Cardiofaciocutaneous syndrome 1

Summary

Cardiofaciocutaneous syndrome 1 (MONDO:0007265) is a disease caused by BRAF (GenCC Definitive), with 4 cohort genes and 3 clinical trials. The dominant Reactome pathway is RAF activation (4 cohort genes).

At a glance

• Causal gene: BRAF (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 150
• Clinical trials: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cardiofaciocutaneous syndrome 1
Mondo ID	MONDO:0007265
OMIM	115150
DOID	DOID:0111460
GARD	0024539
Is cancer (heuristic)	no

Also known as: BRAF cardiofaciocutaneous syndrome · cardiofaciocutaneous syndrome · cardiofaciocutaneous syndrome 1 · cardiofaciocutaneous syndrome caused by mutation in BRAF · cardiofaciocutaneous syndrome type 1 · CFC1

Data availability: 150 ClinVar variants · 5 GenCC gene-disease records · 11 cell lines.

Disease family

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 › cardiofaciocutaneous syndrome 1

Related subtypes (3): 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

150 retrieved; paginated sample, class counts are floors:

51 uncertain significance, 23 pathogenic, 21 pathogenic/likely pathogenic, 19 conflicting classifications of pathogenicity, 13 likely benign, 13 benign/likely benign, 8 likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1325840	NM_004333.6(BRAF):c.1454T>G (p.Leu485Trp)	BRAF	Pathogenic	criteria provided, single submitter
13964	NM_004333.6(BRAF):c.1391G>A (p.Gly464Glu)	BRAF	Pathogenic	reviewed by expert panel
13965	NM_004333.6(BRAF):c.736G>C (p.Ala246Pro)	BRAF	Pathogenic	reviewed by expert panel
13969	NM_004333.6(BRAF):c.1789C>G (p.Leu597Val)	BRAF	Pathogenic	criteria provided, multiple submitters, no conflicts
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
13976	NM_004333.6(BRAF):c.1495A>G (p.Lys499Glu)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
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
13981	NM_004333.6(BRAF):c.1914T>A (p.Asp638Glu)	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
180723	NM_004333.6(BRAF):c.785A>G (p.Gln262Arg)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
180784	NM_004333.6(BRAF):c.739T>C (p.Phe247Leu)	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
222077	NM_004333.6(BRAF):c.1574T>C (p.Leu525Pro)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280033	NM_004333.6(BRAF):c.1796C>G (p.Thr599Arg)	BRAF	Pathogenic	reviewed by expert panel
29805	NM_004333.6(BRAF):c.722C>T (p.Thr241Met)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29807	NM_004333.6(BRAF):c.721A>C (p.Thr241Pro)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3572914	NM_004333.6(BRAF):c.2126A>G (p.Gln709Arg)	BRAF	Pathogenic	criteria provided, single submitter
376289	NM_004333.6(BRAF):c.1798G>C (p.Val600Leu)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40347	NM_004333.6(BRAF):c.735A>C (p.Leu245Phe)	BRAF	Pathogenic	reviewed by expert panel
40364	NM_004333.6(BRAF):c.1391G>T (p.Gly464Val)	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
40372	NM_004333.6(BRAF):c.1497A>T (p.Lys499Asn)	BRAF	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 23 · Orphanet: 26 · 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

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

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

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	clinvar
MAP2K1	HGNC:6840	ENSG00000169032	Q02750	Dual specificity mitogen-activated protein kinase kinase 1	clinvar
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.
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.

