neurofibromatosis-Noonan syndrome

Summary

neurofibromatosis-Noonan syndrome (MONDO:0011035) is a disease caused by NF1 (GenCC Strong), with 6 cohort genes and 2 clinical trials. The dominant Reactome pathway is Oncogenic MAPK signaling (3 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: NF1 (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 706
• Phenotypes (HPO): 18
• Clinical trials: 2

Clinical features

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0000271	Abnormality of the face	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000465	Webbed neck	Very frequent (80-99%)
HP:0000494	Downslanted palpebral fissures	Very frequent (80-99%)
HP:0000508	Ptosis	Very frequent (80-99%)
HP:0001328	Specific learning disability	Very frequent (80-99%)
HP:0001639	Hypertrophic cardiomyopathy	Very frequent (80-99%)
HP:0001642	Pulmonic stenosis	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0007565	Multiple cafe-au-lait spots	Very frequent (80-99%)
HP:0009023	Abdominal wall muscle weakness	Very frequent (80-99%)
HP:0011039	Abnormality of the helix	Very frequent (80-99%)
HP:0000358	Posteriorly rotated ears	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000765	Abnormal thorax morphology	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0003010	Prolonged bleeding time	Frequent (30-79%)
HP:0100763	Abnormality of the lymphatic system	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	neurofibromatosis-Noonan syndrome
Mondo ID	MONDO:0011035
MeSH	C537393
OMIM	601321
Orphanet	638
DOID	DOID:0111683
ICD-11	679913930
SNOMED CT	715344006
UMLS	C2931482
MedGen	419089
GARD	0000372
Is cancer (heuristic)	no

Also known as: neurofibromatosis type 1-Noonan syndrome · neurofibromatosis-Noonan syndrome · NFNS · Noonan neurofibromatosis syndrome

Data availability: 706 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › neurofibromatosis-Noonan syndrome

Related subtypes (51): disorder of sexual differentiation, hereditary neurocutaneous angioma, nevoid basal cell carcinoma syndrome, angioosteohypertrophic syndrome, Larsen syndrome, schwannomatosis, linear nevus sebaceous syndrome, lethal Larsen-like syndrome, pseudodiastrophic dysplasia, focal dermal hypoplasia, microtia, Becker nevus syndrome, Legius syndrome, bone fragility with contractures, arterial rupture, and deafness, blindness - scoliosis - arachnodactyly syndrome, cutis laxa - Marfanoid syndrome, Maffucci syndrome, hydrops fetalis, ankyloblepharon filiforme-imperforate anus syndrome, developmental anomaly of metabolic origin, progeroid syndrome, facial cleft, Desbuquois dysplasia, cysts and fistulae of the face and oral cavity, macroglossia, middle ear anomaly, cleft palate, cutis laxa, infectious embryofetopathy, toxic or drug-related embryofetopathy, hemihyperplasia-multiple lipomatosis syndrome, phakomatosis pigmentokeratotica, phakomatosis pigmentovascularis, PTEN hamartoma tumor syndrome, marfanoid habitus-inguinal hernia-advanced bone age syndrome, neurofibromatosis type 1, multiple congenital anomalies/dysmorphic syndrome, congenital limb malformation, hereditary hemorrhagic telangiectasia, urogenital tract malformation, congenital anomaly of kidney and urinary tract, anotia, central nervous system malformation, Ehlers-Danlos syndrome, X-linked external auditory canal atresia-dilated internal auditory canal-facial dysmorphism syndrome, joint laxity, short stature, and myopia, diaphragmatic malformation, abdominal wall malformation, port-wine nevi-mega cisterna magna-hydrocephalus syndrome, conjoined twins, TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations

Subtypes (1): Watson syndrome

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:

248 conflicting classifications of pathogenicity, 116 uncertain significance, 64 pathogenic, 62 likely benign, 42 pathogenic/likely pathogenic, 37 benign/likely benign, 18 likely pathogenic, 13 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3237178	GRCh37/hg19 17q11.2(chr17:29000019-30416429)	CRLF3	Pathogenic	criteria provided, single submitter
1069238	NM_001042492.3(NF1):c.60+2T>C	LOC111811965	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
186896	NM_001042492.3(NF1):c.55G>T (p.Glu19Ter)	LOC111811965	Pathogenic	criteria provided, multiple submitters, no conflicts
2736490	NM_001042492.3(NF1):c.3G>T (p.Met1Ile)	LOC111811965	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1036158	NM_001042492.3(NF1):c.3586C>T (p.Leu1196Phe)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048693	NM_001042492.3(NF1):c.3556del (p.Ile1186fs)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069722	NM_001042492.3(NF1):c.3628G>T (p.Glu1210Ter)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1070937	NM_001042492.3(NF1):c.5585T>G (p.Leu1862Ter)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072070	NM_001042492.3(NF1):c.5158del (p.Glu1720fs)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1073116	NM_001042492.3(NF1):c.731-1G>C	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1184516	NM_001042492.3(NF1):c.4597del (p.Arg1533fs)	NF1	Pathogenic	no assertion criteria provided
1285535	NM_001042492.3(NF1):c.5409del (p.Ile1803fs)	NF1	Pathogenic	criteria provided, single submitter
1329856	NM_001042492.3(NF1):c.6819+1G>T	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1342908	NM_001042492.3(NF1):c.1008_1009delinsAA (p.Trp336_Glu337delinsTer)	NF1	Pathogenic	criteria provided, single submitter
1360877	NM_001042492.3(NF1):c.4980dup (p.Lys1661Ter)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1387584	NM_001042492.3(NF1):c.4760del (p.Ala1586_Leu1587insTer)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1421521	NM_001042492.3(NF1):c.4515del (p.Ala1506fs)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1527847	NM_001042492.3(NF1):c.6897del (p.Lys2300fs)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1709266	NM_001042492.3(NF1):c.3464C>A (p.Ala1155Asp)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1765006	NM_001042492.3(NF1):c.889-1del	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
184261	NM_001042492.3(NF1):c.7909C>T (p.Arg2637Ter)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
185021	NM_001042492.3(NF1):c.499_502del (p.Cys167fs)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
185082	NM_001042492.3(NF1):c.6855C>A (p.Tyr2285Ter)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
185354	NM_001042492.3(NF1):c.5609G>A (p.Arg1870Gln)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
187652	NM_001042492.3(NF1):c.5782G>T (p.Glu1928Ter)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
187722	NM_001042492.3(NF1):c.910C>T (p.Arg304Ter)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
2024252	NM_001042492.3(NF1):c.1062+2T>A	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2025724	NM_001042492.3(NF1):c.1131dup (p.Asp378Ter)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
2039653	NM_001042492.3(NF1):c.7063-2A>T	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
208853	NM_001042492.3(NF1):c.5488C>T (p.Arg1830Cys)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 16 · 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
NF1	Definitive	Autosomal dominant	neurofibromatosis type 1	9
MAP2K2	Supportive	Autosomal dominant	neurofibromatosis-Noonan syndrome	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MAP2K2	Orphanet:1340	Cardiofaciocutaneous syndrome
MAP2K2	Orphanet:638	Neurofibromatosis-Noonan syndrome
NF1	Orphanet:139474	17q11.2 microduplication syndrome
NF1	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
NF1	Orphanet:293199	Pleomorphic rhabdomyosarcoma
NF1	Orphanet:363700	Neurofibromatosis type 1 due to NF1 mutation or intragenic deletion
NF1	Orphanet:638	Neurofibromatosis-Noonan syndrome
NF1	Orphanet:86834	Juvenile myelomonocytic leukemia
NF1	Orphanet:97685	17q11 microdeletion syndrome
NF1	Orphanet:99756	Alveolar rhabdomyosarcoma
NF1	Orphanet:99757	Embryonal rhabdomyosarcoma
SPRED1	Orphanet:137605	Legius syndrome
PTPN11	Orphanet:2499	Metachondromatosis
PTPN11	Orphanet:500	Noonan syndrome with multiple lentigines
PTPN11	Orphanet:648	Noonan syndrome
PTPN11	Orphanet:86834	Juvenile myelomonocytic leukemia

