Costello syndrome

Summary

Costello syndrome (MONDO:0009026) is a disease caused by HRAS (GenCC Definitive), with 13 cohort genes and 8 clinical trials. The dominant Reactome pathway is RAF activation (7 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: HRAS (GenCC Definitive)
• Cohort genes: 13
• ClinVar variants: 597
• Phenotypes (HPO): 55
• Clinical trials: 8

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 / 1 000 000	0.08	Japan	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000189	Narrow palate	Very frequent (80-99%)
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0000470	Short neck	Very frequent (80-99%)
HP:0000508	Ptosis	Very frequent (80-99%)
HP:0000951	Abnormality of the skin	Very frequent (80-99%)
HP:0000956	Acanthosis nigricans	Very frequent (80-99%)
HP:0000962	Hyperkeratosis	Very frequent (80-99%)
HP:0001231	Abnormal fingernail morphology	Very frequent (80-99%)
HP:0001531	Failure to thrive in infancy	Very frequent (80-99%)
HP:0001582	Redundant skin	Very frequent (80-99%)
HP:0001598	Concave nail	Very frequent (80-99%)
HP:0001629	Ventricular septal defect	Very frequent (80-99%)
HP:0001642	Pulmonic stenosis	Very frequent (80-99%)
HP:0001814	Deep-set nails	Very frequent (80-99%)
HP:0002224	Woolly hair	Very frequent (80-99%)
HP:0002750	Delayed skeletal maturation	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0005280	Depressed nasal bridge	Very frequent (80-99%)
HP:0008872	Feeding difficulties in infancy	Very frequent (80-99%)
HP:0100679	Lack of skin elasticity	Very frequent (80-99%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000158	Macroglossia	Frequent (30-79%)
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0000179	Thick lower lip vermilion	Frequent (30-79%)
HP:0000286	Epicanthus	Frequent (30-79%)
HP:0000293	Full cheeks	Frequent (30-79%)
HP:0000474	Thickened nuchal skin fold	Frequent (30-79%)
HP:0000483	Astigmatism	Frequent (30-79%)
HP:0000543	Optic disc pallor	Frequent (30-79%)
HP:0000545	Myopia	Frequent (30-79%)
HP:0000563	Keratoconus	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000682	Abnormality of dental enamel	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0001561	Polyhydramnios	Frequent (30-79%)
HP:0001634	Mitral valve prolapse	Frequent (30-79%)
HP:0001639	Hypertrophic cardiomyopathy	Frequent (30-79%)
HP:0001800	Hypoplastic toenails	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0002120	Cerebral cortical atrophy	Frequent (30-79%)
HP:0004690	Thickened Achilles tendon	Frequent (30-79%)
HP:0007477	Abnormal dermatoglyphics	Frequent (30-79%)
HP:0009465	Ulnar deviation of finger	Frequent (30-79%)
HP:0012740	Papilloma	Frequent (30-79%)
HP:0000280	Coarse facial features	Occasional (5-29%)
HP:0000358	Posteriorly rotated ears	Occasional (5-29%)
HP:0000540	Hypermetropia	Occasional (5-29%)
HP:0001595	Abnormality of the hair	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Costello syndrome
Mondo ID	MONDO:0009026
MeSH	D056685
OMIM	218040
Orphanet	3071
DOID	DOID:0050469
ICD-11	1946512039
NCIT	C84652
SNOMED CT	309776008
UMLS	C0587248
MedGen	108454
GARD	0001550
MedDRA	10067380
NORD	1011
Is cancer (heuristic)	no

Also known as: congenital myopathy with excess of muscle spindles · Costello syndrome · CSTLO · faciocutaneoskeletal syndrome · FCS syndrome

Data availability: 597 ClinVar variants · 4 ClinGen variant curations · 14 GenCC gene-disease records · 4 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › Costello syndrome

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, Noonan syndrome with multiple lentigines, 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, 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

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

597 retrieved; paginated sample, class counts are floors:

274 uncertain significance, 245 likely benign, 25 conflicting classifications of pathogenicity, 17 pathogenic, 13 likely pathogenic, 12 benign, 6 benign/likely benign, 5 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1209208	NM_005343.4(HRAS):c.35_36delinsTT (p.Gly12Val)	HRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
12600	NM_005343.4(HRAS):c.35G>T (p.Gly12Val)	HRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
12602	NM_005343.4(HRAS):c.34G>A (p.Gly12Ser)	HRAS	Pathogenic	reviewed by expert panel
12603	NM_005343.4(HRAS):c.35G>C (p.Gly12Ala)	HRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
12604	NM_005343.4(HRAS):c.38G>A (p.Gly13Asp)	HRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
12605	NM_005343.4(HRAS):c.350A>G (p.Lys117Arg)	HRAS	Pathogenic	reviewed by expert panel
12606	NM_005343.4(HRAS):c.37G>T (p.Gly13Cys)	HRAS	Pathogenic	reviewed by expert panel
12607	NM_005343.4(HRAS):c.436G>A (p.Ala146Thr)	HRAS	Pathogenic	no assertion criteria provided
12608	NM_005343.4(HRAS):c.187G>A (p.Glu63Lys)	HRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
12610	NM_005343.4(HRAS):c.173C>T (p.Thr58Ile)	HRAS	Pathogenic	reviewed by expert panel
12612	NM_005343.4(HRAS):c.35G>A (p.Gly12Asp)	HRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12613	NM_005343.4(HRAS):c.34G>T (p.Gly12Cys)	HRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1321186	NM_176795.5(HRAS):c.488_497del (p.Leu163fs)	HRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1327492	NM_005343.4(HRAS):c.466T>C (p.Phe156Leu)	HRAS	Pathogenic	criteria provided, single submitter
163690	NM_005343.4(HRAS):c.35_36delinsAA (p.Gly12Glu)	HRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29911	NM_005343.4(HRAS):c.110_111+1dup	HRAS	Pathogenic	no assertion criteria provided
29912	NM_005343.4(HRAS):c.108_110dup (p.Glu37dup)	HRAS	Pathogenic	no assertion criteria provided
35554	NM_005343.4(HRAS):c.37G>C (p.Gly13Arg)	HRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
391700	NM_005343.4(HRAS):c.179G>T (p.Gly60Val)	HRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
40436	NM_005343.4(HRAS):c.179G>A (p.Gly60Asp)	HRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
462149	NM_005343.4(HRAS):c.186_206dup (p.Glu62_Arg68dup)	HRAS	Pathogenic	criteria provided, single submitter
180848	NM_005343.4(HRAS):c.38G>T (p.Gly13Val)	LRRC56	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4072207	NM_004333.6(BRAF):c.1082A>T (p.Asp361Val)	BRAF	Likely pathogenic	criteria provided, single submitter
120223	NM_005343.4(HRAS):c.187_207dup (p.Glu63_Asp69dup)	HRAS	Likely pathogenic	criteria provided, single submitter
12609	NM_005343.4(HRAS):c.64C>A (p.Gln22Lys)	HRAS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
12611	NM_005343.4(HRAS):c.437C>T (p.Ala146Val)	HRAS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1478514	NM_005343.4(HRAS):c.171_185dup (p.Asp57_Gln61dup)	HRAS	Likely pathogenic	criteria provided, single submitter
160364	NM_005343.4(HRAS):c.182A>G (p.Gln61Arg)	HRAS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
179260	NM_005343.4(HRAS):c.175_176delinsCT (p.Ala59Leu)	HRAS	Likely pathogenic	criteria provided, single submitter
375961	NM_005343.4(HRAS):c.34G>C (p.Gly12Arg)	HRAS	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 125 · Orphanet: 54 · 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
HRAS	Definitive	Autosomal dominant	Costello syndrome	8
NRAS	Limited	Autosomal dominant	Costello syndrome	10
BRAF	Disputed Evidence	Autosomal dominant	Costello syndrome	23
KRAS	Disputed Evidence	Autosomal dominant	Costello syndrome	17
MAP2K1	Disputed Evidence	Autosomal dominant	Costello syndrome	11
PTPN11	Disputed Evidence	Autosomal dominant	Costello syndrome	19
RAF1	Disputed Evidence	Autosomal dominant	Costello syndrome	18
SHOC2	Disputed Evidence	Autosomal dominant	Costello syndrome	9
SOS1	Disputed Evidence	Autosomal dominant	Costello 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
HRAS	Orphanet:146	Differentiated thyroid carcinoma
HRAS	Orphanet:2612	Linear nevus sebaceus syndrome
HRAS	Orphanet:2874	Phakomatosis pigmentokeratotica
HRAS	Orphanet:3071	Costello syndrome
HRAS	Orphanet:79414	Woolly hair nevus
SOS1	Orphanet:2024	Hereditary gingival fibromatosis
SOS1	Orphanet:648	Noonan syndrome
SHOC2	Orphanet:2701	Noonan syndrome-like disorder with loose anagen hair
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
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
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
TNNT2	Orphanet:154	Familial isolated dilated cardiomyopathy
TNNT2	Orphanet:54260	Left ventricular noncompaction

