Cardiofaciocutaneous syndrome

Summary

Cardiofaciocutaneous syndrome (MONDO:0015280) is a disease caused by variants in BRAF, MAP2K1, MAP2K2, and 2 other genes, with 10 cohort genes and 7 clinical trials. The dominant Reactome pathway is RAF activation (7 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal genes: BRAF (GenCC Definitive), MAP2K1 (GenCC Definitive), MAP2K2 (GenCC Definitive), KRAS (GenCC Strong) (+1 more)
• Cohort genes: 10
• ClinVar variants: 86
• Phenotypes (HPO): 79
• Clinical trials: 7

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		300	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated
Point prevalence	1-9 / 1 000 000	0.12	Japan	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000463	Anteverted nares	Very frequent (80-99%)
HP:0000478	Abnormality of the eye	Very frequent (80-99%)
HP:0000499	Abnormal eyelash morphology	Very frequent (80-99%)
HP:0000504	Abnormality of vision	Very frequent (80-99%)
HP:0000637	Long palpebral fissure	Very frequent (80-99%)
HP:0000958	Dry skin	Very frequent (80-99%)
HP:0000982	Palmoplantar keratoderma	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001531	Failure to thrive in infancy	Very frequent (80-99%)
HP:0001631	Atrial septal defect	Very frequent (80-99%)
HP:0001642	Pulmonic stenosis	Very frequent (80-99%)
HP:0001654	Abnormal heart valve morphology	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0002213	Fine hair	Very frequent (80-99%)
HP:0002299	Brittle hair	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0007392	Excessive wrinkled skin	Very frequent (80-99%)
HP:0008872	Feeding difficulties in infancy	Very frequent (80-99%)
HP:0009891	Underdeveloped supraorbital ridges	Very frequent (80-99%)
HP:0030680	Abnormal cardiovascular system morphology	Very frequent (80-99%)
HP:0100840	Aplasia/Hypoplasia of the eyebrow	Very frequent (80-99%)
HP:0000276	Long face	Very frequent (80-99%)
HP:0000280	Coarse facial features	Very frequent (80-99%)
HP:0000293	Full cheeks	Very frequent (80-99%)
HP:0000391	Thickened helices	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000256	Macrocephaly	Frequent (30-79%)
HP:0000286	Epicanthus	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000343	Long philtrum	Frequent (30-79%)
HP:0000348	High forehead	Frequent (30-79%)
HP:0000400	Macrotia	Frequent (30-79%)
HP:0000465	Webbed neck	Frequent (30-79%)
HP:0000470	Short neck	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000494	Downslanted palpebral fissures	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000545	Myopia	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000767	Pectus excavatum	Frequent (30-79%)
HP:0000962	Hyperkeratosis	Frequent (30-79%)
HP:0000974	Hyperextensible skin	Frequent (30-79%)
HP:0001003	Multiple lentigines	Frequent (30-79%)
HP:0001048	Cavernous hemangioma	Frequent (30-79%)
HP:0001622	Premature birth	Frequent (30-79%)
HP:0002007	Frontal bossing	Frequent (30-79%)
HP:0002162	Low posterior hairline	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cardiofaciocutaneous syndrome
Mondo ID	MONDO:0015280
MeSH	C535579
OMIM	115150
Orphanet	1340
DOID	DOID:0060233
NCIT	C84617
SNOMED CT	403770008
UMLS	C1275081
MedGen	266149
GARD	0009146
NORD	891
Is cancer (heuristic)	no

Also known as: cardio-facio-cutaneous syndrome · cardiofaciocutaneous (CFC) syndrome · cardiofaciocutaneous syndrome · CFC · CFC syndrome · congenital heart defects characteristic facial appearance ectodermal abnormalities and growth failure

Data availability: 86 ClinVar variants · 14 ClinGen variant curations · 14 GenCC gene-disease records · 11 cell lines.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › multiple congenital anomalies/dysmorphic syndrome › multiple congenital anomalies/dysmorphic syndrome-intellectual disability › cardiofaciocutaneous syndrome

