Noonan syndrome

Summary

Noonan syndrome (MONDO:0018997) is a disease (an umbrella term covering 14 Mondo subtypes) caused by variants in KRAS, LZTR1, NRAS, and 7 other genes, with 29 cohort genes and 27 clinical trials. The dominant Reactome pathway is RAF activation (10 cohort genes). Top therapeutic interventions include somatropin, somapacitan, and vosoritide.

At a glance

• Prevalence: 1-5 / 10 000 (Worldwide) [Orphanet-validated]
• Causal genes: KRAS (GenCC Definitive), LZTR1 (GenCC Definitive), NRAS (GenCC Definitive), PTPN11 (GenCC Definitive) (+6 more)
• Umbrella term: 14 Mondo subtypes
• Cohort genes: 29
• ClinVar variants: 719
• Phenotypes (HPO): 70
• Clinical trials: 27

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000		Worldwide	Validated
Prevalence at birth	6-9 / 10 000	70	United States	Validated

Signs & symptoms

Clinical features (HPO)

70 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001382	Joint hypermobility	Very frequent (80-99%)
HP:0000044	Hypogonadotropic hypogonadism	Very frequent (80-99%)
HP:0000179	Thick lower lip vermilion	Very frequent (80-99%)
HP:0000218	High palate	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000325	Triangular face	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000348	High forehead	Very frequent (80-99%)
HP:0000391	Thickened helices	Very frequent (80-99%)
HP:0000465	Webbed neck	Very frequent (80-99%)
HP:0000474	Thickened nuchal skin fold	Very frequent (80-99%)
HP:0000476	Cystic hygroma	Very frequent (80-99%)
HP:0000494	Downslanted palpebral fissures	Very frequent (80-99%)
HP:0000508	Ptosis	Very frequent (80-99%)
HP:0000520	Proptosis	Very frequent (80-99%)
HP:0000767	Pectus excavatum	Very frequent (80-99%)
HP:0000768	Pectus carinatum	Very frequent (80-99%)
HP:0001260	Dysarthria	Very frequent (80-99%)
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0003115	Abnormal EKG	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0004415	Pulmonary artery stenosis	Very frequent (80-99%)
HP:0006610	Wide intermamillary distance	Very frequent (80-99%)
HP:0010318	Aplasia/Hypoplasia of the abdominal wall musculature	Very frequent (80-99%)
HP:0011800	Midface retrusion	Very frequent (80-99%)
HP:0030680	Abnormal cardiovascular system morphology	Very frequent (80-99%)
HP:0100625	Enlarged thorax	Very frequent (80-99%)
HP:0000358	Posteriorly rotated ears	Very frequent (80-99%)
HP:0001641	Abnormal pulmonary valve morphology	Frequent (30-79%)
HP:0001743	Abnormality of the spleen	Frequent (30-79%)
HP:0001892	Abnormal bleeding	Frequent (30-79%)
HP:0001928	Abnormality of coagulation	Frequent (30-79%)
HP:0002162	Low posterior hairline	Frequent (30-79%)
HP:0002208	Coarse hair	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002750	Delayed skeletal maturation	Frequent (30-79%)
HP:0007477	Abnormal dermatoglyphics	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0011362	Abnormal hair quantity	Frequent (30-79%)
HP:0011675	Arrhythmia	Frequent (30-79%)
HP:0011869	Abnormal platelet function	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0100763	Abnormality of the lymphatic system	Frequent (30-79%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000078	Abnormality of the genital system	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000635	Blue irides	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Noonan syndrome
Mondo ID	MONDO:0018997
MeSH	D009634
OMIM	163950
Orphanet	648
DOID	DOID:3490
ICD-11	1044395354
NCIT	C34854
SNOMED CT	205824006
UMLS	C0028326
MedGen	18073
GARD	0010955
MedDRA	10029748
NORD	1513
Is cancer (heuristic)	no

Also known as: Noonan syndrome · Noonan’s syndrome · Noonan-Ehmke syndrome · pseudo-Ullrich-Turner syndrome · Ullrich-Noonan syndrome

Data availability: 719 ClinVar variants · 20 ClinGen variant curations · 38 GenCC gene-disease records · 23 cell lines.

Disease family

An umbrella term covering 14 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › Noonan syndrome

