Noonan syndrome with multiple lentigines

Summary

Noonan syndrome with multiple lentigines (MONDO:0007893) is a disease caused by variants in PTPN11 and MAP2K1, with 6 cohort genes and 2 clinical trials. The dominant Reactome pathway is Negative feedback regulation of MAPK pathway (4 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal genes: PTPN11 (GenCC Definitive), MAP2K1 (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 26
• Phenotypes (HPO): 50
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		296	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000078	Abnormality of the genital system	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000407	Sensorineural hearing impairment	Very frequent (80-99%)
HP:0000974	Hyperextensible skin	Very frequent (80-99%)
HP:0000995	Melanocytic nevus	Very frequent (80-99%)
HP:0001003	Multiple lentigines	Very frequent (80-99%)
HP:0001480	Freckling	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0001511	Intrauterine growth retardation	Very frequent (80-99%)
HP:0001639	Hypertrophic cardiomyopathy	Very frequent (80-99%)
HP:0001641	Abnormal pulmonary valve morphology	Very frequent (80-99%)
HP:0001642	Pulmonic stenosis	Very frequent (80-99%)
HP:0004414	Abnormality of the pulmonary artery	Very frequent (80-99%)
HP:0008625	Severe sensorineural hearing impairment	Very frequent (80-99%)
HP:0011675	Arrhythmia	Very frequent (80-99%)
HP:0011710	Bundle branch block	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000144	Decreased fertility	Frequent (30-79%)
HP:0000271	Abnormality of the face	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000465	Webbed neck	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000767	Pectus excavatum	Frequent (30-79%)
HP:0000768	Pectus carinatum	Frequent (30-79%)
HP:0000912	Sprengel anomaly	Frequent (30-79%)
HP:0001633	Abnormal mitral valve morphology	Frequent (30-79%)
HP:0001634	Mitral valve prolapse	Frequent (30-79%)
HP:0003691	Scapular winging	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0006695	Atrioventricular canal defect	Frequent (30-79%)
HP:0030680	Abnormal cardiovascular system morphology	Frequent (30-79%)
HP:0000358	Posteriorly rotated ears	Frequent (30-79%)
HP:0000047	Hypospadias	Occasional (5-29%)
HP:0000248	Brachycephaly	Occasional (5-29%)
HP:0000325	Triangular face	Occasional (5-29%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001482	Subcutaneous nodule	Occasional (5-29%)
HP:0001608	Abnormality of the voice	Occasional (5-29%)
HP:0001658	Myocardial infarction	Occasional (5-29%)
HP:0002617	Dilatation	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002861	Melanoma	Occasional (5-29%)
HP:0002863	Myelodysplasia	Occasional (5-29%)
HP:0003006	Neuroblastoma	Occasional (5-29%)
HP:0003298	Spina bifida occulta	Occasional (5-29%)
HP:0004306	Abnormality of the endocardium	Occasional (5-29%)
HP:0007392	Excessive wrinkled skin	Occasional (5-29%)
HP:0010318	Aplasia/Hypoplasia of the abdominal wall musculature	Occasional (5-29%)
HP:0100542	Abnormal localization of kidney	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Noonan syndrome with multiple lentigines
Mondo ID	MONDO:0007893
MeSH	D044542
OMIM	151100
Orphanet	500
DOID	DOID:14291
ICD-11	939197023
NCIT	C84820
SNOMED CT	111306001
UMLS	C0175704
MedGen	104494
GARD	0001100
MedDRA	10062901
NORD	1360
Is cancer (heuristic)	no

Also known as: Cardiomyopathic lentiginosis · familial multiple lentigines syndrome · generalised lentiginosis · lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, Deafnes · lentigines, electrocardiographic conduction defects, 0cular hypertelorism, pulmonary stenosis, abnormalities of the genitals, retarded Growth, deafness · LEOPARD syndrome · Noonan syndrome with multiple lentigines

Data availability: 26 ClinVar variants · 2 ClinGen variant curations · 9 GenCC gene-disease records · 11 cell lines.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › Noonan syndrome with multiple lentigines