Related subtypes (337): Neu-Laxova syndrome, acrofacial dysostosis, Catania type, aortic arch anomaly-facial dysmorphism-intellectual disability syndrome, blepharonasofacial malformation syndrome, brachydactyly-nystagmus-cerebellar ataxia syndrome, craniofaciofrontodigital syndrome, uveal coloboma-cleft lip and palate-intellectual disability, Ramos-Arroyo syndrome, extrasystoles-short stature-hyperpigmentation-microcephaly syndrome, Floating-Harbor syndrome, Myhre syndrome, hirsutism-skeletal dysplasia-intellectual disability syndrome, Johnson neuroectodermal syndrome, KBG syndrome, trichorhinophalangeal syndrome type II, Lenz-Majewski hyperostotic dwarfism, Bannayan-Riley-Ruvalcaba syndrome, microcephaly-deafness-intellectual disability syndrome, ophthalmoplegia-intellectual disability-lingua scrotalis syndrome, omphalocele syndrome, Shprintzen-Goldberg type, Shprintzen-Goldberg syndrome, Smith-Magenis syndrome, delayed speech-facial asymmetry-strabismus-ear lobe creases syndrome, holoprosencephaly-radial heart renal anomalies syndrome, Wolf-Hirschhorn syndrome, pseudoprogeria syndrome, acrocallosal syndrome, acrofacial dysostosis Rodriguez type, agnathia-otocephaly complex, Stimmler syndrome, anencephaly 1, aniridia-renal agenesis-psychomotor retardation syndrome, Biemond syndrome type 2, bird headed-dwarfism, Montreal type, Bowen-Conradi syndrome, Elsahy-Waters syndrome, C syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, Cohen syndrome, cortical blindness-intellectual disability-polydactyly syndrome, Costello syndrome, temtamy syndrome, cardiocranial syndrome, Pfeiffer type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, Dubowitz syndrome, Bonnemann-Meinecke-Reich syndrome, epilepsy-telangiectasia syndrome, faciocardiorenal syndrome, fountain syndrome, Fryns syndrome, GAPO syndrome, Hall-Riggs syndrome, Mowat-Wilson syndrome, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, hypospadias-intellectual disability, Goldblatt type syndrome, Stromme syndrome, Johanson-Blizzard syndrome, Kapur-Toriello syndrome, oculocerebrofacial syndrome, Kaufman type, Keutel syndrome, Lambert syndrome, Laurence-Moon syndrome, intellectual disability-spasticity-ectrodactyly syndrome, prominent glabella-microcephaly-hypogenitalism syndrome, Marden-Walker syndrome, microcephaly-glomerulonephritis-marfanoid habitus syndrome, marfanoid habitus-autosomal recessive intellectual disability syndrome, McDonough syndrome, intellectual disability-dysmorphism-hypogonadism-diabetes mellitus syndrome, intellectual disability, Buenos-Aires type, microcephaly-cardiomyopathy syndrome, Say-Barber-Miller syndrome, microcephaly-cervical spine fusion anomalies syndrome, Jawad syndrome, lethal multiple pterygium syndrome, neurofaciodigitorenal syndrome, oculo-palato-cerebral syndrome, Oliver syndrome, lethal omphalocele-cleft palate syndrome, Peters plus syndrome, Pfeiffer-Palm-Teller syndrome, urban-Rogers-Meyer syndrome, Wiedemann-Rautenstrauch syndrome, holoprosencephaly-postaxial polydactyly syndrome, radioulnar synostosis-developmental delay-hypotonia syndrome, Ulbright-Hodes syndrome, microbrachycephaly-ptosis-cleft lip syndrome, Smith-Lemli-Opitz syndrome, congenital heart defect-round face-developmental delay syndrome, Filippi syndrome, upper limb defect-eye and ear abnormalities syndrome, Weaver syndrome, intellectual disability, Wolff type, CHIME syndrome, X-linked intellectual disability-plagiocephaly syndrome, 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, creatine transporter deficiency, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, chromosome Xp11.23-p11.22 duplication syndrome, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, SSR4-congenital disorder of glycosylation, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, intellectual disability-balding-patella luxation-acromicria syndrome, syndromic X-linked intellectual disability 5, male hypergonadotropic hypogonadism-intellectual disability-skeletal anomalies syndrome, X-linked intellectual disability with marfanoid habitus, N syndrome, pterygium colli-intellectual disability-digital anomalies syndrome, Lowry-MacLean syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, pseudoaminopterin syndrome, acrocardiofacial syndrome, Ayme-Gripp syndrome, Harrod syndrome, fallot complex-intellectual disability-growth delay syndrome, MMEP syndrome, epilepsy-microcephaly-skeletal dysplasia syndrome, Fine-Lubinsky syndrome, intellectual disability-sparse hair-brachydactyly syndrome, colobomatous