Related subtypes (1183): Neu-Laxova syndrome, inclusion body myopathy with Paget disease of bone and frontotemporal dementia, syndromic intellectual disability, abdominal obesity-metabolic syndrome, fibrogenesis imperfecta ossium, Fanconi renotubular syndrome, palindromic rheumatism, hepatorenal syndrome, Potter sequence, vertebral artery insufficiency, sick sinus syndrome, Tietze syndrome, toxic shock syndrome, capillary leak syndrome, dumping syndrome, FG syndrome, basilar artery insufficiency, long QT syndrome, Treacher-Collins syndrome, superior mesenteric artery syndrome, disappearing bone disease, Brown-Sequard syndrome, Froelich syndrome, diffuse infiltrative lymphocytosis syndrome, Capgras syndrome, compartment syndrome, central sleep apnea syndrome, irritable bowel syndrome, nephrotic syndrome, myalgic encephalomeyelitis/chronic fatigue syndrome, acute coronary syndrome, fibromyalgia, substance withdrawal syndrome, acute chest syndrome, Barre-Lieou syndrome, cauda equina syndrome, Kluver-Bucy syndrome, Miller Fisher syndrome, persian gulf syndrome, Reye syndrome, thoracic outlet syndrome, Waterhouse-Friderichsen syndrome, Wissler syndrome, acute respiratory distress syndrome, Achenbach syndrome, miliaria, anterior spinal artery syndrome, burning mouth syndrome, dry eye syndrome, empty sella syndrome, euthyroid sick syndrome, lateral medullary syndrome, subclavian steal syndrome, tarsal tunnel syndrome, tethered spinal cord syndrome, branchio-oto-renal syndrome, prune belly syndrome, Achard syndrome, alopecia-epilepsy-pyorrhea-intellectual disability syndrome, Finnish type amyloidosis, Angelman syndrome, aniridia-absent patella syndrome, ankyloblepharon filiforme adnatum-cleft palate syndrome, Townes-Brocks syndrome, obstructive sleep apnea syndrome, Lown-Ganong-Levine syndrome, Behcet disease, brachydactyly-arterial hypertension syndrome, brachydactyly type A2, fibular aplasia-ectrodactyly syndrome, brachydactyly-nystagmus-cerebellar ataxia syndrome, Sillence syndrome, Brachymorphism-onychodysplasia-dysphalangism syndrome, brachytelephalangy-dysmorphism-Kallmann syndrome, dilated cardiomyopathy 1A, cat-eye syndrome, cerebrocostomandibular syndrome, Alagille syndrome, autosomal dominant chondrodysplasia punctata, cleidocranial dysplasia 1, cleidorhizomelic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Cri-du-chat syndrome, autosomal dominant deafness - onychodystrophy syndrome, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy, Duane retraction syndrome, 3-M syndrome, dyschondrosteosis-nephritis syndrome, hereditary benign intraepithelial dyskeratosis, encephalopathy, recurrent, of childhood, Camurati-Engelmann disease, Felty syndrome, chromosome 16p12.1 deletion syndrome, 520kb, Frasier syndrome, Gamstorp-Wohlfart syndrome, Tourette syndrome, glaucoma-sleep apnea syndrome, renal cysts and diabetes syndrome, hypotrichosis-lymphedema-telangiectasia syndrome (grouping), GMS syndrome, gray platelet syndrome, hand-foot-genital syndrome, facial hemiatrophy, Bencze syndrome, alpha thalassemia-intellectual disability syndrome type 1, Gilbert syndrome, mullerian duct anomalies-limb anomalies syndrome, hypoparathyroidism-deafness-renal disease syndrome, chromosome 18p deletion syndrome, Pallister-Hall syndrome, ichthyosis-cheek-eyebrow syndrome, Jacobsen syndrome, palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome, palmoplantar keratoderma-esophageal carcinoma syndrome, Kleine-Levin syndrome, angioosteohypertrophic syndrome, congenital laryngeal web, Lenz-Majewski hyperostotic dwarfism, Noonan syndrome with multiple lentigines, lymphedema-cerebral arteriovenous anomaly syndrome, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, yellow nail syndrome, lymphedema-distichiasis syndrome, Nager acrofacial dysostosis, jaw-winking syndrome, Marfan syndrome, Melkersson-Rosenthal syndrome, metaphyseal chondrodysplasia, Jansen type, Schmid metaphyseal chondrodysplasia, metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome, microgastria-limb reduction defect syndrome, Mobius syndrome, muscular atrophy-ataxia-retinitis pigmentosa-diabetes mellitus syndrome, nail-patella syndrome, Schilbach-Rott syndrome, syndromic orbital border hypoplasia, Buschke-Ollendorff syndrome, nasopalpebral lipoma-coloboma syndrome, Perry syndrome, Poland syndrome, polydactyly-myopia syndrome, Greig cephalopolysyndactyly syndrome, Prader-Willi syndrome, Guttmacher syndrome, Currarino triad, Hutchinson-Gilford progeria syndrome, progeria-short stature-pigmented nevi syndrome, Liddle syndrome, exfoliation syndrome, ptosis-strabismus-ectopic pupils syndrome, radial hypoplasia-triphalangeal thumbs-hypospadias-maxillary diastema syndrome, radial ray hypoplasia-choanal atresia syndrome, Roussy-Levy syndrome, Silver-Russell syndrome, Ruvalcaba syndrome, oculodental syndrome, Rutherfurd type, aplasia of lacrimal and salivary glands, scalp defects-postaxial polydactyly syndrome, ulnar-mammary syndrome, septooptic dysplasia, Czeizel-Losonci syndrome, polycystic ovary syndrome, stiff-person syndrome, syndactyly-polydactyly-ear lobe syndrome, HELLP syndrome, double uterus-hemivagina-renal agenesis syndrome, VACTERL/vater association, posterior fusion of lumbosacral vertebrae-blepharoptosis syndrome, ptosis-vocal cord paralysis syndrome, Freeman-Sheldon syndrome, Williams syndrome, Denys-Drash syndrome, Wolf-Hirschhorn syndrome, ablepharon macrostomia syndrome, acrocallosal syndrome, PAGOD syndrome, alopecia - intellectual disability syndrome, mitochondrial DNA depletion syndrome 4a, Alstrom syndrome, aniridia-cerebellar ataxia-intellectual disability syndrome, aniridia-renal agenesis-psychomotor retardation syndrome, aplasia cutis congenita-intestinal lymphangiectasia syndrome, fetal akinesia deformation sequence, blepharophimosis-ptosis-esotropia-syndactyly-short stature syndrome, Bloom syndrome, Elsahy-Waters syndrome, campomelia, Cumming type, camptomelic syndrome, long-limb type, congenital cataract-ichthyosis syndrome, colobomatous optic disc-macular atrophy-chorioretinopathy syndrome, hepatic fibrosis-renal cysts-intellectual disability syndrome, Charcot-Marie-Tooth disease-hearing loss-intellectual disability syndrome, CHARGE syndrome, Aagenaes syndrome, infantile choroidocerebral calcification syndrome, Yunis-Varon syndrome, corneal dystrophy-perceptive deafness syndrome, cortical blindness-intellectual disability-polydactyly syndrome, Crigler-Najjar syndrome, cataract-nephropathy-encephalopathy syndrome, Fraser syndrome, cystic fibrosis-gastritis-megaloblastic anemia syndrome, cystinuria, DOORS syndrome, high myopia-sensorineural deafness syndrome, dermochondrocorneal dystrophy, nephrogenic diabetes insipidus-intracranial calcification syndrome, diverticulosis of bowel, hernia, and retinal detachment, Dyggve-Melchior-Clausen disease, cerebellar ataxia, intellectual disability, and dysequilibrium, ectrodactyly-polydactyly syndrome, Bonnemann-Meinecke-Reich syndrome, epidermolysis bullosa simplex 5B, with muscular dystrophy, Wolcott-Rallison syndrome, ermine phenotype, eyebrow duplication-syndactyly syndrome, Fanconi-like syndrome, gingival fibromatosis-facial dysmorphism syndrome, frontofacionasal dysplasia, Fryns syndrome, German syndrome, Bernard-Soulier syndrome, triple-A syndrome, Grubben-de Cock-Borghgraef syndrome, mullerian derivatives-lymphangiectasia-polydactyly syndrome, Hirschsprung disease-hearing loss-polydactyly syndrome, Hirschsprung disease-nail hypoplasia-dysmorphism syndrome, Holzgreve-Wagner-Rehder syndrome, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, growth delay-hydrocephaly-lung hypoplasia syndrome, Dubin-Johnson syndrome, ornithine translocase deficiency, acrofrontofacionasal dysostosis 2, hypertrichotic osteochondrodysplasia Cantu type, hypergonadotropic hypogonadism-cataract syndrome, primary hypergonadotropic hypogonadism-partial alopecia syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, hypospadias-intellectual disability, Goldblatt type syndrome, Bamforth-Lazarus syndrome, ichthyosis-hepatosplenomegaly-cerebellar degeneration syndrome, ichthyosis-intellectual disability-dwarfism-renal impairment syndrome, Vici syndrome, channelopathy-associated congenital insensitivity to pain, autosomal recessive, Joubert syndrome with oculorenal defect, oculocerebrofacial syndrome, Kaufman type, Landau-Kleffner syndrome, laryngo-onycho-cutaneous syndrome, Laurence-Moon syndrome, Donohue syndrome, Miller-Dieker lissencephaly syndrome, Marinesco-Sjogren syndrome, Frank-Ter Haar syndrome, Mietens syndrome, mesomelic dwarfism-cleft palate-camptodactyly syndrome, metaphyseal chondrodysplasia-retinitis pigmentosa syndrome, metaphyseal dysostosis-intellectual disability-conductive deafness syndrome, microcephalic primordial dwarfism, Toriello type, Say-Barber-Miller syndrome, microcephaly and chorioretinopathy 1, Galloway-Mowat syndrome, microtia with meatal atresia and conductive deafness, mucopolysaccharidosis type 6, mulibrey nanism, lethal multiple pterygium syndrome, lethal congenital contracture syndrome 1, Schwartz-Jampel syndrome, Nathalie syndrome, nephronophthisis 1, nephropathy - deafness - hyperparathyroidism syndrome, nephrosis-deafness-urinary tract-digital malformations syndrome, Netherton syndrome, Norman-Roberts syndrome, cloacal exstrophy, ichthyosis-oral and digital anomalies syndrome, Primrose syndrome, familial osteodysplasia, Anderson type, multicentric osteolysis, nodulosis, and arthropathy, osteopenia-intellectual disability-sparse hair syndrome, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, Parana hard-skin syndrome, PEHO syndrome, Imerslund-Grasbeck syndrome, Peters plus syndrome, pili torti-developmental delay-neurological abnormalities syndrome, Rabson-Mendenhall syndrome, postaxial acrofacial dysostosis, Gitelman syndrome, Wiedemann-Rautenstrauch syndrome, Acrootoocular syndrome, holoprosencephaly-postaxial polydactyly syndrome, autosomal recessive multiple pterygium syndrome, Perlman syndrome, retinitis pigmentosa-intellectual disability-deafness-hypogenitalism syndrome, EEC syndrome, SHORT syndrome, Sjogren syndrome, spastic tetraplegia-retinitis pigmentosa-intellectual disability syndrome, corneal-cerebellar syndrome, spastic ataxia-corneal dystrophy syndrome, spondylocostal dysostosis-anal and genitourinary malformations syndrome, familial infantile bilateral striatal necrosis, subaortic stenosis-short stature syndrome, thrombocytopenia-absent radius syndrome, thyrocerebrorenal syndrome, Pendred syndrome, VACTERL with hydrocephalus, Weaver syndrome, Werner syndrome, Wernicke-Korsakoff syndrome, wooly hair-hypotrichosis-everted lower lip-outstanding ears syndrome, de Sanctis-Cacchione syndrome, corpus callosum agenesis-abnormal genitalia syndrome, Alport syndrome-intellectual disability-midface hypoplasia-elliptocytosis syndrome, X-linked lissencephaly with abnormal genitalia, X-linked myotubular myopathy-abnormal genitalia syndrome, Christianson syndrome, Armfield syndrome, Lesch-Nyhan syndrome, Atkin-Flaitz syndrome, alpha-thalassemia-myelodysplastic syndrome, deafness-intellectual disability, Martin-Probst type syndrome, fragile X-associated tremor/ataxia syndrome, fragile X syndrome, syndactyly-telecanthus-anogenital and renal malformations syndrome, X-linked dominant chondrodysplasia, Chassaing-Lacombe type, X-linked central congenital hypothyroidism with late-onset testicular enlargement, Meester-Loeys syndrome, Arts syndrome, X-linked mandibulofacial dysostosis, Abruzzo-Erickson syndrome, Aicardi syndrome, craniofrontonasal syndrome, deafness-hypogonadism syndrome, X-linked corneal dermoid, immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome, hydrocephaly-cerebellar agenesis syndrome, keratosis follicularis-dwarfism-cerebral atrophy syndrome, laryngeal abductor paralysis-intellectual disability syndrome, oculocerebrorenal syndrome, Menkes disease, paraplegia-intellectual disability-hyperkeratosis syndrome, mucopolysaccharidosis type 2, orofaciodigital syndrome I, otopalatodigital syndrome type 1, Pallister-W syndrome, Rett syndrome, SCARF syndrome, Simpson-Golabi-Behmel syndrome, torticollis-keloids-cryptorchidism-renal dysplasia syndrome, trigonocephaly-short stature-developmental delay syndrome, ulnar hypoplasia-split foot syndrome, van den Bosch syndrome, Wildervanck syndrome, Kearns-Sayre syndrome, MELAS syndrome, MERRF syndrome, Pearson syndrome, proximal tubulopathy-diabetes mellitus-cerebellar ataxia syndrome, pancreatic hypoplasia-diabetes-congenital heart disease syndrome, chondrodysplasia-pseudohermaphroditism syndrome, Qazi Markouizos syndrome, familial developmental dysphasia, atrioventricular defect-blepharophimosis-radial and anal defect syndrome, CODAS syndrome, lethal hemolytic anemia-genital anomalies syndrome, HEC syndrome, anophthalmia plus syndrome, infundibulopelvic stenosis-multicystic kidney syndrome, Ayme-Gripp syndrome, dilated cardiomyopathy 1E, diaphragmatic defect-limb deficiency-skull defect syndrome, skeletal dysplasia-epilepsy-short stature syndrome, Potocki-Shaffer syndrome, amelia cleft lip palate hydrocephalus iris coloboma, human HOXA1 syndromes, dyssegmental dysplasia-glaucoma syndrome, lung agenesis-heart defect-thumb anomalies syndrome, tetrasomy 12p, chromosome 18q deletion syndrome, lymphedema-atrial septal defects-facial changes syndrome, infantile convulsions and choreoathetosis, RHYNS syndrome, Pierre Robin sequence with pectus excavatum and rib and scapular anomalies, colobomatous macrophthalmia-microcornea syndrome, Marshall-Smith syndrome, distal monosomy 13q, MPI-congenital disorder of glycosylation, camptodactyly, myopia, and fibrosis of the medial rectus muscle of eye, radioulnar synostosis-microcephaly-scoliosis syndrome, blepharophimosis - intellectual disability syndrome, SBBYS type, complex regional pain syndrome type 1, temtamy preaxial brachydactyly syndrome, Diamond-Blackfan anemia 2, genitopatellar syndrome, Phelan-McDermid syndrome, hypotonia-cystinuria syndrome, DNA ligase IV deficiency, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, Duane-radial ray syndrome, psoriatic arthritis, neonatal ichthyosis-sclerosing cholangitis syndrome, skin fragility-woolly hair-palmoplantar keratoderma syndrome, tubulointerstitial nephritis and uveitis syndrome, caudal duplication, sweet syndrome, ichthyosis prematurity syndrome, Meacham syndrome, BNAR syndrome, PCWH syndrome, foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome, B-cell immunodeficiency, distal limb anomalies, and urogenital malformations, MEDNIK syndrome, Cerebrorenodigital syndrome, fetal valproate syndrome, Goldberg-Shprintzen syndrome, Al-Gazali syndrome, CEDNIK syndrome, osteosclerosis-ichthyosis-premature ovarian failure syndrome, cortical dysplasia-focal epilepsy syndrome, DK1-congenital disorder of glycosylation, Potocki-Lupski syndrome, Pitt-Hopkins syndrome, XFE progeroid syndrome, deafness-infertility syndrome, COG1-congenital disorder of