Protein-family classification

Druggable: 4 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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	3	20.8×	4e-04
Enzyme (other)	1	3.0×	0.294

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

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
calcaneal tendon	1
colonic epithelium	1
nipple	1
pylorus	1
trigeminal ganglion	1
oocyte	1
orbitofrontal cortex	1
secondary oocyte	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
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

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRAS	14,509
BRAF	7,394
MAP2K1	5,944
MAP2K2	3,789

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
KRAS	MAP2K1	biogrid_interaction, string_interaction
KRAS	MAP2K2	string_interaction
MAP2K1	MAP2K2	biogrid_interaction, intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511
BRAF	P15056	131
MAP2K1	Q02750	94
MAP2K2	P36507	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 138. Enrichment computed across 4 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
RAF activation	4	335.9×	4e-09	BRAF, KRAS, MAP2K1, MAP2K2
Signaling by high-kinase activity BRAF mutants	4	317.2×	4e-09	BRAF, KRAS, MAP2K1, MAP2K2
MAP2K and MAPK activation	4	285.5×	4e-09	BRAF, KRAS, MAP2K1, MAP2K2
Signaling by RAF1 mutants	4	278.5×	4e-09	BRAF, KRAS, MAP2K1, MAP2K2
Negative regulation of MAPK pathway	4	265.6×	4e-09	BRAF, KRAS, MAP2K1, MAP2K2
Signaling by moderate kinase activity BRAF mutants	4	253.8×	4e-09	BRAF, KRAS, MAP2K1, MAP2K2
Paradoxical activation of RAF signaling by kinase inactive BRAF	4	253.8×	4e-09	BRAF, KRAS, MAP2K1, MAP2K2
Signaling downstream of RAS mutants	4	253.8×	4e-09	BRAF, KRAS, MAP2K1, MAP2K2
Negative feedback regulation of MAPK pathway	3	1427.5×	5e-09	BRAF, MAP2K1, MAP2K2
Prolonged ERK activation events	3	1070.6×	1e-08	BRAF, MAP2K1, MAP2K2
Signaling by BRAF and RAF1 fusions	4	170.4×	1e-08	BRAF, KRAS, MAP2K1, MAP2K2
Frs2-mediated activation	3	713.8×	4e-08	BRAF, MAP2K1, MAP2K2
Signalling to ERKs	3	450.8×	2e-07	BRAF, MAP2K1, MAP2K2
Signaling by RAS mutants	3	317.2×	5e-07	BRAF, MAP2K1, MAP2K2
RAF/MAP kinase cascade	4	61.1×	6e-07	BRAF, KRAS, MAP2K1, MAP2K2
Oncogenic MAPK signaling	3	186.2×	2e-06	BRAF, MAP2K1, MAP2K2
Signaling by NTRK1 (TRKA)	3	147.7×	4e-06	BRAF, MAP2K1, MAP2K2
Signaling by MAP2K mutants	2	1427.5×	4e-06	MAP2K1, MAP2K2
Signaling by NTRKs	3	135.9×	5e-06	BRAF, MAP2K1, MAP2K2
MAPK1/MAPK3 signaling	3	98.5×	1e-05	BRAF, MAP2K1, MAP2K2
MAPK family signaling cascades	3	77.2×	2e-05	BRAF, MAP2K1, MAP2K2
Uptake and function of anthrax toxins	2	475.8×	4e-05	MAP2K1, MAP2K2
Uptake and actions of bacterial toxins	2	407.9×	5e-05	MAP2K1, MAP2K2
RAF-independent MAPK1/3 activation	2	317.2×	8e-05	MAP2K1, MAP2K2
Signal transduction by L1	2	259.6×	1e-04	MAP2K1, MAP2K2
Diseases of signal transduction by growth factor receptors and second messengers	3	42.6×	1e-04	BRAF, MAP2K1, MAP2K2
Signaling by Receptor Tyrosine Kinases	3	38.8×	1e-04	BRAF, MAP2K1, MAP2K2
Bacterial Infection Pathways	2	167.9×	3e-04	MAP2K1, MAP2K2
L1CAM interactions	2	60.1×	0.002	MAP2K1, MAP2K2
Signaling by RAS GAP mutants	1	951.7×	0.005	KRAS