microphthalmia - obesity - hypogenitalism - intellectual disability syndrome, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, Wiedemann-Steiner syndrome, cerebrooculonasal syndrome, genitopatellar syndrome, intellectual disability-obesity-prognathism-eye and skin anomalies syndrome, intellectual disability-brachydactyly-Pierre Robin syndrome, AICA-ribosiduria, Goldberg-Shprintzen syndrome, complex cortical dysplasia with other brain malformations 7, Kleefstra syndrome, Koolen-de Vries syndrome, agammaglobulinemia-microcephaly-craniosynostosis-severe dermatitis syndrome, mandibulofacial dysostosis-microcephaly syndrome, camptodactyly syndrome, Guadalajara type 3, chromosome 15q13.3 microdeletion syndrome, chromosome 6pter-p24 deletion syndrome, Zechi-Ceide syndrome, chromosome 19q13.11 deletion syndrome, chromosome 5p13 duplication syndrome, chromosome 17p13.3 duplication syndrome, syndromic multisystem autoimmune disease due to ITCH deficiency, chromosome 15q24 deletion syndrome, chromosome 17q21.31 duplication syndrome, chromosome 19p13.13 deletion syndrome, THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome, DYRK1A-related intellectual disability syndrome, chromosome 8q21.11 deletion syndrome, microcephaly-cerebellar hypoplasia-cardiac conduction defect syndrome, chromosome 16q22 deletion syndrome, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, short ulna-dysmorphism-hypotonia-intellectual disability syndrome, microcephaly-intellectual disability-phalangeal and neurological anomalies syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, Hartsfield-Bixler-Demyer syndrome, developmental and epileptic encephalopathy, 18, severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome, CTCF-related neurodevelopmental disorder, severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome, 8q24.3 microdeletion syndrome, microcephaly-thin corpus callosum-intellectual disability syndrome, macrocephaly-developmental delay syndrome, chromosome 5q12 deletion syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Tatton-Brown-Rahman overgrowth syndrome, orofaciodigital syndrome type 14, Catel-Manzke syndrome, cerebellar-facial-dental syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, Houge-Janssens syndrome 2, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome, hypomyelinating leukodystrophy 10, congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome, palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome, macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome, 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, TELO2-related intellectual disability-neurodevelopmental disorder, transketolase deficiency, severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, tall stature-intellectual disability-renal anomalies syndrome, ZTTK syndrome, short stature-brachydactyly-obesity-global developmental delay syndrome, mucopolysaccharidosis-plus syndrome, hypotonia, ataxia, and delayed development syndrome, caudal appendage-deafness syndrome, arachnodactyly-abnormal ossification-intellectual disability syndrome, ataxia-photosensitivity-short stature syndrome, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, brachydactyly-mesomelia-intellectual disability-heart defects syndrome, cataract-intellectual disability-anal atresia-urinary defects syndrome, cataract-deafness-hypogonadism syndrome, Coffin-Siris syndrome, intellectual disability-hypoplastic corpus callosum-preauricular tag syndrome, craniodigital syndrome-intellectual disability syndrome, cryptorchidism-arachnodactyly-intellectual disability syndrome, facial dysmorphism-shawl scrotum-joint laxity syndrome, epiphyseal dysplasia-hearing loss-dysmorphism syndrome, Cornelia de Lange syndrome, cleft palate-short stature-vertebral anomalies syndrome, Hennekam syndrome, Hernández-Aguirre Negrete syndrome, holoprosencephaly, dysmorphism-short stature-deafness-disorder of sex development syndrome, 5q14.3 microdeletion syndrome, Kabuki syndrome, ptosis-syndactyly-learning difficulties syndrome, macrocephaly-short stature-paraplegia syndrome, Warburg micro syndrome, microcephaly-seizures-intellectual disability-heart disease syndrome, microcephaly-cleft palate syndrome, microcephaly-microcornea syndrome, Seemanova type, multiple congenital anomalies due to 14q32.2 maternally expressed gene defect, neuroectodermal-endocrine syndrome, Opitz G/BBB syndrome, Xp22.13p22.2 duplication syndrome, short stature-webbed neck-heart disease syndrome, microtriplication 