glycosylation, autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome, microtia-eye coloboma-imperforation of the nasolacrimal duct syndrome, mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria, ANE syndrome, CLOVES syndrome, Hirschsprung disease-ganglioneuroblastoma syndrome, parkinsonism-dystonia, infantile, alpha 1-antitrypsin deficiency, COG5-congenital disorder of glycosylation, chromosome 13q14 deletion syndrome, deafness-lymphedema-leukemia syndrome, microcephaly-capillary malformation syndrome, EDICT syndrome, peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome, hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism, IMAGe syndrome, short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome, microcephalic primordial dwarfism, Alazami type, intellectual disability-strabismus syndrome, estrogen resistance syndrome, Hartsfield-Bixler-Demyer syndrome, severe dermatitis-multiple allergies-metabolic wasting syndrome, alacrima, achalasia, and intellectual disability syndrome, familial episodic pain syndrome with predominantly lower limb involvement, congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome, diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, tall stature-scoliosis-macrodactyly of the great toes syndrome, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome, retinitis pigmentosa-juvenile cataract-short stature-intellectual disability syndrome, polyendocrine-polyneuropathy syndrome, chronic atrial and intestinal dysrhythmia, motor developmental delay due to 14q32.2 paternally expressed gene defect, peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome, mandibulofacial dysostosis with alopecia, epilepsy with myoclonic atonic seizures, short stature, microcephaly, and endocrine dysfunction, progressive microcephaly-seizures-cortical blindness-developmental delay syndrome, PMP22-RAI1 contiguous gene duplication syndrome, acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome, familial progressive retinal dystrophy-iris coloboma-congenital cataract syndrome, macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome, Luscan-Lumish syndrome, even-plus syndrome, MIRAGE syndrome, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, intellectual disability-epilepsy-extrapyramidal syndrome, 48,XXYY syndrome, FRAXF syndrome, complex hereditary spastic paraplegia, aniridia-ptosis-intellectual disability-familial obesity syndrome, aniridia - intellectual disability syndrome, ankyloblepharon filiforme-imperforate anus syndrome, pentasomy X, Bardet-Biedl syndrome, anophthalmia-megalocornea-cardiopathy-skeletal anomalies syndrome, Bartter syndrome, arachnodactyly-intellectual disability-dysmorphism syndrome, ataxia-photosensitivity-short stature syndrome, Brugada syndrome, Feingold syndrome, cardiomyopathy-cataract-hip spine disease syndrome, cataract - microcornea syndrome, autism-facial port-wine stain syndrome, cataract-intellectual disability-anal atresia-urinary defects syndrome, cataract-deafness-hypogonadism syndrome, syndromic craniosynostosis, drug rash with eosinophilia and systemic symptoms, multicentric reticulohistiocytosis, hereditary sensory and autonomic neuropathy with deafness and global delay, craniofacial microsomia, ring chromosome 10, Coffin-Siris syndrome, corpus callosum agenesis-double urinary collecting system syndrome, short rib-polydactyly syndrome, oromandibular-limb anomalies syndrome, hemophagocytic syndrome, cataract-glaucoma syndrome, diencephalic syndrome, hypereosinophilic syndrome, distal trisomy 14q, intellectual disability-cataracts-kyphosis syndrome, progressive familial intrahepatic cholestasis, thoraco-abdominal enteric duplication, oculomaxillofacial dysostosis, growth hormone insensitivity syndrome, syndromic dyslipidemia, macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, epiphyseal dysplasia-hearing loss-dysmorphism syndrome, eosinophilic granulomatosis with polyangiitis, axial mesodermal dysplasia spectrum, fetal hydantoin syndrome, vitamin K-antagonist embryofetopathy, fetal alcohol syndrome, methimazole embryofetopathy, Evans syndrome, Cornelia de Lange syndrome, cleft lip-retinopathy syndrome, cleft lip/palate-deafness-sacral lipoma syndrome, Crandall syndrome, syndromic microphthalmia, Cole-Carpenter syndrome, myotonic syndrome, Guillain-Barre syndrome, atypical hemolytic-uremic syndrome, Hennekam syndrome, Hernández-Aguirre Negrete syndrome, nodular neuronal heterotopia, Hirschsprung disease-type D brachydactyly syndrome, holoprosencephaly, hydrocephalus-obesity-hypogonadism syndrome, hydrocephalus-blue sclerae-nephropathy syndrome, xeroderma pigmentosum-Cockayne syndrome complex, Joubert syndrome with ocular defect, hypogonadism-mitral valve prolapse-intellectual disability syndrome, hypogonadotropic hypogonadism-retinitis pigmentosa syndrome, hypotrichosis-intellectual disability, Lopes type, congenital ichthyosis-microcephalus-tetraplegia syndrome, Hughes-Stovin syndrome, heart-hand syndrome, ptosis-upper ocular movement limitation-absence of lacrimal punctum syndrome, syndromic agammaglobulinemia, isotretinoin syndrome, microcornea-posterior megalolenticonus-persistent fetal vasculature-coloboma syndrome, Kabuki syndrome, Kenny-Caffey syndrome, muscular pseudohypertrophy-hypothyroidism syndrome, Kousseff syndrome, limb body wall complex, Lennox-Gastaut syndrome, Lowe-Kohn-Cohen syndrome, macrocephaly-short stature-paraplegia syndrome, primary ciliary dyskinesia, familial intestinal malrotation-facial anomalies syndrome, primary hypertrophic osteoarthropathy, Melhem-Fahl syndrome, lower limb deficiency-hypospadias syndrome, 8p23.1 microdeletion syndrome, sickle cell-beta-thalassemia disease syndrome, sickle cell-hemoglobin c disease syndrome, sickle cell-hemoglobin d disease syndrome, sickle cell-hemoglobin E disease syndrome, hereditary persistence of fetal hemoglobin-sickle cell disease syndrome, microcephaly-brain defect-spasticity-hypernatremia syndrome, microcephaly-microcornea syndrome, Seemanova type, Meier-Gorlin syndrome, Mikati-Najjar-Sahli syndrome, shoulder and girdle defects-familial intellectual disability syndrome, myopathy-growth delay-intellectual disability-hypospadias syndrome, Fuchs heterochromic iridocyclitis, microcephalic osteodysplastic primordial dwarfism types I and III, osteochondrodysplatic nanism-deafness-retinitis pigmentosa syndrome, arthrogryposis-renal dysfunction-cholestasis syndrome, oculo-skeletal-renal syndrome, olivopontocerebellar atrophy-deafness syndrome, Opitz G/BBB syndrome, imperforate oropharynx-costo vetebral anomalies syndrome, Bruck syndrome, osteoporosis-macrocephaly-blindness-joint hyperlaxity syndrome, calciphylaxis, recessive intellectual disability-motor dysfunction-multiple joint contractures syndrome, X-linked ichthyosis syndrome, autoimmune polyendocrinopathy, renal caliceal diverticuli-deafness syndrome, tempi syndrome, syndromic oculocutaneous albinism, short stature-deafness-neutrophil dysfunction-dysmorphism syndrome, congenital varicella syndrome, polyneuropathy-intellectual disability-acromicria-premature menopause syndrome, celiac trunk compression syndrome, hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndrome, fetal cytomegalovirus syndrome, Reunion island Larsen syndrome, 46,XX disorder of sex development-anorectal anomalies syndrome, mitochondrial neurogastrointestinal encephalomyopathy, Baraitser-Winter cerebrofrontofacial syndrome, mirror polydactyly-vertebral segmentation-limbs defects syndrome, intellectual disability-hypotonia-skin hyperpigmentation syndrome, congenital hereditary facial paralysis-variable hearing loss syndrome, intellectual disability-microcephaly-phalangeal-facial abnormalities syndrome, Mayer-Rokitansky-Kuster-Hauser syndrome, developmental and speech delay due to SOX5 deficiency, Spigelian hernia-cryptorchidism syndrome, autosomal recessive leukoencephalopathy-ischemic stroke-retinitis pigmentosa syndrome, severe neonatal hypotonia-seizures-encephalopathy syndrome due to 5q31.3 microdeletion, multiple sclerosis-ichthyosis-factor VIII deficiency syndrome, X-linked spasticity-intellectual disability-epilepsy syndrome, spina bifida-hypospadias syndrome, hantavirus pulmonary syndrome, white matter hypoplasia-corpus callosum agenesis-intellectual disability syndrome, deafness-genital anomalies-metacarpal and metatarsal synostosis syndrome, hearing loss-familial salivary gland insensitivity to aldosterone syndrome, multiple synostoses syndrome, central nervous system calcification-deafness-tubular acidosis-anemia syndrome, multiple paragangliomas associated with polycythemia, syngnathia multiple anomalies, Takayasu arteritis, severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiency, spondylocostal dysostosis-hypospadias-intellectual disability syndrome, hypotrichosis-deafness syndrome, thalidomide embryopathy, trisomy X, trisomy 13, trisomy 18, umbilical cord ulceration-intestinal atresia syndrome, microcephaly-brachydactyly-kyphoscoliosis syndrome, Waardenburg syndrome, Weill-Marchesani syndrome, infantile spasms, Wolfram syndrome, epidermal nevus syndrome, digital anomalies-intellectual disability-short stature syndrome, intellectual disability-obesity-brain malformations-facial dysmorphism syndrome, Erdheim-Chester disease, Stevens-Johnson syndrome, CADDS, finger hyperphalangy - toe anomalies - severe pectus excavatum syndrome, ataxia - telangiectasia variant, growth retardation-mild developmental delay-chronic hepatitis syndrome, primary microcephaly-mild intellectual disability-young-onset diabetes syndrome, ferro-cerebro-cutaneous syndrome, dystonia-aphonia syndrome, microcephaly-complex motor and sensory axonal neuropathy syndrome, X-linked microcephaly-growth retardation-prognathism-cryptorchidism syndrome, severe intellectual disability-hypotonia-strabismus-coarse face-planovalgus syndrome, intrauterine growth restriction-short stature-early adult-onset diabetes syndrome, pseudoxanthoma elasticum-like skin manifestations with retinitis pigmentosa, familial chylomicronemia syndrome, caudal regression-sirenomelia spectrum, visceral heterotaxy, Holmes-Adie syndrome, microcephalic primordial dwarfism due to RTTN deficiency, Joubert syndrome, congenital generalized hypercontractile muscle stiffness syndrome, Kallmann syndrome, Caroli syndrome, X-linked female restricted facial dysmorphism-short stature-choanal atresia-intellectual disability, microlissencephaly-micromelia syndrome, branchiootic syndrome, Plummer-Vinson syndrome, Cushing syndrome, McCune-Albright syndrome, Meckel syndrome, SUNCT syndrome, mucopolysaccharidosis type 3, mucopolysaccharidosis type 4, congenital myasthenic syndrome, Loeys-Dietz syndrome, Alport syndrome, schisis association, Tolosa-Hunt syndrome, iridocorneal endothelial syndrome, short fifth metacarpals-insulin resistance syndrome, progressive supranuclear palsy, benign exophthalmos syndrome, Sandifer syndrome, global developmental delay-osteopenia-ectodermal defect syndrome, tubular renal disease-cardiomyopathy syndrome, angioosteohypotrophic syndrome, 6q terminal deletion syndrome, Axenfeld-Rieger syndrome, peroxisome biogenesis disorder, ectodermal dysplasia syndrome, Seckel syndrome, Sotos syndrome, Stickler syndrome, pelvis syndrome, Susac syndrome, ischio-vertebral syndrome, BRESEK syndrome, Turner syndrome, Usher syndrome, obesity-colitis-hypothyroidism-cardiac hypertrophy-developmental delay syndrome, CREST syndrome, Sheehan syndrome, polymyalgia rheumatica, autoinflammatory syndrome, neuroleptic malignant syndrome, pituitary stalk interruption syndrome, monosomy 13q34, ring chromosome 13, 48,XXXY syndrome, 49,XXXXY syndrome, hereditary continuous muscle fiber activity, Eisenmenger syndrome, Robinow syndrome, Ehlers-Danlos syndrome, hypoplastic right heart syndrome, shone complex, 48,XYYY syndrome, subcortical band heterotopia, complex regional pain syndrome type 2, faciodigitogenital syndrome, neoplastic syndrome, paraneoplastic syndrome, post-infectious syndrome, Achard-Thiers syndrome, acral dysostosis dyserythropoiesis syndrome, agnathia-microstomia-synotia, Aksu von Stockhausen syndrome, Aloi Tomasini Isaia syndrome, temporomandibular joint dysfunction syndrome, Apert-like polydactyly syndrome, arakawa syndrome 2, arena syndrome, Arnold stickler bourne syndrome, baetz-greenwalt syndrome, bagatelle Cassidy syndrome, baker Vinters syndrome, bobble-head doll syndrome, Boerhaave syndrome, Cantu Sanchez-Corona Fragoso syndrome, Cantu Sanchez-Corona Hernandez syndrome, carbon baby syndrome, Carnevale hernandez castillo syndrome, Cartwright Nelson Fryns syndrome, Charles bonnet syndrome, Parinaud syndrome, corticobasal degeneration disorder, hair defect with photosensitivity and intellectual disability syndrome, AIDS dysmorphic syndrome, congenital acardia, acute lymphoblastic leukemia congenital sporadic aniridia, aglossia and situs inversus, agyria pachygyria polymicrogyria, agyria-pachygyria type 1, Ahumada Del Castillo syndrome, alopecia congenita keratosis palmoplantaris, alpha-mannosidosis type 1, aluminosis, Mauriac syndrome, ankle defects short stature, ankyloblepharon filiforme imperforate anus, annular constricting bands, anophthalmia cleft palate micrognathia, anophthalmia esophageal atresia cryptorchidism, anotia facial palsy cardiac defect, aortic dissection lentiginosis, childhood aortic valve stenosis, arthrogryposis IUGR thoracic dystrophy, arthrogryposis multiplex congenita CNS calcification, arthrogryposis spinal muscular atrophy, asternia, atlanto-axial fusion, atrophoderma of Pierini and Pasini, Barnicoat Baraitser syndrome, Basedow’s coma, BD syndrome, Beardwell syndrome, bhaskar jagannathan syndrome, bidirectional tachycardia, bilirubin induced brain injury in the newborn, blepharo naso facial syndrome van Maldergem type, bone dysplasia corpus callosum agenesis, brachydactyly absence of distal phalanges, brachydactyly anonychia, brachydactyly small stature face anomalies, brachydactyly tibial hypoplasia, brittle bone syndrome lethal type, bronchiectasis oligospermia, Brunsting-Perry syndrome, bruyn scheltens syndrome, burn goodship syndrome, camptodactyly joint contractures and facial skeletal dysplasia, camptodactyly vertebral fusion, Cantu Sanchez-Corona Garcia-Cruz syndrome, cardiac hydatid cysts with intracavitary expansion, cardioencephalomyopathy, cardiofacial syndrome short limbs, cardiomelic syndrome stratton Koehler type, cardiomyopathy and deafness due to tRNA lysine gene mutation, cardiomyopathy diabetes deafness, cardiomyopathy hypogonadism collagenoma syndrome, cardiomyopathy hypogonadism metabolic anomalies, cardiomyopathy spherocytosis, carpo tarsal osteolysis recessive, autosomal dominant cataract, cataract skeletal anomalies, cennamo gangemi syndrome, cerebellar agenesis, cerebello-olivary atrophy, cerebral calcification cerebellar hypoplasia, cerebral calcifications opalescent teeth phosphaturia, oculo digital syndrome, chondrodysplasia, choreoacanthocytosis amyotrophic, chorioretinopathy dominant