Cohort genes → proteins

6 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MAP2K2	HGNC:6842	ENSG00000126934	P36507	Dual specificity mitogen-activated protein kinase kinase 2	gencc,clinvar
NF1	HGNC:7765	ENSG00000196712	P21359	Neurofibromin	gencc,clinvar
CRLF3	HGNC:17177	ENSG00000176390	Q8IUI8	Cytokine receptor-like factor 3	clinvar
SPRED1	HGNC:20249	ENSG00000166068	Q7Z699	Sprouty-related, EVH1 domain-containing protein 1	clinvar
MIR4733HG	HGNC:55332	ENSG00000264107		MIR4733 host gene	clinvar
PTPN11	HGNC:9644	ENSG00000179295	Q06124	Tyrosine-protein phosphatase non-receptor type 11	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
NF1	Neurofibromin	Stimulates the GTPase activity of Ras.
CRLF3	Cytokine receptor-like factor 3	May play a role in the negative regulation of cell cycle progression.
SPRED1	Sprouty-related, EVH1 domain-containing protein 1	Tyrosine kinase substrate that inhibits growth-factor-mediated activation of MAP kinase.
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.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.5

Family distribution

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

Family	Genes	Fold	FDR
Phosphatase	1	14.0×	0.264
Antibody/Immunoglobulin	1	4.9×	0.264
Kinase	1	4.6×	0.264
Other/Unknown	3	0.9×	0.758

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MAP2K2	Kinase	yes	2.7.12.2	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
NF1	Other/Unknown	no		CRAL-TRIO_dom, RasGAP_dom, Rho_GTPase_activation_prot
CRLF3	Antibody/Immunoglobulin	yes		FN3_dom, Ig-like_fold, FN3_sf
SPRED1	Other/Unknown	no		WH1/EVH1_dom, Sprouty, PH-like_dom_sf
MIR4733HG	Other/Unknown	no
PTPN11	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, SH2

Expression context

Cohort genes with no expression data: 0.

5 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
calcaneal tendon	2
left testis	1
mucosa of transverse colon	1
right testis	1
adrenal tissue	1
colonic epithelium	1
leukocyte	1
mononuclear cell	1
trabecular bone tissue	1
mucosa of sigmoid colon	1
ventricular zone	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
sural nerve	1
dorsal motor nucleus of vagus nerve	1
globus pallidus	1
medial globus pallidus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MAP2K2	291	ubiquitous	marker	mucosa of transverse colon, right testis, left testis
NF1	283	ubiquitous	marker	colonic epithelium, calcaneal tendon, adrenal tissue
CRLF3	287	ubiquitous	marker	trabecular bone tissue, mononuclear cell, leukocyte
SPRED1	248	ubiquitous	marker	ventricular zone, mucosa of sigmoid colon, calcaneal tendon
MIR4733HG	130		yes	sural nerve, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
PTPN11	295	ubiquitous	marker	medial globus pallidus, dorsal motor nucleus of vagus nerve, globus pallidus

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTPN11	6,009
NF1	5,540
MAP2K2	3,789
SPRED1	2,744
CRLF3	776
MIR4733HG	0