11q24.1, preaxial polydactyly-colobomata-intellectual disability syndrome, blepharophimosis - intellectual disability syndrome, 3MC syndrome, Baraitser-Winter cerebrofrontofacial syndrome, 11p15.4 microduplication syndrome, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, intellectual disability-short stature-hypertelorism syndrome, intellectual disability-polydactyly-uncombable hair syndrome, 20p13 microdeletion syndrome, 7p22.1 microduplication syndrome, intellectual disability-hypotonia-brachycephaly-pyloric stenosis-cryptorchidism syndrome, 15q overgrowth syndrome, van Maldergem syndrome, distal 17p13.1 microdeletion syndrome, deafness-genital anomalies-metacarpal and metatarsal synostosis syndrome, muscular hypertrophy-hepatomegaly-polyhydramnios syndrome, aphonia-deafness-retinal dystrophy-bifid halluces-intellectual disability syndrome, spondylocostal dysostosis-hypospadias-intellectual disability syndrome, telecanthus-hypertelorism-strabismus-pes cavus syndrome, microcephaly-brachydactyly-kyphoscoliosis syndrome, Weaver-Williams syndrome, 20q11.2 microduplication syndrome, 2p13.2 microdeletion syndrome, intellectual disability-seizures-macrocephaly-obesity syndrome, intellectual disability-facial dysmorphism-hand anomalies syndrome, XYLT1-congenital disorder of glycosylation, 3q27.3 microdeletion syndrome, 9q31.1q31.3 microdeletion syndrome, 14q24.1q24.3 microdeletion syndrome, FBLN1-related developmental delay-central nervous system anomaly-syndactyly syndrome, 13q12.3 microdeletion syndrome, cono-spondylar dysplasia, microcephaly-short stature-intellectual disability-facial dysmorphism syndrome, severe intellectual disability-hypotonia-strabismus-coarse face-planovalgus syndrome, 11q22.2q22.3 microdeletion syndrome, 20q11.2 microdeletion syndrome, 19p13.3 microduplication syndrome, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, 1p35.2 microdeletion syndrome, megalencephaly-severe kyphoscoliosis-overgrowth syndrome, intellectual disability-muscle weakness-short stature-facial dysmorphism syndrome, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, corpus callosum agenesis-macrocephaly-hypertelorism syndrome, DeSanto-Shinawi syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, Ritscher-Schinzel syndrome, visceral neuropathy-brain anomalies-facial dysmorphism-developmental delay syndrome, brain malformation-congenital heart disease-postaxial polydactyly 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, osteopenia-myopia-hearing loss-intellectual disability-facial dysmorphism syndrome, severe intellectual disability-epilepsy-anal anomalies-distal phalangeal hypoplasia, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, skeletal dysplasia-T-cell immunodeficiency-developmental delay syndrome, congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome, developmental and epileptic encephalopathy, 73, pancreatic agenesis-holoprosencephaly syndrome, oculocerebrodental syndrome, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, KAT6B-related multiple congenital anomalies syndrome, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 16p12.1p12.3 triplication syndrome, 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, early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, Gabriele de Vries syndrome, Skraban-Deardorff syndrome, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, Pilarowski-Bjornsson syndrome, glycosylphosphatidylinositol biosynthesis defect 15, multiple congenital anomalies-hypotonia-seizures syndrome, mesomelic dysplasia-digital anomalies-intellectual disability syndrome, KDM3B-related intellectual disability-facial dysmorphism-short stature syndrome, SLC12A2-related developmental delay-intellectual disability-sensorineural deafness syndrome, intellectual disability-early-onset cataract-microcephaly syndrome, cleft palate-congenital heart defect-intellectual disability syndrome, PRC-2 complex-related overgrowth spectrum, orofacial clefting-cardiac anomalies-facial dysmorphism syndrome, severe congenital myelofibrosis-pancytopenia-intellectual disability-neurologic and ophthalmic abnormalities syndrome, progressive hypotonia-intellectual disability-facial dysmorphism syndrome due to FYVE-defective RBSN, intellectual disability-epilepsy-dental anomalies-facial dysmorphism syndrome, 2q13 microdeletion syndrome, 10p13-p14 deletion syndrome, 3q26q28 deletion syndrome, Pitt-Hopkins or Pitt-Hopkins-like syndrome, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, Martsolf syndrome 1