form microcephaly, Christian Demyer Franken syndrome, Christian Johnson angenieta syndrome, chromosome 3 duplication syndrome, chronic demyelinizing neuropathy with IgM monoclonal, ciliary dyskinesia-bronchiectasis, circumscribed cutaneous aplasia of the vertex, circumscribed disseminated keratosis Jadassohn lew type, cleft lip and palate malrotation cardiopathy, cleft lip and/or palate with mucous cysts of lower, cleft lip palate dysmorphism kumar type, cleft lip palate intellectual disability corneal opacity, cleft lip palate oligodontia syndactyly pili torti, cleft lip palate pituitary deficiency, cleft lip palate-tetraphocomelia, cleft lower lip cleft lateral canthi chorioretinal, cleft palate cardiac defect ectrodactyly, cleft palate colobomata radial synostosis deafness, cleft palate heart disease polydactyly absent tibia, cleft tongue, coarse face hypotonia constipation, Cohen Lockood Wyborney syndrome, type 2 collagenopathy, Collins-Sakati syndrome, coloboma porencephaly hydronephrosis, colobomata unilobar lung heart defect, colonic malakoplakia, Colver Steer Godman syndrome, Combarros Calleja Leno syndrome, complement receptor deficiency, congenital absence of the sternocleidomastoid muscle, congenital amputation, congenital aneurysms of the great vessels, congenital articular rigidity, congenital benign spinal muscular atrophy dominant, congenital cardiovascular shunt, congenital contractures, congenital craniosynostosis maternal hyperthyroiditis, congenital cystic eye, congenital heart disease ptosis hypodontia craniostosis, congenital heart disease radio ulnar synostosis intellectual disability, congenital mumps, congenital stenosis of cervical medullary canal, Dennis-Fairhurst-Moore syndrome, congenital unilateral pulmonary hypoplasia, congenital vagal hyperreflexivity, Cormier Rustin Munnich syndrome, corneal crystals myopathy neuropathy, corneal dystrophy ichthyosis microcephaly intellectual disability, corneal dystrophy pigmentary anomaly malabsorption, corpus callosum agenesis of blepharophimosis robin type, corpus callosum dysgenesis X-linked recessive, corpus callosum dysgenesis cleft spasm, corpus callosum dysgenesis hypopituitarism, cortada Koussef Matsumoto syndrome, Cortes Lacassie syndrome, craniofacial and skeletal defects, craniofacial dysostosis arthrogryposis progeroid appearance, craniofrontonasal syndrome Teebi type, craniostenosis with congenital heart disease intellectual disability, crawfurd syndrome, cutis gyratum acanthosis nigricans craniosynostosis, cutis laxa osteoporosis, Davenport-Donlan syndrome, Davis Lafer syndrome, de Hauwere Leroy adriaenssens syndrome, deafness conductive stapedial ear malformation facial palsy, deafness goiter stippled epiphyses, deafness hypospadias metacarpal and metatarsal syndrome, deafness mesenteric diverticula of small bowel neuropathy, deafness peripheral neuropathy arterial disease, deafness progressive cataract autosomal dominant, dermatocardioskeletal syndrome boronne type, dextrocardia with situs inversus, diabetes persistent mullerian ducts, diaphragmatic agenesis radial aplasia omphalocele, diaphragmatic hernia exomphalos corpus callosum agenesis, diaphragmatic hernia upper limb defects, die Smulders droog van dijk syndrome, diomedi bernardi placidi syndrome, diphallus rachischisis imperforate anus, distichiasis heart congenital anomalies, double discordia, double uterus-hemivagina-renal agenesis, Drachtman Weinblatt Sitarz syndrome, Duker-Weiss-Siber syndrome, duodenal atresia tetralogy of fallot, duplication of leg mirror foot, duplication of the thumb unilateral biphalangeal, dupont sellier chochillon syndrome, dwarfism bluish sclerae, dwarfism deafness retinitis pigmentosa, dwarfism lethal type advanced bone age, dwarfism thin bones multiple fractures, dysmorphism cleft palate loose skin, Eagle syndrome, ectrodactyly cardiopathy dysmorphism, Elliott ludman Teebi syndrome, enamel hypoplasia cataract hydrocephaly, encephalocele anencephaly, enchondromatosis dwarfism deafness, Engelhard Yatziv syndrome, enlarged vestibular aqueduct syndrome, epidermal nevus vitamin D resistant rickets, epimetaphyseal dysplasia cataract, epiphyseal dysplasia dysmorphism camptodactyly, esophageal atresia coloboma talipes, extrasystoles short stature hyperpigmentation microcephaly, facial clefting corpus callosum agenesis, facio digito genital syndrome recessive form, facio skeletal genital syndrome rippberger type, familial capillaro-venous leptomeningeal angiomatosis, Dursun syndrome, Faye-Petersen-Ward-Carey syndrome, feigenbaum Bergeron syndrome, Feingold trainer syndrome, fetal brain disruption sequence, fetal enterovirus syndrome, fetal parainfluenza virus type 3 syndrome, fetal phenothiazine syndrome, fibromatosis multiple non ossifying, fibula aplasia complex brachydactyly, fibular hypoplasia scapulo pelvic dysplasia absent, Fitz-Hugh-Curtis syndrome, focal alopecia congenital megalencephaly, focal or multifocal malformations in neuronal migration, foix chavany Marie syndrome, Fontaine farriaux blanckaert syndrome, Fraser Jequier Chen syndrome, Freiberg disease, Friedman Goodman syndrome, frontonasal malformation cloacal exstrophy, frontonasal dysplasia Klippel feil syndrome, frontonasal dysplasia phocomelic upper limbs, Fryns Fabry Remans syndrome, Fryns Smeets Thiry syndrome, Fuchs atrophia gyrata chorioideae et retinae, Fukuda-Miyanomae-Nakata syndrome, Fuqua Berkovitz syndrome, Garret-Tripp syndrome, gas bloat syndrome, Gaucher ichthyosis restrictive dermopathy, gershinibaruch Leibo syndrome, Ghose-Sachdev-Kumar syndrome, gigantism advanced bone age hoarse cry, glossopalatine ankylosis micrognathia ear anomalies, goldstein hutt syndrome, goniodysgenesis intellectual disability short stature, green sandford davison syndrome, grix Blankenship Peterson syndrome, Ho-Kaufman-McAlister syndrome, Jaffer-Beighton syndrome, Judge Misch wright syndrome, Kashani-Strom-Utley syndrome, Kasznica-Carlson-Coppedge syndrome, Katsantoni-Papadakou-Lagoyanni syndrome, Kocher-debre-Semelaigne syndrome, Koone-Rizzo-Elias syndrome, Kozlowski Brown Hardwick syndrome, Kozlowski Ouvrier syndrome, Kozlowski Rafinski Klicharska syndrome, Kozlowski Warren Fisher syndrome, Krauss Herman Holmes syndrome, Krieble Bixler syndrome, Kuster Majewski Hammerstein syndrome, Kuster syndrome, Laugier-Hunziker syndrome, Laurence-Prosser-Rocker syndrome, le Marec-Bracq-Picaud syndrome, levator syndrome, Marinesco-Sjogren-like syndrome, Milner-Khallouf-Gibson syndrome, radio-digito-facial dysplasia, Seckel like syndrome majoor-krakauer type, neonatal aspiration syndrome, muscular fibrosis multifocal obstructed vessels, short stature contractures hypotonia, Alice in Wonderland syndrome, megacystis-microcolon-intestinal hypoperistalsis syndrome, Basilicata-Akhtar syndrome, Liberfarb syndrome, craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome, cardiac, facial, and digital anomalies with developmental delay, fibrosis, neurodegeneration, and cerebral angiomatosis, Duane anomaly-myopathy-scoliosis syndrome, congenital cataract-severe neonatal hepatopathy-global developmental delay syndrome, infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome, acute radiation syndrome, monoclonal mast cell activation syndrome, oculocerebrodental syndrome, syndromic congenital sodium diarrhea, congenital brachyesophagus-intrathoracic stomach-vertebral anomalies syndrome, intellectual disability-cardiac anomalies-short stature-joint laxity syndrome, intrauterine growth restriction-congenital multiple café-au-lait macules-increased sister chromatid exchange syndrome, frontonasal dysplasia-bifid nose-upper limb anomalies syndrome, microcephaly-facial dysmorphism-ocular anomalies-multiple congenital anomalies syndrome, diaphragmatic hernia-short bowel-asplenia syndrome, warts-immunodeficiency-lymphedema-anogenital dysplasia syndrome, Cramp-fasciculation syndrome, choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome, blepharophimosis-intellectual disability syndrome/genitopatellar overlap syndrome, CCNK-related neurodevelopmental disorder-severe intellectual disability-facial dysmorphism syndrome, cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome, KLHL7-related Bohring-Opitz-like syndrome, KLHL7-related cold-induced sweating-like syndrome, KAT6B-related multiple congenital anomalies syndrome, oculogastrointestinal-neurodevelopmental syndrome, spastic paraparesis-cataracts-speech delay syndrome, Ruzicka-Goerz-Anton syndrome, Sammartino-Decreccio syndrome, Samson-Gardner syndrome, Samson-Viljoen syndrome, Sanderson-Fraser syndrome, Sandhaus-Ben-Ami syndrome, prostatic malacoplakia associated with prostatic abscess, Saul-Wilkes-Stevenson syndrome, macrogyria, pseudobulbar palsy and intellectual disability, Schwartz-Cohen-addad-Lambert syndrome, Schlegelberger-Grote syndrome, Schrander-stumpel-Theunissen-Hulsmans syndrome, Saal-Bulas syndrome, Sackey-Sakati-Aur syndrome, Slti-Salem syndrome, Zerres Rietschel Majewski syndrome, Zazam Sheriff Phillips syndrome, Zadik-Barak-Levin syndrome, weinstein kliman scully syndrome, thickened earlobes with conductive deafness from incus-stapes abnormalities, ichthyosis linearis circumflexa, infantile striato thalamic degeneration, Landy-Donnai syndrome, merlob grunebaum reisner syndrome, Pavone Fiumara Rizzo syndrome, pfeiffer rockelein syndrome, Pfeiffer Tietze Welte syndrome, phosphoribosylpyrophosphate synthetase deficiency, piepkorn karp hickok syndrome, podder-tolmie syndrome, pointer syndrome, richieri-costa guion-almeida cohen syndrome, Rubinstein Taybi like syndrome, ruvalcaba churesigaew myhre syndrome, short limb dwarf lethal colavita kozlowski type, Mallory-Weiss syndrome, superior vena cava syndrome, piriformis syndrome, engraftment syndrome, Adams-Stokes syndrome, Leriche syndrome, multiple organ dysfunction syndrome, posterior leukoencephalopathy syndrome, cardio-renal syndrome, Rahman syndrome, X-linked keloid scarring-reduced joint mobility-increased optic cup-to-disc ratio syndrome, retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, Lopes-Maciel-Rodan syndrome, Stankiewicz-Isidor syndrome, Skraban-Deardorff syndrome, joint laxity, short stature, and myopia, Sweeney-Cox syndrome, Alkuraya-Kucinskas syndrome, Jaberi-Elahi syndrome, neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures, hearing impairment and infertile male syndrome, cardiocutaneous syndrome, neonatal diabetes, congenital sensorineural hearing loss and congenital cataracts, cardioectodermal syndrome, cannabinoid hyperemesis syndrome, retrograde cricopharyngeus dysfunction, Zinner syndrome, retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome, IFAP syndrome, DICER1-related tumor predisposition, Roberts-SC phocomelia syndrome, carcinoid syndrome, Bonnevie-Ullrich syndrome, NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction, RNU4ATAC spectrum disorder, syndromic congenital heart disease, hand-foot syndrome, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, gastrointestinal defects and immunodeficiency syndrome 1, achalasia-alacrima syndrome, black locks with albinism and deafness syndrome, Birt-Hogg-Dube syndrome, trigeminal trophic syndrome, developmental and/or epileptic encephalopathy with spike-wave activation in sleep, syndromic microspherophakia, painful legs and moving toes syndrome, congenital aphakia-iris hypoplasia-microphthalmia-microcornea syndrome, hereditary persistence of fetal hemoglobin-intellectual disability syndrome, developmental delay-immunodeficiency-leukoencephalopathy-hypohomocysteinemia syndrome, primary hypomagnesemia-generalized seizures-intellectual disability-obesity syndrome, post-cardiac arrest syndrome, early-onset obesity-hyperphagia-severe developmental delay syndrome, hereditary alpha tryptasemia syndrome, KINSSHIP syndrome, developmental delay, hypotrophy, and dysmorphic features without moebius syndrome, breast implant illness, cataracts, hearing impairment, nephrotic syndrome, and enterocolitis, craniosynostosis-facial dysmorphism-chiari-1 malformation-developmental and language delay syndrome, MYT1L-related developmental delay-intellectual disability-obesity syndrome, Houge-Janssens syndrome, xerosis and growth failure with immune and pulmonary dysfunction syndrome, Fliedner-Zweier syndrome, Lui-Jee-Baron syndrome, Long-Olsen-Distelmaier syndrome, Tan-Almurshedi syndrome, diabetes, deafness, developmental delay, and short stature syndrome, Alfadhel syndrome, Hoxha-Aliu syndrome, cleft palate-congenital heart defect-intellectual disability syndrome, congenital insensitivity to pain syndrome, Marsili type, Yuksel-Vogel-Bauer syndrome, polydactyly-macrocephaly syndrome, pyoderma gangrenosum-acne-hidradenitis suppurativa-ankylosing spondylitis syndrome, psoriatic arthritis-pyoderma gangrenosum-acne-hidradenitis suppurativa syndrome, megalencephaly-polydactyly syndrome, Leigh syndrome, mitochondrial, auroneurodental syndrome, orofacial clefting-cardiac anomalies-facial dysmorphism syndrome, Grisel syndrome, arterial tortuosity-bone fragility syndrome, dialysis disequilibrium syndrome, brain abnormalities-severe developmental delay-facial dysmorphism-intellectual disability syndrome due to MEF2C mutation, Kariminejad neurodevelopmental syndrome, myelofibrosis, congenital, with anemia, neutropenia, developmental delay, and ocular abnormalities, brain malformation renal syndrome, myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis 2, Karayol-Borroto-Haghshenas neurodevelopmental syndrome, neurodegeneration, infantile-onset, with optic atrophy and brain abnormalities, Morimoto-Ryu-Malicdan neuromuscular syndrome, neurodevelopmental disorder with dysmorphic facies, absent speech and ambulation, and brain abnormalities, neurodevelopmental disorder with variable familial hypercholanemia, Pan-Chung-Bellen syndrome, telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature, Muggenthaler-Chowdhury-Chioza syndrome, Tayoun-Maawali syndrome, ragopathy, cardiovascular-kidney-metabolic syndrome, craniofaciocardiohepatic syndrome, FICUS syndrome, Li-Takada-Miyake syndrome, Guillouet-Gordon syndrome, ICHAD syndrome, cataract, alopecia, oral mucosal disorder, and psoriasis-like syndrome, RAC2-related combined immunodeficiency-bronchiectasis-cancer-predisposing syndrome, oculovertebral syndrome, Alsahan-Harris syndrome, Ververi-Brady syndrome, Dursun-Ozgul neurodevelopmental syndrome, immune dysregulation, neurodevelopmental defects, and colitis, Harel-Tora neurodevelopmental syndrome, Valence-Farazi cerebellar ataxia syndrome, dyschromatosis, ichthyosis, deafness, and atopic disease, Ramond-Elliott neurodevelopmental syndrome, STAD syndrome, craniosynostosis-scoliosis syndrome, loin pain hematuria syndrome, IRF6-related condition, linkeropathy, NDUFB11-related disorders, CRYAB-related myofibrillar myopathy-cataract-cardiomyopathy spectrum disorder, TSEN2-related neurodevelopmental disorder with or without thrombotic microangiopathy, antiphospholipid syndrome