Intra-cohort edges

A	B	Sources
MAP2K2	PTPN11	string_interaction
MAP2K2	SPRED1	string_interaction
NF1	PTPN11	string_interaction
NF1	SPRED1	biogrid_interaction, intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTPN11	Q06124	115
NF1	P21359	26
MAP2K2	P36507	3
SPRED1	Q7Z699	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CRLF3	Q8IUI8	90.15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 92. Enrichment computed across 6 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Oncogenic MAPK signaling	3	186.2×	2e-05	MAP2K2, NF1, SPRED1
RAS signaling downstream of NF1 loss-of-function variants	2	815.7×	6e-05	NF1, SPRED1
MAPK1/MAPK3 signaling	3	98.5×	6e-05	MAP2K2, NF1, SPRED1
MAPK1 (ERK2) activation	2	571.0×	8e-05	MAP2K2, PTPN11
MAPK family signaling cascades	3	77.2×	8e-05	MAP2K2, NF1, SPRED1
RAF/MAP kinase cascade	3	45.8×	3e-04	MAP2K2, NF1, SPRED1
Diseases of signal transduction by growth factor receptors and second messengers	3	42.6×	3e-04	MAP2K2, NF1, SPRED1
Regulation of RAS by GAPs	2	96.8×	0.002	NF1, SPRED1
Signaling by MAP2K mutants	1	713.8×	0.013	MAP2K2
MET activates PTPN11	1	571.0×	0.013	PTPN11
Co-inhibition by BTLA	1	571.0×	0.013	PTPN11
Disease	3	9.8×	0.013	MAP2K2, NF1, SPRED1
Negative feedback regulation of MAPK pathway	1	475.8×	0.014	MAP2K2
STAT5 Activation	1	407.9×	0.014	PTPN11
Prolonged ERK activation events	1	356.9×	0.014	MAP2K2
Netrin mediated repulsion signals	1	317.2×	0.014	PTPN11
STAT5 activation downstream of FLT3 ITD mutants	1	285.5×	0.014	PTPN11
MAPK3 (ERK1) activation	1	259.6×	0.014	PTPN11
Signaling by Leptin	1	259.6×	0.014	PTPN11
Interleukin-6 signaling	1	237.9×	0.014	PTPN11
Frs2-mediated activation	1	237.9×	0.014	MAP2K2
Uptake and function of anthrax toxins	1	237.9×	0.014	MAP2K2
Activated NTRK2 signals through FRS2 and FRS3	1	237.9×	0.014	PTPN11
PECAM1 interactions	1	219.6×	0.014	PTPN11
FGFRL1 modulation of FGFR1 signaling	1	219.6×	0.014	SPRED1
Uptake and actions of bacterial toxins	1	203.9×	0.014	MAP2K2
Signaling by FGFR1	1	203.9×	0.014	SPRED1
Regulation of IFNG signaling	1	203.9×	0.014	PTPN11
Prolactin receptor signaling	1	190.3×	0.014	PTPN11
Signaling by FLT3 ITD and TKD mutants	1	190.3×	0.014	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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
Schwann cell development	2	421.3×	0.002	MAP2K2, NF1
heart development	3	47.2×	0.002	MAP2K2, NF1, PTPN11
negative regulation of MAPK cascade	2	120.4×	0.007	NF1, SPRED1
positive regulation of mast cell apoptotic process	1	3370.4×	0.007	NF1
regulation of glial cell differentiation	1	3370.4×	0.007	NF1
negative regulation of cortisol secretion	1	3370.4×	0.007	PTPN11
negative regulation of growth hormone secretion	1	3370.4×	0.007	PTPN11
observational learning	1	3370.4×	0.007	NF1
negative regulation of angiogenesis	2	67.4×	0.007	NF1, SPRED1
microvillus organization	1	1685.2×	0.007	PTPN11
gamma-aminobutyric acid secretion, neurotransmission	1	1685.2×	0.007	NF1
intestinal epithelial cell migration	1	1685.2×	0.007	PTPN11
Schwann cell proliferation	1	1123.5×	0.007	NF1
cerebellar cortex formation	1	1123.5×	0.007	PTPN11
forebrain astrocyte development	1	1123.5×	0.007	NF1
Schwann cell migration	1	1123.5×	0.007	NF1
vasculogenesis involved in coronary vascular morphogenesis	1	1123.5×	0.007	SPRED1
glutamate secretion, neurotransmission	1	1123.5×	0.007	NF1
negative regulation of mast cell proliferation	1	1123.5×	0.007	NF1
negative regulation of Schwann cell migration	1	1123.5×	0.007	NF1
vascular associated smooth muscle cell migration	1	1123.5×	0.007	NF1
MAPK cascade	2	61.3×	0.007	MAP2K2, NF1
mast cell apoptotic process	1	842.6×	0.008	NF1
negative regulation of Rac protein signal transduction	1	842.6×	0.008	NF1
regulation of type I interferon-mediated signaling pathway	1	842.6×	0.008	PTPN11
regulation of Golgi inheritance	1	842.6×	0.008	MAP2K2
myeloid leukocyte migration	1	842.6×	0.008	NF1
peptidyl-serine autophosphorylation	1	674.1×	0.009	MAP2K2
ERBB signaling pathway	1	674.1×	0.009	PTPN11
epithelial cell proliferation involved in lung morphogenesis	1	674.1×	0.009	MAP2K2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 6 evidence-associated genes (33%) 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
MAP2K2	VEMURAFENIB
PTPN11	ESTRAMUSTINE PHOSPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAP2K2	52	4
PTPN11	8	4
NF1	0	0
CRLF3	0	0
SPRED1	0	0
MIR4733HG	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	MAP2K2
SELUMETINIB	4	MAP2K2
TRAMETINIB	4	MAP2K2
COBIMETINIB	4	MAP2K2
BINIMETINIB	4	MAP2K2
DASATINIB	4	MAP2K2
FEDRATINIB	4	MAP2K2
AXITINIB	4	MAP2K2
RUXOLITINIB	4	MAP2K2
NERATINIB	4	MAP2K2
VANDETANIB	4	MAP2K2
BOSUTINIB	4	MAP2K2
GILTERITINIB	4	MAP2K2
NINTEDANIB	4	MAP2K2
SUNITINIB	4	MAP2K2
ESTRAMUSTINE PHOSPHATE	4	PTPN11
SARACATINIB	3	MAP2K2
AVUTOMETINIB	3	MAP2K2
LINSITINIB	3	MAP2K2
LINIFANIB	3	MAP2K2
ORANTINIB	3	MAP2K2
CANERTINIB	3	MAP2K2
CEDIRANIB	3	MAP2K2
DOVITINIB	3	MAP2K2
LESTAURTINIB	3	MAP2K2
CI-1040	2	MAP2K2
MIRDAMETINIB	2	MAP2K2
FORETINIB	2	MAP2K2
REFAMETINIB	2	MAP2K2
TAK-733	2	MAP2K2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
MAP2K2	615	Binding:581, Functional:33, ADMET:1
PTPN11	588	Binding:585, Functional:2, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MAP2K2	2.7.12.2	mitogen-activated protein kinase kinase
PTPN11	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
MAP2K2	615
PTPN11	588