Subtypes (4): cardiofaciocutaneous syndrome 1, cardiofaciocutaneous syndrome 2, cardiofaciocutaneous syndrome 3, cardiofaciocutaneous syndrome 4

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

86 retrieved; paginated sample, class counts are floors:

34 pathogenic, 26 pathogenic/likely pathogenic, 16 likely pathogenic, 5 conflicting classifications of pathogenicity, 3 uncertain significance, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
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
13970	NM_004333.6(BRAF):c.1405G>C (p.Gly469Arg)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13973	NM_004333.6(BRAF):c.770A>G (p.Gln257Arg)	BRAF	Pathogenic	reviewed by expert panel
13974	NM_004333.6(BRAF):c.1406G>A (p.Gly469Glu)	BRAF	Pathogenic	reviewed by expert panel
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
13978	NM_004333.6(BRAF):c.1502A>G (p.Glu501Gly)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13979	NM_004333.6(BRAF):c.1741A>G (p.Asn581Asp)	BRAF	Pathogenic	reviewed by expert panel
13980	NM_004333.6(BRAF):c.1600G>C (p.Gly534Arg)	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
162797	NM_004333.6(BRAF):c.1914T>G (p.Asp638Glu)	BRAF	Pathogenic	criteria provided, multiple submitters, no conflicts
177672	NM_004333.6(BRAF):c.1785T>G (p.Phe595Leu)	BRAF	Pathogenic	reviewed by expert panel
177844	NM_004333.6(BRAF):c.1455G>T (p.Leu485Phe)	BRAF	Pathogenic	reviewed by expert panel
202193	NM_004333.6(BRAF):c.1783T>C (p.Phe595Leu)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
223138	NM_004333.6(BRAF):c.1399T>G (p.Ser467Ala)	BRAF	Pathogenic	criteria provided, single submitter
29805	NM_004333.6(BRAF):c.722C>T (p.Thr241Met)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29807	NM_004333.6(BRAF):c.721A>C (p.Thr241Pro)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372572	NM_004333.6(BRAF):c.1390G>A (p.Gly464Arg)	BRAF	Pathogenic	criteria provided, multiple submitters, no conflicts
375946	NM_004333.6(BRAF):c.1781A>T (p.Asp594Val)	BRAF	Pathogenic	reviewed by expert panel
40346	NM_004333.6(BRAF):c.730A>C (p.Thr244Pro)	BRAF	Pathogenic	reviewed by expert panel
40347	NM_004333.6(BRAF):c.735A>C (p.Leu245Phe)	BRAF	Pathogenic	reviewed by expert panel
40348	NM_004333.6(BRAF):c.735A>T (p.Leu245Phe)	BRAF	Pathogenic	reviewed by expert panel
40351	NM_004333.6(BRAF):c.769C>A (p.Gln257Lys)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40366	NM_004333.6(BRAF):c.1403T>C (p.Phe468Ser)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40369	NM_004333.6(BRAF):c.1447A>C (p.Lys483Gln)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40371	NM_004333.6(BRAF):c.1497A>C (p.Lys499Asn)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40374	NM_004333.6(BRAF):c.1502A>T (p.Glu501Val)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40383	NM_004333.6(BRAF):c.1695T>G (p.Asp565Glu)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 126 · Orphanet: 46 · 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	cardiofaciocutaneous syndrome 1	23
KRAS	Definitive	Autosomal dominant	cardiofaciocutaneous syndrome 2	17
MAP2K1	Definitive	Autosomal dominant	cardiofaciocutaneous syndrome	11
MAP2K2	Definitive	Autosomal dominant	cardiofaciocutaneous syndrome	9
NRAS	Strong	Autosomal dominant	cardiofaciocutaneous syndrome	10
PTPN11	Disputed Evidence	Autosomal dominant	cardiofaciocutaneous syndrome	19
RAF1	Disputed Evidence	Autosomal dominant	cardiofaciocutaneous syndrome	18
SHOC2	Disputed Evidence	Autosomal dominant	cardiofaciocutaneous syndrome	9
SOS1	Disputed Evidence	Autosomal dominant	cardiofaciocutaneous syndrome	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
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
MAP2K1	Orphanet:1340	Cardiofaciocutaneous syndrome
MAP2K1	Orphanet:389	Langerhans cell histiocytosis
MAP2K2	Orphanet:1340	Cardiofaciocutaneous syndrome
MAP2K2	Orphanet:638	Neurofibromatosis-Noonan syndrome
PTPN11	Orphanet:2499	Metachondromatosis
PTPN11	Orphanet:500	Noonan syndrome with multiple lentigines
PTPN11	Orphanet:648	Noonan syndrome
PTPN11	Orphanet:86834	Juvenile myelomonocytic leukemia
SOS1	Orphanet:2024	Hereditary gingival fibromatosis
SOS1	Orphanet:648	Noonan syndrome
SHOC2	Orphanet:2701	Noonan syndrome-like disorder with loose anagen hair
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
NRAS	Orphanet:648	Noonan syndrome
NRAS	Orphanet:86834	Juvenile myelomonocytic leukemia
RAF1	Orphanet:154	Familial isolated dilated cardiomyopathy
RAF1	Orphanet:251615	Pilomyxoid astrocytoma
RAF1	Orphanet:500	Noonan syndrome with multiple lentigines
RAF1	Orphanet:626	Large/giant congenital melanocytic nevus
RAF1	Orphanet:648	Noonan syndrome
RIT1	Orphanet:648	Noonan syndrome

Cohort genes → proteins

10 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	gencc,clinvar
KRAS	HGNC:6407	ENSG00000133703	P01116	GTPase KRas	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
PTPN11	HGNC:9644	ENSG00000179295	Q06124	Tyrosine-protein phosphatase non-receptor type 11	gencc,clinvar
SOS1	HGNC:11187	ENSG00000115904	Q07889	Son of sevenless homolog 1	gencc
SHOC2	HGNC:15454	ENSG00000108061	Q9UQ13	Leucine-rich repeat protein SHOC-2	gencc
NRAS	HGNC:7989	ENSG00000213281	P01111	GTPase NRas	gencc
RAF1	HGNC:9829	ENSG00000132155	P04049	RAF proto-oncogene serine/threonine-protein kinase	gencc
RIT1	HGNC:10023	ENSG00000143622	Q92963	GTP-binding protein Rit1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
KRAS	GTPase KRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
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.
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.
SOS1	Son of sevenless homolog 1	Promotes the exchange of Ras-bound GDP by GTP.
SHOC2	Leucine-rich repeat protein SHOC-2	Core component of the SHOC2-MRAS-PP1c (SMP) holophosphatase complex that regulates activation of the MAPK pathway.
NRAS	GTPase NRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
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…
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.