Subtypes (14): Noonan syndrome 1, Noonan syndrome 2, Noonan syndrome 3, Noonan syndrome 4, Noonan syndrome 5, Noonan syndrome 6, Noonan syndrome 7, Noonan syndrome 8, Noonan syndrome 9, Noonan syndrome 10, Noonan syndrome 14, Noonan syndrome 11, noonan syndrome 12, Noonan syndrome 13

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

176 uncertain significance, 118 pathogenic, 104 likely benign, 71 pathogenic/likely pathogenic, 50 conflicting classifications of pathogenicity, 37 benign, 22 benign/likely benign, 22 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4075175	NM_001374828.1(ARID1B):c.3506del (p.Lys1169fs)	ARID1B	Pathogenic	criteria provided, single submitter
13964	NM_004333.6(BRAF):c.1391G>A (p.Gly464Glu)	BRAF	Pathogenic	reviewed by expert panel
13965	NM_004333.6(BRAF):c.736G>C (p.Ala246Pro)	BRAF	Pathogenic	reviewed by expert panel
13969	NM_004333.6(BRAF):c.1789C>G (p.Leu597Val)	BRAF	Pathogenic	criteria provided, multiple submitters, no conflicts
13975	NM_004333.6(BRAF):c.1455G>C (p.Leu485Phe)	BRAF	Pathogenic	reviewed by expert panel
13977	NM_004333.6(BRAF):c.1501G>A (p.Glu501Lys)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162795	NM_004333.6(BRAF):c.2135C>A (p.Ala712Asp)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
177844	NM_004333.6(BRAF):c.1455G>T (p.Leu485Phe)	BRAF	Pathogenic	reviewed by expert panel
180784	NM_004333.6(BRAF):c.739T>C (p.Phe247Leu)	BRAF	Pathogenic	reviewed by expert panel
29805	NM_004333.6(BRAF):c.722C>T (p.Thr241Met)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40351	NM_004333.6(BRAF):c.769C>A (p.Gln257Lys)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40373	NM_004333.6(BRAF):c.1502A>C (p.Glu501Ala)	BRAF	Pathogenic	criteria provided, multiple submitters, no conflicts
40375	NM_004333.6(BRAF):c.1513C>T (p.Leu505Phe)	BRAF	Pathogenic	criteria provided, multiple submitters, no conflicts
40387	NM_004333.6(BRAF):c.1787G>T (p.Gly596Val)	BRAF	Pathogenic	reviewed by expert panel
40388	NM_004333.6(BRAF):c.1796C>T (p.Thr599Ile)	BRAF	Pathogenic	reviewed by expert panel
41446	NM_004333.6(BRAF):c.1801A>C (p.Lys601Gln)	BRAF	Pathogenic	criteria provided, multiple submitters, no conflicts
44818	NM_004333.6(BRAF):c.1802A>C (p.Lys601Thr)	BRAF	Pathogenic	criteria provided, multiple submitters, no conflicts
44829	NM_004333.6(BRAF):c.722C>A (p.Thr241Lys)	BRAF	Pathogenic	reviewed by expert panel
44831	NM_004333.6(BRAF):c.785A>C (p.Gln262Pro)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
55793	NM_004333.6(BRAF):c.741T>G (p.Phe247Leu)	BRAF	Pathogenic	reviewed by expert panel
13807	NM_005188.4(CBL):c.1100A>C (p.Gln367Pro)	CBL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
177959	NM_005188.4(CBL):c.1228-2A>G	CBL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
180815	NM_005188.4(CBL):c.1096-1G>T	CBL	Pathogenic	criteria provided, multiple submitters, no conflicts
45196	NM_005188.4(CBL):c.1096-1G>C	CBL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
45197	NM_005188.4(CBL):c.1096-4_1096-1del	CBL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4072118	NM_004380.3(CREBBP):c.5658del (p.Ser1887fs)	CREBBP	Pathogenic	criteria provided, single submitter
420168	NM_006494.4(ERF):c.1201_1202del (p.Lys401fs)	ERF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12606	NM_005343.4(HRAS):c.37G>T (p.Gly13Cys)	HRAS	Pathogenic	reviewed by expert panel
12586	NM_004985.5(KRAS):c.178G>C (p.Gly60Arg)	KRAS	Pathogenic	reviewed by expert panel
12587	NM_004985.5(KRAS):c.458A>T (p.Asp153Val)	KRAS	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 217 · Orphanet: 85 · 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
BRAF	Definitive	Autosomal dominant	Noonan syndrome 7	23
KRAS	Definitive	Autosomal dominant	Noonan syndrome 3	17
LZTR1	Definitive	Autosomal dominant	Noonan syndrome 10	15
MRAS	Definitive	Autosomal dominant	Noonan syndrome 11	7
NRAS	Definitive	Autosomal dominant	Noonan syndrome	10
PTPN11	Definitive	Autosomal dominant	Noonan syndrome 1	19
RAF1	Definitive	Autosomal dominant	Noonan syndrome	18
RIT1	Definitive	Autosomal dominant	Noonan syndrome	6
RRAS2	Definitive	Autosomal dominant	Noonan syndrome	8
SHOC2	Definitive	Autosomal dominant	Noonan syndrome-like disorder with loose anagen hair	9
SOS1	Definitive	Autosomal dominant	Noonan syndrome	10
SOS2	Definitive	Autosomal dominant	Noonan syndrome 9	7
ERF	Strong	Autosomal dominant	Noonan syndrome	10
ETF1	Strong	Autosomal dominant	Noonan syndrome	10
MAP2K1	Strong	Autosomal dominant	Noonan syndrome with multiple lentigines	11
RRAS	Strong	Autosomal dominant	Noonan syndrome and Noonan-related syndrome	4
RASA2	Moderate	Autosomal dominant	Noonan syndrome	3
A2ML1	Supportive	Autosomal dominant	Noonan syndrome	4
CBL	Supportive	Autosomal dominant	Noonan syndrome	8
MAP2K2	Supportive	Autosomal dominant	neurofibromatosis-Noonan syndrome	9
RASA1	Disputed Evidence	Autosomal dominant	Noonan syndrome	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RIT1	Orphanet:648	Noonan syndrome
RRAS	Orphanet:648	Noonan syndrome
RRAS	Orphanet:86834	Juvenile myelomonocytic leukemia
BRAF	Orphanet:1340	Cardiofaciocutaneous syndrome
BRAF	Orphanet:146	Differentiated thyroid carcinoma
BRAF	Orphanet:251615	Pilomyxoid astrocytoma
BRAF	Orphanet:389	Langerhans cell histiocytosis
BRAF	Orphanet:500	Noonan syndrome with multiple lentigines
BRAF	Orphanet:54595	Craniopharyngioma
BRAF	Orphanet:58017	Classic hairy cell leukemia
BRAF	Orphanet:626	Large/giant congenital melanocytic nevus
BRAF	Orphanet:648	Noonan syndrome
BRAF	Orphanet:840	Syringocystadenoma papilliferum
BRAF	Orphanet:96253	Cushing disease
SOS1	Orphanet:2024	Hereditary gingival fibromatosis
SOS1	Orphanet:648	Noonan syndrome
SOS2	Orphanet:648	Noonan syndrome
CBL	Orphanet:363972	Noonan syndrome-like disorder with juvenile myelomonocytic leukemia
CBL	Orphanet:648	Noonan syndrome
CBL	Orphanet:86834	Juvenile myelomonocytic leukemia
CBL	Orphanet:98850	Aggressive systemic mastocytosis
SHOC2	Orphanet:2701	Noonan syndrome-like disorder with loose anagen hair
RRAS2	Orphanet:648	Noonan syndrome
ERF	Orphanet:207	Crouzon syndrome
ERF	Orphanet:647681	Craniosynostosis-facial dysmorphism-Chiari-1 malformation-developmental and language delay syndrome
KRAS	Orphanet:1333	Familial pancreatic carcinoma
KRAS	Orphanet:1340	Cardiofaciocutaneous syndrome
KRAS	Orphanet:144	Lynch syndrome
KRAS	Orphanet:146	Differentiated thyroid carcinoma
KRAS	Orphanet:2396	Encephalocraniocutaneous lipomatosis
KRAS	Orphanet:251615	Pilomyxoid astrocytoma
KRAS	Orphanet:2612	Linear nevus sebaceus syndrome
KRAS	Orphanet:268114	RAS-associated autoimmune leukoproliferative disease
KRAS	Orphanet:3339	Oculoectodermal syndrome
KRAS	Orphanet:648	Noonan syndrome
KRAS	Orphanet:86834	Juvenile myelomonocytic leukemia
LZTR1	Orphanet:251576	Gliosarcoma
LZTR1	Orphanet:251579	Giant cell glioblastoma
LZTR1	Orphanet:2678	Familial isolated café-au-lait macules
LZTR1	Orphanet:648	Noonan syndrome
LZTR1	Orphanet:93921	Full schwannomatosis
MAP2K1	Orphanet:1340	Cardiofaciocutaneous syndrome
MAP2K1	Orphanet:389	Langerhans cell histiocytosis
MAP2K2	Orphanet:1340	Cardiofaciocutaneous syndrome
MAP2K2	Orphanet:638	Neurofibromatosis-Noonan syndrome
NRAS	Orphanet:146	Differentiated thyroid carcinoma
NRAS	Orphanet:2612	Linear nevus sebaceus syndrome
NRAS	Orphanet:268114	RAS-associated autoimmune leukoproliferative disease
NRAS	Orphanet:389	Langerhans cell histiocytosis
NRAS	Orphanet:626	Large/giant congenital melanocytic nevus