Cohort genes → proteins

13 cohort genes, 13 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	13

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	gencc,clinvar
HRAS	HGNC:5173	ENSG00000174775	P01112	GTPase HRas	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
KRAS	HGNC:6407	ENSG00000133703	P01116	GTPase KRas	gencc
MAP2K1	HGNC:6840	ENSG00000169032	Q02750	Dual specificity mitogen-activated protein kinase kinase 1	gencc
NRAS	HGNC:7989	ENSG00000213281	P01111	GTPase NRas	gencc
PTPN11	HGNC:9644	ENSG00000179295	Q06124	Tyrosine-protein phosphatase non-receptor type 11	gencc
RAF1	HGNC:9829	ENSG00000132155	P04049	RAF proto-oncogene serine/threonine-protein kinase	gencc
TNNT2	HGNC:11949	ENSG00000118194	P45379	Troponin T, cardiac muscle	clinvar
SPRED1	HGNC:20249	ENSG00000166068	Q7Z699	Sprouty-related, EVH1 domain-containing protein 1	clinvar
EPS8L2	HGNC:21296	ENSG00000177106	Q9H6S3	Epidermal growth factor receptor kinase substrate 8-like protein 2	clinvar
LRRC56	HGNC:25430	ENSG00000161328	Q8IYG6	Leucine-rich repeat-containing protein 56	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.
HRAS	GTPase HRas	Involved in the activation of Ras protein signal transduction.
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.
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.
NRAS	GTPase NRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
PTPN11	Tyrosine-protein phosphatase non-receptor type 11	Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus.
RAF1	RAF proto-oncogene serine/threonine-protein kinase	Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including prolifer…
TNNT2	Troponin T, cardiac muscle	Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
SPRED1	Sprouty-related, EVH1 domain-containing protein 1	Tyrosine kinase substrate that inhibits growth-factor-mediated activation of MAP kinase.
EPS8L2	Epidermal growth factor receptor kinase substrate 8-like protein 2	Stimulates guanine exchange activity of SOS1.
LRRC56	Leucine-rich repeat-containing protein 56	Required for the assembly of dynein arms.

Protein-family classification

Druggable: 6 · Difficult: 2 · Unknown: 5 · Druggable fraction: 0.46

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	6.4×	0.051
Phosphatase	1	6.5×	0.285
Scaffold/PPI	2	2.7×	0.285
Enzyme (other)	2	1.8×	0.370
Other/Unknown	5	0.7×	0.938

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
HRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
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
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
NRAS	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
PTPN11	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, SH2
RAF1	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
TNNT2	Other/Unknown	no		Troponin, TNNT, Troponin_sf
SPRED1	Other/Unknown	no		WH1/EVH1_dom, Sprouty, PH-like_dom_sf
EPS8L2	Scaffold/PPI	no		SH3_domain, PTB/PI_dom, PH-like_dom_sf
LRRC56	Other/Unknown	no		Leu-rich_rpt, Leu-rich_rpt_4, LRR_dom_sf

Expression context

Cohort genes with no expression data: 0.