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
MAPK cascade	4	153.2×	2e-07	BRAF, KRAS, MAP2K1, MAP2K2
face development	3	601.9×	4e-07	BRAF, MAP2K1, MAP2K2
positive regulation of axonogenesis	3	435.8×	6e-07	BRAF, MAP2K1, MAP2K2
thyroid gland development	3	407.7×	6e-07	BRAF, MAP2K1, MAP2K2
thymus development	3	252.8×	2e-06	BRAF, MAP2K1, MAP2K2
ERK1 and ERK2 cascade	3	238.5×	2e-06	BRAF, MAP2K1, MAP2K2
regulation of Golgi inheritance	2	2106.5×	4e-06	MAP2K1, MAP2K2
epithelial cell proliferation involved in lung morphogenesis	2	1685.2×	6e-06	MAP2K1, MAP2K2
positive regulation of gene expression	4	38.7×	6e-06	BRAF, KRAS, MAP2K1, MAP2K2
regulation of axon regeneration	2	1203.7×	9e-06	MAP2K1, MAP2K2
trachea formation	2	1203.7×	9e-06	MAP2K1, MAP2K2
regulation of early endosome to late endosome transport	2	1053.2×	1e-05	MAP2K1, MAP2K2
regulation of stress-activated MAPK cascade	2	936.2×	1e-05	MAP2K1, MAP2K2
ERBB2-ERBB3 signaling pathway	2	842.6×	2e-05	MAP2K1, MAP2K2
positive regulation of protein serine/threonine kinase activity	2	648.1×	3e-05	MAP2K1, MAP2K2
Schwann cell development	2	526.6×	4e-05	MAP2K1, MAP2K2
insulin-like growth factor receptor signaling pathway	2	247.8×	2e-04	MAP2K1, MAP2K2
response to glucocorticoid	2	162.0×	4e-04	KRAS, MAP2K1
visual learning	2	153.2×	4e-04	BRAF, KRAS
myelination	2	125.8×	5e-04	MAP2K1, MAP2K2
response to mineralocorticoid	1	4213.0×	0.001	KRAS
negative regulation of homotypic cell-cell adhesion	1	2106.5×	0.002	MAP2K1
Golgi inheritance	1	2106.5×	0.002	MAP2K1
negative regulation of neuron apoptotic process	2	55.4×	0.002	BRAF, KRAS
cerebellar cortex formation	1	1404.3×	0.003	MAP2K1
forebrain astrocyte development	1	1404.3×	0.003	KRAS
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	1	1404.3×	0.003	BRAF
positive regulation of endodermal cell differentiation	1	1404.3×	0.003	MAP2K1
positive regulation of ERK1 and ERK2 cascade	2	42.6×	0.003	BRAF, MAP2K1
response to isolation stress	1	1053.2×	0.004	KRAS

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 4 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
KRAS	VEMURAFENIB
MAP2K1	VEMURAFENIB
MAP2K2	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAP2K1	54	4
MAP2K2	52	4
BRAF	48	4
KRAS	11	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	BRAF, KRAS, MAP2K1, MAP2K2
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF, MAP2K1, MAP2K2
SORAFENIB	4	BRAF, MAP2K1
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF, MAP2K1, MAP2K2
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF, KRAS
COBIMETINIB	4	BRAF, MAP2K1, MAP2K2
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF
DASATINIB	4	BRAF, MAP2K1, MAP2K2
ERLOTINIB	4	BRAF
GEFITINIB	4	BRAF
IMATINIB	4	BRAF
LONAFARNIB	4	KRAS
SOTORASIB	4	KRAS
ADAGRASIB	4	KRAS
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): 4.

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
MAP2K2	615	Binding:581, Functional:33, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
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

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

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF, MAP2K1, MAP2K2
SORAFENIB	4	BRAF, MAP2K1
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF, MAP2K1, MAP2K2
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF, KRAS
COBIMETINIB	4	BRAF, MAP2K1, MAP2K2
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF
DASATINIB	4	BRAF, MAP2K1, MAP2K2
ERLOTINIB	4	BRAF
GEFITINIB	4	BRAF
IMATINIB	4	BRAF
LONAFARNIB	4	KRAS
SOTORASIB	4	KRAS
ADAGRASIB	4	KRAS
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)	4	BRAF, KRAS, MAP2K1, MAP2K2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	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: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

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