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

Subtypes (3): LEOPARD syndrome 2, LEOPARD syndrome 3, LEOPARD syndrome 1

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

26 retrieved; paginated sample, class counts are floors:

15 pathogenic, 5 pathogenic/likely pathogenic, 2 uncertain significance, 1 benign, 1 not provided, 1 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
29807	NM_004333.6(BRAF):c.721A>C (p.Thr241Pro)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40348	NM_004333.6(BRAF):c.735A>T (p.Leu245Phe)	BRAF	Pathogenic	reviewed by expert panel
13328	NM_002834.5(PTPN11):c.836A>G (p.Tyr279Cys)	PTPN11	Pathogenic	reviewed by expert panel
13331	NM_002834.5(PTPN11):c.1403C>T (p.Thr468Met)	PTPN11	Pathogenic	reviewed by expert panel
13342	NM_002834.5(PTPN11):c.1381G>A (p.Ala461Thr)	PTPN11	Pathogenic	reviewed by expert panel
13343	NM_002834.5(PTPN11):c.1391G>C (p.Gly464Ala)	PTPN11	Pathogenic	reviewed by expert panel
13344	NM_002834.5(PTPN11):c.1529A>C (p.Gln510Pro)	PTPN11	Pathogenic	reviewed by expert panel
40500	NM_002834.5(PTPN11):c.214G>C (p.Ala72Pro)	PTPN11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40518	NM_002834.5(PTPN11):c.767A>G (p.Gln256Arg)	PTPN11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40523	NM_002834.5(PTPN11):c.802G>T (p.Gly268Cys)	PTPN11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40525	NM_002834.5(PTPN11):c.844A>G (p.Ile282Val)	PTPN11	Pathogenic	criteria provided, multiple submitters, no conflicts
40546	NM_002834.5(PTPN11):c.1381G>T (p.Ala461Ser)	PTPN11	Pathogenic	criteria provided, multiple submitters, no conflicts
40547	NM_002834.5(PTPN11):c.1402A>C (p.Thr468Pro)	PTPN11	Pathogenic	criteria provided, multiple submitters, no conflicts
40553	NM_002834.5(PTPN11):c.1492C>T (p.Arg498Trp)	PTPN11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40554	NM_002834.5(PTPN11):c.1493G>T (p.Arg498Leu)	PTPN11	Pathogenic	criteria provided, multiple submitters, no conflicts
40563	NM_002834.5(PTPN11):c.1517A>C (p.Gln506Pro)	PTPN11	Pathogenic	reviewed by expert panel
40566	NM_002834.5(PTPN11):c.1528C>G (p.Gln510Glu)	PTPN11	Pathogenic	criteria provided, multiple submitters, no conflicts
13957	NM_002880.4(RAF1):c.770C>T (p.Ser257Leu)	RAF1	Pathogenic	reviewed by expert panel
13960	NM_002880.4(RAF1):c.1837C>G (p.Leu613Val)	RAF1	Pathogenic	reviewed by expert panel
21342	NM_002880.4(RAF1):c.1472C>T (p.Thr491Ile)	RAF1	Pathogenic	reviewed by expert panel
3780504	NM_002834.5(PTPN11):c.934-59T>A	PTPN11	Likely pathogenic	criteria provided, single submitter
505022	NM_030662.4(MAP2K2):c.183A>T (p.Lys61Asn)	MAP2K2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
666414	NM_004333.6(BRAF):c.89G>A (p.Gly30Asp)	BRAF	Uncertain significance	criteria provided, multiple submitters, no conflicts
40818	NM_030662.4(MAP2K2):c.692G>T (p.Arg231Leu)	MAP2K2	Uncertain significance	reviewed by expert panel
181509	NM_002880.4(RAF1):c.1141G>A (p.Asp381Asn)	RAF1	Benign	reviewed by expert panel
21341	NM_002880.4(RAF1):c.1456G>A (p.Asp486Asn)	RAF1	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 81 · Orphanet: 31 · 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
NRAS	Definitive	Autosomal dominant	Noonan syndrome	10
PTPN11	Definitive	Autosomal dominant	Noonan syndrome 1	19
RAF1	Definitive	Autosomal dominant	Noonan syndrome	18
MAP2K1	Strong	Autosomal dominant	Noonan syndrome with multiple lentigines	11