Cohort genes → proteins

29 cohort genes, 29 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	29

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RIT1	HGNC:10023	ENSG00000143622	Q92963	GTP-binding protein Rit1	gencc,clinvar
RRAS	HGNC:10447	ENSG00000126458	P10301	Ras-related protein R-Ras	gencc,clinvar
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	gencc,clinvar
SOS1	HGNC:11187	ENSG00000115904	Q07889	Son of sevenless homolog 1	gencc,clinvar
SOS2	HGNC:11188	ENSG00000100485	Q07890	Son of sevenless homolog 2	gencc,clinvar
CBL	HGNC:1541	ENSG00000110395	P22681	E3 ubiquitin-protein ligase CBL	gencc,clinvar
SHOC2	HGNC:15454	ENSG00000108061	Q9UQ13	Leucine-rich repeat protein SHOC-2	gencc,clinvar
RRAS2	HGNC:17271	ENSG00000133818	P62070	Ras-related protein R-Ras2	gencc,clinvar
A2ML1	HGNC:23336	ENSG00000166535	A8K2U0	Alpha-2-macroglobulin-like protein 1	gencc,clinvar
ERF	HGNC:3444	ENSG00000105722	P50548	ETS domain-containing transcription factor ERF	gencc,clinvar
ETF1	HGNC:3477	ENSG00000120705	P62495	Eukaryotic peptide chain release factor subunit 1	gencc,clinvar
KRAS	HGNC:6407	ENSG00000133703	P01116	GTPase KRas	gencc,clinvar
LZTR1	HGNC:6742	ENSG00000099949	Q8N653	Leucine-zipper-like transcriptional regulator 1	gencc,clinvar
MAP2K1	HGNC:6840	ENSG00000169032	Q02750	Dual specificity mitogen-activated protein kinase kinase 1	gencc,clinvar
MAP2K2	HGNC:6842	ENSG00000126934	P36507	Dual specificity mitogen-activated protein kinase kinase 2	gencc,clinvar
NRAS	HGNC:7989	ENSG00000213281	P01111	GTPase NRas	gencc,clinvar
PTPN11	HGNC:9644	ENSG00000179295	Q06124	Tyrosine-protein phosphatase non-receptor type 11	gencc,clinvar
RAF1	HGNC:9829	ENSG00000132155	P04049	RAF proto-oncogene serine/threonine-protein kinase	gencc,clinvar
RASA2	HGNC:9872	ENSG00000155903	Q15283	Ras GTPase-activating protein 2	gencc,clinvar
MRAS	HGNC:7227	ENSG00000158186	O14807	Ras-related protein M-Ras	gencc
RASA1	HGNC:9871	ENSG00000145715	P20936	Ras GTPase-activating protein 1	gencc
SPRED2	HGNC:17722	ENSG00000198369	Q7Z698	Sprouty-related, EVH1 domain-containing protein 2	clinvar
ARID1B	HGNC:18040	ENSG00000049618	Q8NFD5	AT-rich interactive domain-containing protein 1B	clinvar
SPRED1	HGNC:20249	ENSG00000166068	Q7Z699	Sprouty-related, EVH1 domain-containing protein 1	clinvar
CREBBP	HGNC:2348	ENSG00000005339	Q92793	CREB-binding protein	clinvar
LRRC56	HGNC:25430	ENSG00000161328	Q8IYG6	Leucine-rich repeat-containing protein 56	clinvar
DMPK	HGNC:2933	ENSG00000104936	Q09013	Myotonin-protein kinase	clinvar
HRAS	HGNC:5173	ENSG00000174775	P01112	GTPase HRas	clinvar
PPP1CB	HGNC:9282	ENSG00000213639	P62140	Serine/threonine-protein phosphatase PP1-beta catalytic subunit	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RIT1	GTP-binding protein Rit1	Plays a crucial role in coupling NGF stimulation to the activation of both EPHB2 and MAPK14 signaling pathways and in NGF-dependent neuronal differentiation.
RRAS	Ras-related protein R-Ras	GTP-binding protein with GTPase activity, likely involved in the regulation of MAPK signaling pathway and thereby controlling multiple cellular processes.
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
SOS1	Son of sevenless homolog 1	Promotes the exchange of Ras-bound GDP by GTP.
SOS2	Son of sevenless homolog 2	Acts as guanine nucleotide exchange factor (GEF) for RAS proteins.
CBL	E3 ubiquitin-protein ligase CBL	E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors.
SHOC2	Leucine-rich repeat protein SHOC-2	Core component of the SHOC2-MRAS-PP1c (SMP) holophosphatase complex that regulates activation of the MAPK pathway.
RRAS2	Ras-related protein R-Ras2	GTP-binding protein with GTPase activity, involved in the regulation of MAPK signaling pathway and thereby controlling multiple cellular processes.
A2ML1	Alpha-2-macroglobulin-like protein 1	Is able to inhibit all four classes of proteinases by a unique ’trapping’ mechanism.
ERF	ETS domain-containing transcription factor ERF	Potent transcriptional repressor that binds to the H1 element of the Ets2 promoter.
ETF1	Eukaryotic peptide chain release factor subunit 1	Component of the eRF1-eRF3-GTP ternary complex, a ternary complex that mediates translation termination in response to the termination codons.
KRAS	GTPase KRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
LZTR1	Leucine-zipper-like transcriptional regulator 1	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates ubiquitination of Ras (K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS).
MAP2K1	Dual specificity mitogen-activated protein kinase kinase 1	Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway.
MAP2K2	Dual specificity mitogen-activated protein kinase kinase 2	Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases.
NRAS	GTPase NRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
PTPN11	Tyrosine-protein phosphatase non-receptor type 11	Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus.
RAF1	RAF proto-oncogene serine/threonine-protein kinase	Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including prolifer…
RASA2	Ras GTPase-activating protein 2	Inhibitory regulator of the Ras-cyclic AMP pathway.
MRAS	Ras-related protein M-Ras	Signal transducer in the Ras-MAPK signaling pathway that regulates cell proliferation and survival.
RASA1	Ras GTPase-activating protein 1	GTPase-activating protein (GAP) that stimulates the intrinsic GTPase activity of Ras proteins, such as NRAS, facilitating their transition from the active GTP-bound state to the inactive GDP-bound state, thereby terminating Ras signaling.
SPRED2	Sprouty-related, EVH1 domain-containing protein 2	Negatively regulates Ras signaling pathways and downstream activation of MAP kinases.
ARID1B	AT-rich interactive domain-containing protein 1B	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
SPRED1	Sprouty-related, EVH1 domain-containing protein 1	Tyrosine kinase substrate that inhibits growth-factor-mediated activation of MAP kinase.
CREBBP	CREB-binding protein	Acetylates histones, giving a specific tag for transcriptional activation.
LRRC56	Leucine-rich repeat-containing protein 56	Required for the assembly of dynein arms.
DMPK	Myotonin-protein kinase	Non-receptor serine/threonine protein kinase which is necessary for the maintenance of skeletal muscle structure and function.
HRAS	GTPase HRas	Involved in the activation of Ras protein signal transduction.
PPP1CB	Serine/threonine-protein phosphatase PP1-beta catalytic subunit	Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets.

Protein-family classification

Druggable: 10 · Difficult: 6 · Unknown: 13 · Druggable fraction: 0.34

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	5	4.8×	0.024
Phosphatase	2	5.8×	0.163
Complement	1	9.2×	0.240
Scaffold/PPI	3	1.8×	0.410
Transcription factor	3	0.8×	0.827
Enzyme (other)	2	0.8×	0.827
Other/Unknown	13	0.8×	0.916

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RIT1	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
RRAS	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
SOS1	Scaffold/PPI	no		DH_dom, Ras-like_Gua-exchang_fac_N, PH_domain
SOS2	Scaffold/PPI	no		DH_dom, Ras-like_Gua-exchang_fac_N, PH_domain
CBL	Transcription factor	no	2.3.2.27	Znf_RING, Adaptor_Cbl_N_hlx, UBA-like_sf
SHOC2	Other/Unknown	no		Leu-rich_rpt, Leu-rich_rpt_typical-subtyp, LRR_dom_sf
RRAS2	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
A2ML1	Complement	yes		Macroglobln_a2, MG2, Terpenoid_cyclase/PrenylTrfase
ERF	Other/Unknown	no		Ets_dom, WH-like_DNA-bd_sf, WH_DNA-bd_sf
ETF1	Other/Unknown	no		Peptide_chain-rel_eRF1/aRF1, eRF1_Pelota-like_N, eRF1_2
KRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
LZTR1	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
MAP2K1	Kinase	yes	2.7.12.2	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
MAP2K2	Kinase	yes	2.7.12.2	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
NRAS	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
PTPN11	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, SH2
RAF1	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
RASA2	Transcription factor	no		C2_dom, Znf_Btk_motif, PH_domain
MRAS	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
RASA1	Scaffold/PPI	no		C2_dom, SH2, SH3_domain
SPRED2	Other/Unknown	no		WH1/EVH1_dom, Sprouty, PH-like_dom_sf
ARID1B	Other/Unknown	no		ARID_dom, BAF250/Osa, BAF250_C
SPRED1	Other/Unknown	no		WH1/EVH1_dom, Sprouty, PH-like_dom_sf
CREBBP	Transcription factor	no	2.3.1.48	Znf_TAZ, Znf_ZZ, Bromodomain
LRRC56	Other/Unknown	no		Leu-rich_rpt, Leu-rich_rpt_4, LRR_dom_sf
DMPK	Kinase	yes	2.7.11.1	Prot_kinase_dom, AGC-kinase_C, Ser/Thr_kinase_AS
HRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
PPP1CB	Phosphatase	yes	3.1.3.16	Calcineurin-like_PHP, Ser/Thr-sp_prot-phosphatase, Metallo-depent_PP-like

Expression context

Cohort genes with no expression data: 0.

