription of nucleolar large rRNA by RNA polymerase I	1	766.0×	0.005	MTOR
cellular response to L-leucine	1	702.2×	0.005	MTOR
cellular response to leucine starvation	1	702.2×	0.005	MTOR
anoikis	1	648.1×	0.005	MTOR
positive regulation of keratinocyte migration	1	648.1×	0.005	MTOR
epithelial cilium movement involved in determination of left/right asymmetry	1	648.1×	0.005	CCDC40
cellular response to osmotic stress	1	601.9×	0.005	MTOR
negative regulation of macroautophagy	1	561.7×	0.005	MTOR

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MTOR	164	4
CCDC40	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): 0.

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

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

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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)	1	MTOR
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	CCDC40

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)
CCDC40	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04395495	Not specified	RECRUITING	RASopathy Biorepository