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
PTPN11	Orphanet:2499	Metachondromatosis
PTPN11	Orphanet:500	Noonan syndrome with multiple lentigines
PTPN11	Orphanet:648	Noonan syndrome
PTPN11	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
MAP2K1	Orphanet:1340	Cardiofaciocutaneous syndrome
MAP2K1	Orphanet:389	Langerhans cell histiocytosis
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
MAP2K2	Orphanet:1340	Cardiofaciocutaneous syndrome
MAP2K2	Orphanet:638	Neurofibromatosis-Noonan syndrome

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	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
MAP2K1	HGNC:6840	ENSG00000169032	Q02750	Dual specificity mitogen-activated protein kinase kinase 1	gencc
NRAS	HGNC:7989	ENSG00000213281	P01111	GTPase NRas	gencc
MAP2K2	HGNC:6842	ENSG00000126934	P36507	Dual specificity mitogen-activated protein kinase kinase 2	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.
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…
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.
NRAS	GTPase NRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
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.

Protein-family classification

Druggable: 5 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.83

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	18.5×	7e-05
Phosphatase	1	14.0×	0.104
Other/Unknown	1	0.3×	0.993

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
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
MAP2K1	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
MAP2K2	Kinase	yes	2.7.12.2	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

6 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
secondary oocyte	2
buccal mucosa cell	1
calcaneal tendon	1
colonic epithelium	1
dorsal motor nucleus of vagus nerve	1
globus pallidus	1
medial globus pallidus	1
gastrocnemius	1
muscle of leg	1
ventricular zone	1
oocyte	1
orbitofrontal cortex	1
epithelium of nasopharynx	1
gingival epithelium	1
left testis	1
mucosa of transverse colon	1
right testis	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
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
MAP2K1	298	ubiquitous	marker	secondary oocyte, oocyte, orbitofrontal cortex
NRAS	278	ubiquitous	marker	gingival epithelium, epithelium of nasopharynx, secondary oocyte
MAP2K2	291	ubiquitous	marker	mucosa of transverse colon, right testis, left testis

Protein interactions among cohort

Intra-cohort edges: 13.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NRAS	7,598
BRAF	7,394
RAF1	6,574
PTPN11	6,009
MAP2K1	5,944
MAP2K2	3,789

Intra-cohort edges

A	B	Sources
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
MAP2K1	MAP2K2	biogrid_interaction, intact, string_interaction
MAP2K1	NRAS	string_interaction
MAP2K1	PTPN11	biogrid_interaction, string_interaction
MAP2K1	RAF1	biogrid_interaction, intact, string_interaction
MAP2K2	NRAS	intact, string_interaction
MAP2K2	PTPN11	string_interaction
MAP2K2	RAF1	biogrid_interaction, intact
NRAS	PTPN11	string_interaction
NRAS	RAF1	biogrid_interaction, intact, string_interaction