Protein-family classification

Druggable: 6 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.6

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	4	11.1×	0.001
Phosphatase	1	8.4×	0.283
Scaffold/PPI	1	1.7×	0.727
Enzyme (other)	1	1.2×	0.727
Other/Unknown	3	0.5×	0.976

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
KRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
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
PTPN11	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, SH2
SOS1	Scaffold/PPI	no		DH_dom, Ras-like_Gua-exchang_fac_N, PH_domain
SHOC2	Other/Unknown	no		Leu-rich_rpt, Leu-rich_rpt_typical-subtyp, LRR_dom_sf
NRAS	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
RAF1	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
RIT1	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type

Expression context

Cohort genes with no expression data: 0.

10 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)	10
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	2
colonic epithelium	2
secondary oocyte	2
buccal mucosa cell	1
nipple	1
pylorus	1
trigeminal ganglion	1
oocyte	1
orbitofrontal cortex	1
left testis	1
mucosa of transverse colon	1
right testis	1
dorsal motor nucleus of vagus nerve	1
globus pallidus	1
medial globus pallidus	1
jejunal mucosa	1
tendon of biceps brachii	1
bone marrow	1
sural nerve	1
epithelium of nasopharynx	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon
KRAS	298	ubiquitous	marker	trigeminal ganglion, pylorus, nipple
MAP2K1	298	ubiquitous	marker	secondary oocyte, oocyte, orbitofrontal cortex
MAP2K2	291	ubiquitous	marker	mucosa of transverse colon, right testis, left testis
PTPN11	295	ubiquitous	marker	medial globus pallidus, dorsal motor nucleus of vagus nerve, globus pallidus
SOS1	289	ubiquitous	marker	colonic epithelium, jejunal mucosa, tendon of biceps brachii
SHOC2	299	ubiquitous	marker	calcaneal tendon, sural nerve, bone marrow
NRAS	278	ubiquitous	marker	gingival epithelium, epithelium of nasopharynx, secondary oocyte
RAF1	299	ubiquitous	marker	gastrocnemius, muscle of leg, ventricular zone
RIT1	268	ubiquitous	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 33.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRAS	14,509
NRAS	7,598
BRAF	7,394
RAF1	6,574
PTPN11	6,009
MAP2K1	5,944
MAP2K2	3,789
SOS1	3,625
RIT1	3,298
SHOC2	2,149

Intra-cohort edges

A	B	Sources
BRAF	KRAS	biogrid_interaction, intact, string_interaction
BRAF	MAP2K1	biogrid_interaction, intact, string_interaction
BRAF	MAP2K2	biogrid_interaction, intact, string_interaction
BRAF	NRAS	biogrid_interaction, intact, string_interaction
BRAF	RAF1	biogrid_interaction, intact, string_interaction
BRAF	SHOC2	string_interaction
BRAF	SOS1	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
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	SHOC2	string_interaction
MAP2K2	SOS1	string_interaction
NRAS	PTPN11	string_interaction
NRAS	RAF1	biogrid_interaction, intact, string_interaction
NRAS	SHOC2	biogrid_interaction, intact, string_interaction
NRAS	SOS1	string_interaction
PTPN11	SHOC2	string_interaction
PTPN11	SOS1	biogrid_interaction, string_interaction
RAF1	SHOC2	biogrid_interaction
RAF1	SOS1	string_interaction
RIT1	SHOC2	string_interaction
SHOC2	SOS1	string_interaction