13 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)	13
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	3
colonic epithelium	2
secondary oocyte	2
ventricular zone	2
buccal mucosa cell	1
skin of abdomen	1
skin of leg	1
zone of skin	1
jejunal mucosa	1
tendon of biceps brachii	1
bone marrow	1
sural nerve	1
nipple	1
pylorus	1
trigeminal ganglion	1
oocyte	1
orbitofrontal cortex	1
epithelium of nasopharynx	1
gingival epithelium	1
dorsal motor nucleus of vagus nerve	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
HRAS	139	ubiquitous	marker	skin of abdomen, skin of leg, zone of skin
SOS1	289	ubiquitous	marker	colonic epithelium, jejunal mucosa, tendon of biceps brachii
SHOC2	299	ubiquitous	marker	calcaneal tendon, sural nerve, bone marrow
KRAS	298	ubiquitous	marker	trigeminal ganglion, pylorus, nipple
MAP2K1	298	ubiquitous	marker	secondary oocyte, oocyte, orbitofrontal cortex
NRAS	278	ubiquitous	marker	gingival epithelium, epithelium of nasopharynx, secondary oocyte
PTPN11	295	ubiquitous	marker	medial globus pallidus, dorsal motor nucleus of vagus nerve, globus pallidus
RAF1	299	ubiquitous	marker	gastrocnemius, muscle of leg, ventricular zone
TNNT2	154	broad	marker	apex of heart, right atrium auricular region, cardiac atrium
SPRED1	248	ubiquitous	marker	ventricular zone, mucosa of sigmoid colon, calcaneal tendon
EPS8L2	230	ubiquitous	marker	lower esophagus mucosa, metanephros cortex, esophagus mucosa
LRRC56	129	broad	marker	right uterine tube, right testis, left testis

Protein interactions among cohort

Intra-cohort edges: 37.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRAS	14,509
HRAS	8,064
NRAS	7,598
BRAF	7,394
RAF1	6,574
PTPN11	6,009
MAP2K1	5,944
SOS1	3,625
SPRED1	2,744
SHOC2	2,149

Intra-cohort edges

A	B	Sources
BRAF	HRAS	intact, string_interaction
BRAF	KRAS	biogrid_interaction, intact, string_interaction
BRAF	MAP2K1	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
BRAF	SPRED1	string_interaction
EPS8L2	SOS1	biogrid_interaction
EPS8L2	SPRED1	intact
HRAS	MAP2K1	string_interaction
HRAS	RAF1	intact, string_interaction
HRAS	SHOC2	intact, string_interaction
HRAS	SOS1	intact, string_interaction
KRAS	MAP2K1	biogrid_interaction, string_interaction
KRAS	NRAS	intact
KRAS	RAF1	intact, string_interaction
KRAS	SHOC2	intact, string_interaction
KRAS	SOS1	string_interaction
KRAS	SPRED1	string_interaction
MAP2K1	NRAS	string_interaction
MAP2K1	PTPN11	biogrid_interaction, string_interaction
MAP2K1	RAF1	biogrid_interaction, intact, string_interaction
MAP2K1	SHOC2	string_interaction
NRAS	PTPN11	string_interaction
NRAS	RAF1	biogrid_interaction, intact, string_interaction
NRAS	SHOC2	biogrid_interaction, intact, string_interaction
NRAS	SOS1	string_interaction
NRAS	SPRED1	string_interaction
PTPN11	SHOC2	string_interaction
PTPN11	SOS1	biogrid_interaction, string_interaction
RAF1	SHOC2	biogrid_interaction
RAF1	SOS1	string_interaction
RAF1	SPRED1	string_interaction
SHOC2	SOS1	string_interaction
SHOC2	SPRED1	string_interaction
SOS1	SPRED1	string_interaction