Structural data

PDB: 6 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BRAF	P15056	131
PTPN11	Q06124	115
MAP2K1	Q02750	94
RAF1	P04049	76
NRAS	P01111	35
MAP2K2	P36507	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 174. Enrichment computed across 6 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Negative feedback regulation of MAPK pathway	4	1268.9×	6e-11	BRAF, RAF1, MAP2K1, MAP2K2
RAF activation	5	279.9×	8e-11	BRAF, RAF1, MAP2K1, MAP2K2, NRAS
Signaling by high-kinase activity BRAF mutants	5	264.4×	8e-11	BRAF, RAF1, MAP2K1, MAP2K2, NRAS
MAP2K and MAPK activation	5	237.9×	9e-11	BRAF, RAF1, MAP2K1, MAP2K2, NRAS
Signaling by RAF1 mutants	5	232.1×	9e-11	BRAF, RAF1, MAP2K1, MAP2K2, NRAS
Negative regulation of MAPK pathway	5	221.3×	9e-11	BRAF, RAF1, MAP2K1, MAP2K2, NRAS
Signaling by moderate kinase activity BRAF mutants	5	211.5×	9e-11	BRAF, RAF1, MAP2K1, MAP2K2, NRAS
Paradoxical activation of RAF signaling by kinase inactive BRAF	5	211.5×	9e-11	BRAF, RAF1, MAP2K1, MAP2K2, NRAS
Signaling downstream of RAS mutants	5	211.5×	9e-11	BRAF, RAF1, MAP2K1, MAP2K2, NRAS
Signaling by BRAF and RAF1 fusions	5	142.0×	6e-10	BRAF, RAF1, MAP2K1, MAP2K2, NRAS
Prolonged ERK activation events	3	713.8×	7e-08	BRAF, MAP2K1, MAP2K2
Frs2-mediated activation	3	475.8×	3e-07	BRAF, MAP2K1, MAP2K2
Signalling to ERKs	3	300.5×	1e-06	BRAF, MAP2K1, MAP2K2
Signaling by RAS mutants	3	211.5×	3e-06	BRAF, MAP2K1, MAP2K2
RAF/MAP kinase cascade	4	40.7×	1e-05	BRAF, MAP2K1, MAP2K2, NRAS
Oncogenic MAPK signaling	3	124.1×	1e-05	BRAF, MAP2K1, MAP2K2
Signaling by MAP2K mutants	2	951.7×	1e-05	MAP2K1, MAP2K2
Signaling by NTRK1 (TRKA)	3	98.5×	2e-05	BRAF, MAP2K1, MAP2K2
Signaling by NTRKs	3	90.6×	3e-05	BRAF, MAP2K1, MAP2K2
SHOC2 M1731 mutant abolishes MRAS complex function	2	475.8×	5e-05	BRAF, RAF1
Gain-of-function MRAS complexes activate RAF signaling	2	475.8×	5e-05	BRAF, RAF1
MAPK1/MAPK3 signaling	3	65.6×	7e-05	BRAF, MAP2K1, MAP2K2
MAPK1 (ERK2) activation	2	380.7×	8e-05	PTPN11, MAP2K2
MAPK3 (ERK1) activation	2	346.1×	9e-05	PTPN11, MAP2K1
Uptake and function of anthrax toxins	2	317.2×	1e-04	MAP2K1, MAP2K2
Activated NTRK2 signals through FRS2 and FRS3	2	317.2×	1e-04	PTPN11, NRAS
MAPK family signaling cascades	3	51.4×	1e-04	BRAF, MAP2K1, MAP2K2
Uptake and actions of bacterial toxins	2	271.9×	1e-04	MAP2K1, MAP2K2
Signaling by FLT3 ITD and TKD mutants	2	253.8×	1e-04	PTPN11, NRAS
Spry regulation of FGF signaling	2	237.9×	2e-04	BRAF, PTPN11