Structural data

PDB: 10 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511
BRAF	P15056	131
PTPN11	Q06124	115
MAP2K1	Q02750	94
SOS1	Q07889	91
RAF1	P04049	76
NRAS	P01111	35
SHOC2	Q9UQ13	13
MAP2K2	P36507	3
RIT1	Q92963	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 238. Enrichment computed across 10 evidence-associated genes (10 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 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RAF activation	7	235.1×	3e-14	BRAF, KRAS, MAP2K1, MAP2K2, SHOC2, NRAS, RAF1
Signaling by high-kinase activity BRAF mutants	6	190.3×	2e-11	BRAF, KRAS, MAP2K1, MAP2K2, NRAS, RAF1
MAP2K and MAPK activation	6	171.3×	2e-11	BRAF, KRAS, MAP2K1, MAP2K2, NRAS, RAF1
Signaling by RAF1 mutants	6	167.1×	2e-11	BRAF, KRAS, MAP2K1, MAP2K2, NRAS, RAF1
Negative regulation of MAPK pathway	6	159.3×	2e-11	BRAF, KRAS, MAP2K1, MAP2K2, NRAS, RAF1
Signaling by moderate kinase activity BRAF mutants	6	152.3×	2e-11	BRAF, KRAS, MAP2K1, MAP2K2, NRAS, RAF1
Paradoxical activation of RAF signaling by kinase inactive BRAF	6	152.3×	2e-11	BRAF, KRAS, MAP2K1, MAP2K2, NRAS, RAF1
Signaling downstream of RAS mutants	6	152.3×	2e-11	BRAF, KRAS, MAP2K1, MAP2K2, NRAS, RAF1
Negative feedback regulation of MAPK pathway	4	761.3×	1e-10	BRAF, MAP2K1, MAP2K2, RAF1
Signaling by BRAF and RAF1 fusions	6	102.3×	2e-10	BRAF, KRAS, MAP2K1, MAP2K2, NRAS, RAF1
RAF/MAP kinase cascade	7	42.8×	7e-10	BRAF, KRAS, MAP2K1, MAP2K2, SOS1, SHOC2, NRAS
Activated NTRK2 signals through FRS2 and FRS3	4	380.7×	3e-09	KRAS, PTPN11, SOS1, NRAS
Signaling by FLT3 ITD and TKD mutants	4	304.5×	7e-09	KRAS, PTPN11, SOS1, NRAS
Signalling to ERKs	4	240.4×	2e-08	BRAF, MAP2K1, MAP2K2, SOS1
Tie2 Signaling	4	240.4×	2e-08	KRAS, PTPN11, SOS1, NRAS
FRS-mediated FGFR3 signaling	4	217.5×	3e-08	KRAS, PTPN11, SOS1, NRAS
FRS-mediated FGFR4 signaling	4	198.6×	4e-08	KRAS, PTPN11, SOS1, NRAS
FRS-mediated FGFR1 signaling	4	182.7×	5e-08	KRAS, PTPN11, SOS1, NRAS
FRS-mediated FGFR2 signaling	4	175.7×	6e-08	KRAS, PTPN11, SOS1, NRAS
MAPK1/MAPK3 signaling	5	65.6×	7e-08	BRAF, MAP2K1, MAP2K2, SOS1, SHOC2
Downstream signal transduction	4	152.3×	9e-08	KRAS, PTPN11, SOS1, NRAS
FLT3 Signaling	4	138.4×	1e-07	KRAS, PTPN11, SOS1, NRAS
MAPK family signaling cascades	5	51.4×	2e-07	BRAF, MAP2K1, MAP2K2, SOS1, SHOC2
SOS-mediated signalling	3	428.2×	2e-07	KRAS, SOS1, NRAS
Prolonged ERK activation events	3	428.2×	2e-07	BRAF, MAP2K1, MAP2K2
SHOC2 M1731 mutant abolishes MRAS complex function	3	428.2×	2e-07	BRAF, SHOC2, RAF1
Gain-of-function MRAS complexes activate RAF signaling	3	428.2×	2e-07	BRAF, SHOC2, RAF1
Activated NTRK3 signals through RAS	3	380.7×	3e-07	KRAS, SOS1, NRAS
Signaling by SCF-KIT	4	99.3×	4e-07	KRAS, PTPN11, SOS1, NRAS
Oncogenic MAPK signaling	4	99.3×	4e-07	BRAF, MAP2K1, MAP2K2, SHOC2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
MAPK cascade	6	91.9×	3e-09	BRAF, KRAS, MAP2K1, MAP2K2, NRAS, RAF1
Schwann cell development	4	421.3×	1e-08	MAP2K1, MAP2K2, SOS1, RAF1
face development	4	321.0×	3e-08	BRAF, MAP2K1, MAP2K2, RAF1
thyroid gland development	4	217.4×	1e-07	BRAF, MAP2K1, MAP2K2, RAF1
insulin-like growth factor receptor signaling pathway	4	198.3×	1e-07	MAP2K1, MAP2K2, SOS1, RAF1
thymus development	4	134.8×	5e-07	BRAF, MAP2K1, MAP2K2, RAF1
ERBB2-ERBB3 signaling pathway	3	505.6×	5e-07	MAP2K1, MAP2K2, RAF1
myelination	4	100.6×	1e-06	MAP2K1, MAP2K2, SOS1, RAF1
neurotrophin TRK receptor signaling pathway	3	316.0×	2e-06	PTPN11, SOS1, RAF1
Ras protein signal transduction	4	82.2×	2e-06	KRAS, RIT1, SOS1, NRAS
positive regulation of axonogenesis	3	174.3×	1e-05	BRAF, MAP2K1, MAP2K2
cerebellar cortex formation	2	1123.5×	2e-05	MAP2K1, PTPN11
regulation of Golgi inheritance	2	842.6×	3e-05	MAP2K1, MAP2K2
epithelial cell proliferation involved in lung morphogenesis	2	674.1×	5e-05	MAP2K1, MAP2K2
ERK1 and ERK2 cascade	3	95.4×	5e-05	BRAF, MAP2K1, MAP2K2
fibroblast growth factor receptor signaling pathway	3	85.7×	6e-05	PTPN11, SOS1, SHOC2
regulation of axon regeneration	2	481.5×	8e-05	MAP2K1, MAP2K2
trachea formation	2	481.5×	8e-05	MAP2K1, MAP2K2
epidermal growth factor receptor signaling pathway	3	74.3×	8e-05	BRAF, PTPN11, SOS1
regulation of early endosome to late endosome transport	2	421.3×	9e-05	MAP2K1, MAP2K2
regulation of stress-activated MAPK cascade	2	374.5×	1e-04	MAP2K1, MAP2K2
Bergmann glial cell differentiation	2	306.4×	2e-04	MAP2K1, PTPN11
positive regulation of protein serine/threonine kinase activity	2	259.3×	2e-04	MAP2K1, MAP2K2
type B pancreatic cell proliferation	2	177.4×	4e-04	MAP2K1, RAF1
positive regulation of Ras protein signal transduction	2	177.4×	4e-04	MAP2K1, SHOC2
cytokine-mediated signaling pathway	3	39.2×	4e-04	KRAS, PTPN11, SOS1
positive regulation of peptidyl-serine phosphorylation	2	153.2×	6e-04	BRAF, RAF1
positive regulation of gene expression	4	15.5×	6e-04	BRAF, KRAS, MAP2K1, MAP2K2
positive regulation of Rac protein signal transduction	2	129.6×	8e-04	KRAS, SOS1
positive regulation of ERK1 and ERK2 cascade	3	25.5×	0.001	BRAF, MAP2K1, PTPN11