29 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)	29
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	5
calcaneal tendon	4
buccal mucosa cell	3
colonic epithelium	3
secondary oocyte	3
mucosa of sigmoid colon	3
ventricular zone	3
right coronary artery	2
trigeminal ganglion	2
oocyte	2
gingival epithelium	2
mucosa of stomach	2
right uterine tube	2
left testis	2
right testis	2
epithelium of nasopharynx	2
medial globus pallidus	2
amniotic fluid	2
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RIT1	268	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
RRAS	242	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon
SOS1	289	ubiquitous	marker	colonic epithelium, jejunal mucosa, tendon of biceps brachii
SOS2	298	ubiquitous	marker	vastus lateralis, biceps brachii, buccal mucosa cell
CBL	271	ubiquitous	marker	primordial germ cell in gonad, trigeminal ganglion, male germ line stem cell (sensu Vertebrata) in testis
SHOC2	299	ubiquitous	marker	calcaneal tendon, sural nerve, bone marrow
RRAS2	287	ubiquitous	marker	secondary oocyte, oocyte, skeletal muscle tissue of rectus abdominis
A2ML1	176	tissue_specific	marker	lower esophagus mucosa, gingiva, gingival epithelium
ERF	242	ubiquitous	marker	right uterine tube, mucosa of stomach, gall bladder
ETF1	293	ubiquitous	marker	islet of Langerhans, upper leg skin, mucosa of sigmoid colon
KRAS	298	ubiquitous	marker	trigeminal ganglion, pylorus, nipple
LZTR1	134	ubiquitous	marker	sural nerve, pituitary gland, adenohypophysis
MAP2K1	298	ubiquitous	marker	secondary oocyte, oocyte, orbitofrontal cortex
MAP2K2	291	ubiquitous	marker	mucosa of transverse colon, right testis, left testis
NRAS	278	ubiquitous	marker	gingival epithelium, epithelium of nasopharynx, secondary oocyte
PTPN11	295	ubiquitous	marker	medial globus pallidus, dorsal motor nucleus of vagus nerve, globus pallidus
RAF1	299	ubiquitous	marker	gastrocnemius, muscle of leg, ventricular zone
RASA2	269	ubiquitous	marker	epithelium of nasopharynx, superficial temporal artery, trabecular bone tissue
MRAS	263	ubiquitous	marker	lateral globus pallidus, medial globus pallidus, nucleus accumbens
RASA1	298	ubiquitous	marker	endothelial cell, placenta, choroid plexus epithelium
SPRED2	270	ubiquitous	marker	sural nerve, mucosa of sigmoid colon, ventricular zone
ARID1B	256	ubiquitous	marker	bone marrow cell, colonic epithelium, sural nerve
SPRED1	248	ubiquitous	marker	ventricular zone, mucosa of sigmoid colon, calcaneal tendon
CREBBP	297	ubiquitous	marker	sural nerve, tibia, amniotic fluid
LRRC56	129	broad	marker	right uterine tube, right testis, left testis
DMPK	246	broad	marker	apex of heart, right coronary artery, mucosa of stomach
HRAS	139	ubiquitous	marker	skin of abdomen, skin of leg, zone of skin
PPP1CB	295	ubiquitous	marker	calcaneal tendon, amniotic fluid, buccal mucosa cell

Protein interactions among cohort

Intra-cohort edges: 87.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRAS	14,509
HRAS	8,064
NRAS	7,598
BRAF	7,394
CREBBP	6,959
RAF1	6,574
PTPN11	6,009
MAP2K1	5,944
CBL	4,575
RASA1	4,407

Intra-cohort edges

A	B	Sources
A2ML1	LZTR1	string_interaction
A2ML1	RASA2	string_interaction
A2ML1	RIT1	string_interaction
A2ML1	SHOC2	string_interaction
BRAF	HRAS	intact, string_interaction
BRAF	KRAS	biogrid_interaction, intact, string_interaction
BRAF	MAP2K1	biogrid_interaction, intact, string_interaction
BRAF	MAP2K2	biogrid_interaction, intact, string_interaction
BRAF	MRAS	biogrid_interaction
BRAF	NRAS	biogrid_interaction, intact, string_interaction
BRAF	RAF1	biogrid_interaction, intact, string_interaction
BRAF	SHOC2	string_interaction
BRAF	SOS1	string_interaction
BRAF	SPRED1	string_interaction
BRAF	SPRED2	string_interaction
HRAS	LZTR1	biogrid_interaction
HRAS	MAP2K1	string_interaction
HRAS	MAP2K2	string_interaction
HRAS	MRAS	intact
HRAS	RAF1	intact, string_interaction
HRAS	RASA1	biogrid_interaction, string_interaction
HRAS	SHOC2	intact, string_interaction
HRAS	SOS1	intact, string_interaction
HRAS	SOS2	string_interaction
KRAS	LZTR1	string_interaction
KRAS	MAP2K1	biogrid_interaction, string_interaction
KRAS	MAP2K2	string_interaction
KRAS	NRAS	intact
KRAS	RAF1	intact, string_interaction
KRAS	SHOC2	intact, string_interaction
KRAS	SOS1	string_interaction
KRAS	SOS2	string_interaction
KRAS	SPRED1	string_interaction
LZTR1	MRAS	biogrid_interaction
LZTR1	NRAS	biogrid_interaction, intact, string_interaction
LZTR1	RASA2	string_interaction
LZTR1	RIT1	biogrid_interaction, intact, string_interaction
LZTR1	SHOC2	string_interaction
LZTR1	SOS1	string_interaction
LZTR1	SOS2	string_interaction
MAP2K1	MAP2K2	biogrid_interaction, intact, string_interaction
MAP2K1	NRAS	string_interaction
MAP2K1	PTPN11	biogrid_interaction, string_interaction
MAP2K1	RAF1	biogrid_interaction, intact, string_interaction
MAP2K1	SHOC2	string_interaction
MAP2K2	NRAS	intact, string_interaction
MAP2K2	PTPN11	string_interaction
MAP2K2	RAF1	biogrid_interaction, intact
MAP2K2	RASA2	string_interaction
MAP2K2	SHOC2	string_interaction

Structural data

PDB: 26 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511
HRAS	P01112	246
CREBBP	Q92793	144
BRAF	P15056	131
PTPN11	Q06124	115
MAP2K1	Q02750	94
SOS1	Q07889	91
RAF1	P04049	76
NRAS	P01111	35
CBL	P22681	33
ETF1	P62495	33
RASA1	P20936	15
SHOC2	Q9UQ13	13
SOS2	Q07890	11
MRAS	O14807	11
A2ML1	A8K2U0	5
RIT1	Q92963	3
RRAS2	P62070	3
LZTR1	Q8N653	3
MAP2K2	P36507	3
SPRED1	Q7Z699	3
RRAS	P10301	2
ERF	P50548	2
SPRED2	Q7Z698	2
ARID1B	Q8NFD5	2
DMPK	Q09013	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PPP1CB	P62140	91.91
RASA2	Q15283	83.63
LRRC56	Q8IYG6	56.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 402. Enrichment computed across 29 evidence-associated genes (26 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 26 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RAF activation	10	129.2×	3e-17	BRAF, SHOC2, KRAS, MAP2K1, MAP2K2, NRAS, RAF1, HRAS (+2 more)
RAS signaling downstream of NF1 loss-of-function variants	5	313.7×	1e-10	KRAS, NRAS, SPRED2, SPRED1, HRAS
Signaling by high-kinase activity BRAF mutants	7	85.4×	1e-10	BRAF, KRAS, MAP2K1, MAP2K2, NRAS, RAF1, HRAS
SHOC2 M1731 mutant abolishes MRAS complex function	5	274.5×	2e-10	BRAF, SHOC2, RAF1, MRAS, PPP1CB
Gain-of-function MRAS complexes activate RAF signaling	5	274.5×	2e-10	BRAF, SHOC2, RAF1, MRAS, PPP1CB
MAP2K and MAPK activation	7	76.9×	2e-10	BRAF, KRAS, MAP2K1, MAP2K2, NRAS, RAF1, HRAS
Signaling by RAF1 mutants	7	75.0×	2e-10	BRAF, KRAS, MAP2K1, MAP2K2, NRAS, RAF1, HRAS
Negative regulation of MAPK pathway	7	71.5×	2e-10	BRAF, KRAS, MAP2K1, MAP2K2, NRAS, RAF1, HRAS
Signaling by moderate kinase activity BRAF mutants	7	68.3×	2e-10	BRAF, KRAS, MAP2K1, MAP2K2, NRAS, RAF1, HRAS
Paradoxical activation of RAF signaling by kinase inactive BRAF	7	68.3×	2e-10	BRAF, KRAS, MAP2K1, MAP2K2, NRAS, RAF1, HRAS
Signaling downstream of RAS mutants	7	68.3×	2e-10	BRAF, KRAS, MAP2K1, MAP2K2, NRAS, RAF1, HRAS
RAF/MAP kinase cascade	10	23.5×	2e-10	BRAF, SOS1, SHOC2, KRAS, MAP2K1, MAP2K2, NRAS, SPRED2 (+2 more)
Activated NTRK2 signals through FRS2 and FRS3	5	183.0×	1e-09	SOS1, KRAS, NRAS, PTPN11, HRAS
Downstream signal transduction	6	87.8×	1e-09	SOS1, KRAS, NRAS, PTPN11, HRAS, RASA1
Regulation of RAS by GAPs	7	52.1×	1e-09	KRAS, NRAS, RASA2, SPRED2, SPRED1, HRAS, RASA1
Signaling by FGFR1	5	156.9×	2e-09	BRAF, SOS1, CBL, SPRED2, SPRED1
FLT3 Signaling	6	79.9×	2e-09	SOS1, CBL, KRAS, NRAS, PTPN11, HRAS
Signaling by BRAF and RAF1 fusions	7	45.9×	2e-09	BRAF, KRAS, MAP2K1, MAP2K2, NRAS, RAF1, HRAS
Signaling by FLT3 ITD and TKD mutants	5	146.4×	3e-09	SOS1, KRAS, NRAS, PTPN11, HRAS
Constitutive Signaling by EGFRvIII	5	137.3×	4e-09	SOS1, CBL, KRAS, NRAS, HRAS
Negative feedback regulation of MAPK pathway	4	292.8×	6e-09	BRAF, MAP2K1, MAP2K2, RAF1
Diseases of signal transduction by growth factor receptors and second messengers	9	19.7×	6e-09	BRAF, SOS1, CBL, SHOC2, MAP2K1, MAP2K2, SPRED2, SPRED1 (+1 more)
Tie2 Signaling	5	115.6×	8e-09	SOS1, KRAS, NRAS, PTPN11, HRAS
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	5	109.8×	1e-08	SOS1, CBL, KRAS, NRAS, HRAS
Signaling by SCF-KIT	6	57.3×	1e-08	SOS1, CBL, KRAS, NRAS, PTPN11, HRAS
Oncogenic MAPK signaling	6	57.3×	1e-08	BRAF, SHOC2, MAP2K1, MAP2K2, SPRED2, SPRED1
MAPK1/MAPK3 signaling	7	35.3×	1e-08	BRAF, SOS1, SHOC2, MAP2K1, MAP2K2, SPRED2, SPRED1
FRS-mediated FGFR3 signaling	5	104.6×	1e-08	SOS1, KRAS, NRAS, PTPN11, HRAS
CD209 (DC-SIGN) signaling	5	99.8×	1e-08	KRAS, NRAS, RAF1, CREBBP, HRAS
FRS-mediated FGFR4 signaling	5	95.5×	2e-08	SOS1, KRAS, NRAS, PTPN11, HRAS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 29 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
Ras protein signal transduction	9	63.8×	3e-12	RIT1, RRAS, SOS1, SOS2, RRAS2, KRAS, NRAS, HRAS (+1 more)
MAPK cascade	8	42.3×	2e-09	BRAF, KRAS, MAP2K1, MAP2K2, NRAS, RAF1, HRAS, PPP1CB
Schwann cell development	5	181.6×	5e-09	SOS1, MAP2K1, MAP2K2, RAF1, HRAS
face development	4	110.7×	4e-06	BRAF, MAP2K1, MAP2K2, RAF1
myelination	5	43.4×	6e-06	SOS1, MAP2K1, MAP2K2, RAF1, HRAS
thyroid gland development	4	75.0×	1e-05	BRAF, MAP2K1, MAP2K2, RAF1
insulin-like growth factor receptor signaling pathway	4	68.4×	2e-05	SOS1, MAP2K1, MAP2K2, RAF1
ERBB2-ERBB3 signaling pathway	3	174.3×	2e-05	MAP2K1, MAP2K2, RAF1
thymus development	4	46.5×	6e-05	BRAF, MAP2K1, MAP2K2, RAF1
neurotrophin TRK receptor signaling pathway	3	109.0×	9e-05	SOS1, PTPN11, RAF1
cerebellar cortex formation	2	387.4×	2e-04	MAP2K1, PTPN11
Schwann cell migration	2	387.4×	2e-04	RRAS, RRAS2
insulin receptor signaling pathway	4	30.6×	2e-04	SOS1, SOS2, RAF1, HRAS
regulation of Golgi inheritance	2	290.6×	4e-04	MAP2K1, MAP2K2
positive regulation of axonogenesis	3	60.1×	4e-04	BRAF, MAP2K1, MAP2K2
epithelial cell proliferation involved in lung morphogenesis	2	232.4×	6e-04	MAP2K1, MAP2K2
regulation of pro-B cell differentiation	2	232.4×	6e-04	SOS1, SOS2
negative regulation of lens fiber cell differentiation	2	193.7×	8e-04	SPRED2, SPRED1
signal transduction	9	5.0×	8e-04	RIT1, SOS1, CBL, MAP2K1, RAF1, RASA2, CREBBP, HRAS (+1 more)
regulation of T cell differentiation in thymus	2	166.0×	9e-04	SOS1, SOS2
regulation of axon regeneration	2	166.0×	9e-04	MAP2K1, MAP2K2
trachea formation	2	166.0×	9e-04	MAP2K1, MAP2K2
cytokine-mediated signaling pathway	4	18.0×	0.001	SOS1, CBL, KRAS, PTPN11
negative regulation of intracellular signal transduction	2	145.3×	0.001	SPRED2, SPRED1
regulation of early endosome to late endosome transport	2	145.3×	0.001	MAP2K1, MAP2K2
regulation of stress-activated MAPK cascade	2	129.1×	0.001	MAP2K1, MAP2K2
ERK1 and ERK2 cascade	3	32.9×	0.001	BRAF, MAP2K1, MAP2K2
negative regulation of neuron apoptotic process	4	15.3×	0.002	BRAF, KRAS, HRAS, RASA1
fibroblast growth factor receptor signaling pathway	3	29.6×	0.002	SOS1, SHOC2, PTPN11
Bergmann glial cell differentiation	2	105.7×	0.002	MAP2K1, PTPN11