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
face development	4	535.0×	4e-09	BRAF, RAF1, MAP2K1, MAP2K2
MAPK cascade	5	127.7×	5e-09	BRAF, RAF1, MAP2K1, MAP2K2, NRAS
thyroid gland development	4	362.4×	7e-09	BRAF, RAF1, MAP2K1, MAP2K2
thymus development	4	224.7×	4e-08	BRAF, RAF1, MAP2K1, MAP2K2
ERBB2-ERBB3 signaling pathway	3	842.6×	1e-07	RAF1, MAP2K1, MAP2K2
Schwann cell development	3	526.6×	4e-07	RAF1, MAP2K1, MAP2K2
positive regulation of axonogenesis	3	290.6×	2e-06	BRAF, MAP2K1, MAP2K2
insulin-like growth factor receptor signaling pathway	3	247.8×	3e-06	RAF1, MAP2K1, MAP2K2
cerebellar cortex formation	2	1872.4×	6e-06	PTPN11, MAP2K1
regulation of Golgi inheritance	2	1404.3×	9e-06	MAP2K1, MAP2K2
ERK1 and ERK2 cascade	3	159.0×	9e-06	BRAF, MAP2K1, MAP2K2
epithelial cell proliferation involved in lung morphogenesis	2	1123.5×	1e-05	MAP2K1, MAP2K2
myelination	3	125.8×	1e-05	RAF1, MAP2K1, MAP2K2
regulation of axon regeneration	2	802.5×	2e-05	MAP2K1, MAP2K2
trachea formation	2	802.5×	2e-05	MAP2K1, MAP2K2
regulation of early endosome to late endosome transport	2	702.2×	3e-05	MAP2K1, MAP2K2
regulation of stress-activated MAPK cascade	2	624.1×	4e-05	MAP2K1, MAP2K2
Bergmann glial cell differentiation	2	510.7×	5e-05	PTPN11, MAP2K1
positive regulation of protein serine/threonine kinase activity	2	432.1×	7e-05	MAP2K1, MAP2K2
neurotrophin TRK receptor signaling pathway	2	351.1×	1e-04	PTPN11, RAF1
type B pancreatic cell proliferation	2	295.6×	1e-04	RAF1, MAP2K1
positive regulation of peptidyl-serine phosphorylation	2	255.3×	2e-04	BRAF, RAF1
positive regulation of ERK1 and ERK2 cascade	3	42.6×	2e-04	BRAF, PTPN11, MAP2K1
heart development	3	39.4×	3e-04	PTPN11, MAP2K1, MAP2K2
epidermal growth factor receptor signaling pathway	2	82.6×	0.001	BRAF, PTPN11
somatic stem cell population maintenance	2	82.6×	0.001	BRAF, RAF1
positive regulation of gene expression	3	19.4×	0.002	BRAF, MAP2K1, MAP2K2
negative regulation of cortisol secretion	1	2808.7×	0.002	PTPN11
negative regulation of growth hormone secretion	1	2808.7×	0.002	PTPN11
microvillus organization	1	1404.3×	0.003	PTPN11

Therapeutics

Drug target analysis

Approved (phase 4): 5 · Phase ≥3: 5 · Phased (≥1): 6 · Undrugged: 0

Druggability breadth: 6 of 6 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
BRAF	VEMURAFENIB
PTPN11	ESTRAMUSTINE PHOSPHATE
RAF1	VEMURAFENIB
MAP2K1	VEMURAFENIB
MAP2K2	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAP2K1	54	4
MAP2K2	52	4
BRAF	48	4
RAF1	31	4
PTPN11	8	4
NRAS	1	1

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	BRAF, 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, 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
ESTRAMUSTINE PHOSPHATE	4	PTPN11
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
BOSUTINIB	4	MAP2K1, MAP2K2
GILTERITINIB	4	MAP2K1, MAP2K2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

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
RAF1	839	Binding:803, Functional:31, ADMET:5
MAP2K2	615	Binding:581, Functional:33, ADMET:1
PTPN11	588	Binding:585, Functional:2, ADMET:1
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
PTPN11	3.1.3.48	protein-tyrosine-phosphatase
RAF1	2.7.10.2	non-specific protein-tyrosine kinase
MAP2K1	2.7.12.2	mitogen-activated protein kinase kinase
MAP2K2	2.7.12.2	mitogen-activated protein kinase 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
PTPN11	588
RAF1	839
MAP2K1	1,200
MAP2K2	615

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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, 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, 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
ESTRAMUSTINE PHOSPHATE	4	PTPN11
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
BOSUTINIB	4	MAP2K1, MAP2K2
GILTERITINIB	4	MAP2K1, MAP2K2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	5	BRAF, PTPN11, RAF1, MAP2K1, MAP2K2
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04395495	Not specified	RECRUITING	RASopathy Biorepository
NCT02486731	Not specified	COMPLETED	Hormonal Sensitivity in Patients With Noonan and LEOPARD Syndromes