Therapeutics

Drug target analysis

Approved (phase 4): 7 · Phase ≥3: 7 · Phased (≥1): 8 · Undrugged: 2

Druggability breadth: 8 of 10 evidence-associated genes (80%) 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
KRAS	VEMURAFENIB
MAP2K1	VEMURAFENIB
MAP2K2	VEMURAFENIB
PTPN11	ESTRAMUSTINE PHOSPHATE
SOS1	IDARUBICIN
RAF1	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAP2K1	54	4
MAP2K2	52	4
BRAF	48	4
RAF1	31	4
KRAS	11	4
PTPN11	8	4
SOS1	5	4
NRAS	1	1
SHOC2	0	0
RIT1	0	0

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, MAP2K1, MAP2K2
SORAFENIB	4	BRAF, MAP2K1, RAF1
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF, 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, MAP2K1, MAP2K2, RAF1
ERLOTINIB	4	BRAF, RAF1
GEFITINIB	4	BRAF
IMATINIB	4	BRAF, RAF1
LONAFARNIB	4	KRAS
SOTORASIB	4	KRAS, SOS1
ADAGRASIB	4	KRAS, SOS1
SELUMETINIB	4	MAP2K1, MAP2K2
TRAMETINIB	4	MAP2K1, MAP2K2
BINIMETINIB	4	MAP2K1, MAP2K2
AXITINIB	4	MAP2K1, MAP2K2
NERATINIB	4	MAP2K1, MAP2K2
TOFACITINIB	4	MAP2K1
VANDETANIB	4	MAP2K1, MAP2K2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 6.

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
MAP2K2	615	Binding:581, Functional:33, ADMET:1
PTPN11	588	Binding:585, Functional:2, ADMET:1
SOS1	421	Binding:409, Functional:12
NRAS	18	Binding:18

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
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

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
KRAS	861
MAP2K1	1,200
MAP2K2	615
PTPN11	588
SOS1	421
RAF1	839

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; 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, MAP2K1, MAP2K2
SORAFENIB	4	BRAF, MAP2K1, RAF1
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF, 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, MAP2K1, MAP2K2, RAF1
ERLOTINIB	4	BRAF, RAF1
GEFITINIB	4	BRAF
IMATINIB	4	BRAF, RAF1
LONAFARNIB	4	KRAS
SOTORASIB	4	KRAS, SOS1
ADAGRASIB	4	KRAS, SOS1
SELUMETINIB	4	MAP2K1, MAP2K2
TRAMETINIB	4	MAP2K1, MAP2K2
BINIMETINIB	4	MAP2K1, MAP2K2
AXITINIB	4	MAP2K1, MAP2K2
NERATINIB	4	MAP2K1, MAP2K2
TOFACITINIB	4	MAP2K1
VANDETANIB	4	MAP2K1, MAP2K2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	7	BRAF, KRAS, MAP2K1, MAP2K2, PTPN11, SOS1, RAF1
B	Phased (≥1) drug, not yet approved	1	NRAS
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SHOC2, RIT1

Undrugged target profiles

2 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
RIT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	7

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04395495	Not specified	RECRUITING	RASopathy Biorepository
NCT04888936	Not specified	RECRUITING	Clinical, Genetic, and Epidemiologic Study of Children and Adults With RASopathies
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
NCT07005297	Not specified	NOT_YET_RECRUITING	Clinical Genetics Branch Eligibility Screening Survey
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