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	MAP2K2
SELUMETINIB	4	MAP2K2
TRAMETINIB	4	MAP2K2
COBIMETINIB	4	MAP2K2
BINIMETINIB	4	MAP2K2
DASATINIB	4	MAP2K2
FEDRATINIB	4	MAP2K2
AXITINIB	4	MAP2K2
RUXOLITINIB	4	MAP2K2
NERATINIB	4	MAP2K2
VANDETANIB	4	MAP2K2
BOSUTINIB	4	MAP2K2
GILTERITINIB	4	MAP2K2
NINTEDANIB	4	MAP2K2
SUNITINIB	4	MAP2K2
ESTRAMUSTINE PHOSPHATE	4	PTPN11
SARACATINIB	3	MAP2K2
AVUTOMETINIB	3	MAP2K2
LINSITINIB	3	MAP2K2
LINIFANIB	3	MAP2K2
ORANTINIB	3	MAP2K2
CANERTINIB	3	MAP2K2
CEDIRANIB	3	MAP2K2
DOVITINIB	3	MAP2K2
LESTAURTINIB	3	MAP2K2
CI-1040	2	MAP2K2
MIRDAMETINIB	2	MAP2K2
FORETINIB	2	MAP2K2
REFAMETINIB	2	MAP2K2
TAK-733	2	MAP2K2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	MAP2K2, PTPN11
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	CRLF3
E	Difficult family or no structure, no drug	3	NF1, SPRED1, MIR4733HG

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NF1	0	—
CRLF3	0	—
SPRED1	0	—
MIR4733HG	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04395495	Not specified	RECRUITING	RASopathy Biorepository
NCT06147414	Not specified	RECRUITING	Development of Non-Invasive Prenatal Diagnosis for Single Gene Disorders