Therapeutics

Drugs indicated for this disease

0 approved, 2 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Simvastatin	Phase 3 (in late-stage trials)
Somatropin	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Mecasermin.

Drug target analysis

Approved (phase 4): 11 · Phase ≥3: 11 · Phased (≥1): 12 · Undrugged: 17

Druggability breadth: 16 of 29 evidence-associated genes (55%) 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
BRAF	VEMURAFENIB
SOS1	IDARUBICIN
SOS2	TACRINE
KRAS	VEMURAFENIB
MAP2K1	VEMURAFENIB
MAP2K2	VEMURAFENIB
PTPN11	ESTRAMUSTINE PHOSPHATE
RAF1	VEMURAFENIB
CREBBP	COLCHICINE
DMPK	FEDRATINIB
HRAS	LONAFARNIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAP2K1	54	4
MAP2K2	52	4
BRAF	48	4
RAF1	31	4
DMPK	20	4
CREBBP	13	4
KRAS	11	4
PTPN11	8	4
SOS1	5	4
HRAS	4	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	BRAF, KRAS, MAP2K1, MAP2K2, RAF1
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF, DMPK, MAP2K1, MAP2K2
SORAFENIB	4	BRAF, MAP2K1, RAF1
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF, DMPK, MAP2K1, MAP2K2
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF, RAF1
DABRAFENIB	4	BRAF, KRAS, RAF1
COBIMETINIB	4	BRAF, MAP2K1, MAP2K2
NILOTINIB	4	BRAF, RAF1
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF, RAF1
PAZOPANIB	4	BRAF, RAF1
DASATINIB	4	BRAF, DMPK, MAP2K1, MAP2K2, RAF1
ERLOTINIB	4	BRAF, DMPK, RAF1
GEFITINIB	4	BRAF, DMPK
IMATINIB	4	BRAF, RAF1
IDARUBICIN	4	SOS1
DOXORUBICIN	4	SOS1
SOTORASIB	4	KRAS, SOS1
ADAGRASIB	4	KRAS, SOS1
TACRINE	4	SOS2
LONAFARNIB	4	HRAS, KRAS
SELUMETINIB	4	MAP2K1, MAP2K2
TRAMETINIB	4	MAP2K1, MAP2K2
BINIMETINIB	4	MAP2K1, MAP2K2
AXITINIB	4	MAP2K1, MAP2K2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 11.

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

Symbol	Assays	Type breakdown
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
MAP2K1	1,200	Binding:1150, Functional:47, ADMET:3
KRAS	861	Binding:829, Functional:32
RAF1	839	Binding:803, Functional:31, ADMET:5
CREBBP	687	Binding:644, Functional:43
MAP2K2	615	Binding:581, Functional:33, ADMET:1
PTPN11	588	Binding:585, Functional:2, ADMET:1
SOS1	421	Binding:409, Functional:12
DMPK	210	Binding:210
HRAS	48	Binding:45, Functional:3
NRAS	18	Binding:18
SOS2	10	Binding:10
PPP1CB	9	Binding:9
CBL	4	Binding:2, Toxicity:2
RRAS2	3	Binding:3
ETF1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
CBL	2.3.2.27	RING-type E3 ubiquitin transferase
KRAS	3.6.5.2	small monomeric GTPase
MAP2K1	2.7.12.2	mitogen-activated protein kinase kinase
MAP2K2	2.7.12.2	mitogen-activated protein kinase kinase
PTPN11	3.1.3.48	protein-tyrosine-phosphatase
RAF1	2.7.10.2	non-specific protein-tyrosine kinase
CREBBP	2.3.1.48	histone acetyltransferase
DMPK	2.7.11.1	non-specific serine/threonine protein kinase
HRAS	3.6.5.2	small monomeric GTPase
PPP1CB	3.1.3.16	protein-serine/threonine phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
BRAF	1,442
SOS1	421
KRAS	861
MAP2K1	1,200
MAP2K2	615
PTPN11	588
RAF1	839
CREBBP	687
DMPK	210

Pharmacogenomics

Cohort genes with a PharmGKB record: 29; 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)
VEMURAFENIB	4	BRAF, KRAS, MAP2K1, MAP2K2, RAF1
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF, DMPK, MAP2K1, MAP2K2
SORAFENIB	4	BRAF, MAP2K1, RAF1
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF, DMPK, MAP2K1, MAP2K2
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF, RAF1
DABRAFENIB	4	BRAF, KRAS, RAF1
COBIMETINIB	4	BRAF, MAP2K1, MAP2K2
NILOTINIB	4	BRAF, RAF1
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF, RAF1
PAZOPANIB	4	BRAF, RAF1
DASATINIB	4	BRAF, DMPK, MAP2K1, MAP2K2, RAF1
ERLOTINIB	4	BRAF, DMPK, RAF1
GEFITINIB	4	BRAF, DMPK
IMATINIB	4	BRAF, RAF1
IDARUBICIN	4	SOS1
DOXORUBICIN	4	SOS1
SOTORASIB	4	KRAS, SOS1
ADAGRASIB	4	KRAS, SOS1
TACRINE	4	SOS2
LONAFARNIB	4	HRAS, KRAS
SELUMETINIB	4	MAP2K1, MAP2K2
TRAMETINIB	4	MAP2K1, MAP2K2
BINIMETINIB	4	MAP2K1, MAP2K2
AXITINIB	4	MAP2K1, MAP2K2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	11	BRAF, SOS1, SOS2, KRAS, MAP2K1, MAP2K2, PTPN11, RAF1, CREBBP, DMPK (+1 more)
B	Phased (≥1) drug, not yet approved	1	NRAS
C	Druggable family + PDB, no drug	1	A2ML1
D	Druggable family + AlphaFold only, no drug	1	PPP1CB
E	Difficult family or no structure, no drug	15	RIT1, RRAS, CBL, SHOC2, RRAS2, ERF, ETF1, LZTR1, RASA2, MRAS (+5 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SHOC2	0	SOS1, NRAS
RASA2	0	SOS1, SOS2
MRAS	0	RAF1
RASA1	0	HRAS
SPRED1	0	RAF1
RIT1	0	—
RRAS	0	—
CBL	4	—
RRAS2	3	—
A2ML1	0	—
ERF	0	—
ETF1	1	—
LZTR1	0	—
SPRED2	0	—
ARID1B	0	—
LRRC56	0	—
PPP1CB	9	—

Clinical trials & evidence

Clinical trials

Clinical trials: 27.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	18
PHASE3	6
PHASE2	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05723835	PHASE3	ACTIVE_NOT_RECRUITING	A Research Study Looking at How Safe Somapacitan is and How Well it Works in Children Who Need Help to Grow - REAL 9
NCT00452725	PHASE3	COMPLETED	Effect of MAXOMAT ® on the Growth of Small Children to NOONAN’s Syndrome
NCT01529840	PHASE3	COMPLETED	Somatropin Effect on Linear Growth and Final Height in Subjects With Noonan Syndrome
NCT01529944	PHASE3	COMPLETED	Genetic Testing of Noonan Subjects Previously Treated With Norditropin®. An Extension to Trial GHNOO-1658
NCT01927861	PHASE3	COMPLETED	Investigating the Long-term Efficacy and Safety of Two Doses of NN-220 (Somatropin) in Short Stature Due to Noonan Syndrome
NCT02713945	PHASE3	COMPLETED	Treatment With HMG-COA Reductase Inhibitor of Growth and Bone Abnormalities in Children With Noonan Syndrome
NCT06555237	PHASE2	RECRUITING	MEK Inhibitors for the Treatment of Hypertrophic Cardiomyopathy in Patients With RASopathies
NCT06668805	PHASE2	RECRUITING	A Study of Vosoritide in Children With Noonan Syndrome With Inadequate Growth During or After Human Growth Hormone Treatment
NCT00351221	PHASE2	TERMINATED	Research Study Using Recombinant Human Insulin-Like Growth Factor-1/Recombinant Human Insulin-Like Growth Factor Binding Protein-3 for Children With Noonan Syndrome
NCT04395495	Not specified	RECRUITING	RASopathy Biorepository
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT04888936	Not specified	RECRUITING	Clinical, Genetic, and Epidemiologic Study of Children and Adults With RASopathies
NCT05202210	Not specified	RECRUITING	Constitution of a Biological Collection to Study the Pathophysiology in Noonan Syndrome
NCT05308927	Not specified	ENROLLING_BY_INVITATION	French Registry of Children Treated With Norditropin® for Short Stature Associated With Noonan Syndrome
NCT05361811	Not specified	RECRUITING	Acceptance and Commitment Therapy for Caregivers of Children With a RASopathy: An Internal Pilot Feasibility Study and Follow-up Randomized Controlled Trial
NCT05761314	Not specified	RECRUITING	Solid Tumors in RASopathies
NCT06938542	Not specified	ENROLLING_BY_INVITATION	Palliative Care Needs of Children With Rare Diseases and Their Families
NCT07259135	Not specified	NOT_YET_RECRUITING	Link Between Abnormal Bleeding and Coagulation Disorders in Noonan Syndromes
NCT07336394	Not specified	RECRUITING	Precision Diagnosis and Risk Stratification of Rare Cardiomyopathies Based on Novel Cardiac Magnetic Resonance Techniques
NCT07464821	Not specified	RECRUITING	National Multicentre Study on Lipid Profile in Noonan Syndrome and Related Disorders: Trends by Age, Gender and Genotype
NCT00960128	Not specified	COMPLETED	Observational Prospective Study on Patients Treated With Norditropin®
NCT02486731	Not specified	COMPLETED	Hormonal Sensitivity in Patients With Noonan and LEOPARD Syndromes
NCT03435627	Not specified	COMPLETED	Post Marketing Surveillance on Long-term Use With Norditropin® (Short Stature Due to Noonan Syndrome)
NCT06267807	Not specified	COMPLETED	Lymphatic Phenotype in Noonan Syndrome Spectrum Disorders
NCT06331117	Not specified	UNKNOWN	Effect of RAS/MAPK Pathway Hyperactivation on Growth’ and Bone’ Profile of the RASopathies
NCT06355622	Not specified	UNKNOWN	Prevalence and Characterization of Pain in RASopathies
NCT06550635	Not specified	COMPLETED	Joint and Hematologic Disorders of Noonan Syndrome: French Descriptive Cross-sectional Study

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SOMATROPIN	4	6
SOMAPACITAN	4	1
VOSORITIDE	4	1
RINFABATE	2	1
CHEMBL4216935	0	1