Structural data

PDB: 12 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511
HRAS	P01112	246
BRAF	P15056	131
PTPN11	Q06124	115
MAP2K1	Q02750	94
SOS1	Q07889	91
RAF1	P04049	76
NRAS	P01111	35
TNNT2	P45379	25
SHOC2	Q9UQ13	13
SPRED1	Q7Z699	3
EPS8L2	Q9H6S3	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LRRC56	Q8IYG6	56.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 243. Enrichment computed across 13 evidence-associated genes (12 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 12 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	195.9×	2e-13	BRAF, HRAS, SHOC2, KRAS, MAP2K1, NRAS, RAF1
Activated NTRK2 signals through FRS2 and FRS3	5	396.5×	5e-11	HRAS, SOS1, KRAS, NRAS, PTPN11
Signaling by high-kinase activity BRAF mutants	6	158.6×	5e-11	BRAF, HRAS, KRAS, MAP2K1, NRAS, RAF1
Signaling by FLT3 ITD and TKD mutants	5	317.2×	5e-11	HRAS, SOS1, KRAS, NRAS, PTPN11
MAP2K and MAPK activation	6	142.8×	5e-11	BRAF, HRAS, KRAS, MAP2K1, NRAS, RAF1
Signaling by RAF1 mutants	6	139.3×	5e-11	BRAF, HRAS, KRAS, MAP2K1, NRAS, RAF1
Negative regulation of MAPK pathway	6	132.8×	5e-11	BRAF, HRAS, KRAS, MAP2K1, NRAS, RAF1
Signaling by moderate kinase activity BRAF mutants	6	126.9×	5e-11	BRAF, HRAS, KRAS, MAP2K1, NRAS, RAF1
Paradoxical activation of RAF signaling by kinase inactive BRAF	6	126.9×	5e-11	BRAF, HRAS, KRAS, MAP2K1, NRAS, RAF1
Signaling downstream of RAS mutants	6	126.9×	5e-11	BRAF, HRAS, KRAS, MAP2K1, NRAS, RAF1
RAF/MAP kinase cascade	8	40.7×	5e-11	BRAF, HRAS, SOS1, SHOC2, SPRED1, KRAS, MAP2K1, NRAS
Tie2 Signaling	5	250.4×	1e-10	HRAS, SOS1, KRAS, NRAS, PTPN11
FRS-mediated FGFR3 signaling	5	226.6×	2e-10	HRAS, SOS1, KRAS, NRAS, PTPN11
FRS-mediated FGFR4 signaling	5	206.9×	3e-10	HRAS, SOS1, KRAS, NRAS, PTPN11
RAS signaling downstream of NF1 loss-of-function variants	4	543.8×	4e-10	HRAS, SPRED1, KRAS, NRAS
FRS-mediated FGFR1 signaling	5	190.3×	4e-10	HRAS, SOS1, KRAS, NRAS, PTPN11
Signaling by BRAF and RAF1 fusions	6	85.2×	4e-10	BRAF, HRAS, KRAS, MAP2K1, NRAS, RAF1
FRS-mediated FGFR2 signaling	5	183.0×	4e-10	HRAS, SOS1, KRAS, NRAS, PTPN11
SOS-mediated signalling	4	475.8×	6e-10	HRAS, SOS1, KRAS, NRAS
Downstream signal transduction	5	158.6×	8e-10	HRAS, SOS1, KRAS, NRAS, PTPN11
Activated NTRK3 signals through RAS	4	423.0×	1e-09	HRAS, SOS1, KRAS, NRAS
FLT3 Signaling	5	144.2×	1e-09	HRAS, SOS1, KRAS, NRAS, PTPN11
EGFR Transactivation by Gastrin	4	380.7×	1e-09	HRAS, SOS1, KRAS, NRAS
SHC-related events triggered by IGF1R	4	380.7×	1e-09	HRAS, SOS1, KRAS, NRAS
Activated NTRK2 signals through RAS	4	380.7×	1e-09	HRAS, SOS1, KRAS, NRAS
MET activates RAS signaling	4	346.1×	2e-09	HRAS, SOS1, KRAS, NRAS
Signaling by FGFR4 in disease	4	317.2×	3e-09	HRAS, SOS1, KRAS, NRAS
Constitutive Signaling by Overexpressed ERBB2	4	317.2×	3e-09	HRAS, SOS1, KRAS, NRAS
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	4	292.8×	4e-09	HRAS, SOS1, KRAS, NRAS
Signaling by PDGFRA extracellular domain mutants	4	292.8×	4e-09	HRAS, SOS1, KRAS, NRAS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 13 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	70.7×	3e-08	BRAF, HRAS, KRAS, MAP2K1, NRAS, RAF1
Schwann cell development	4	324.1×	5e-08	HRAS, SOS1, MAP2K1, RAF1
neurotrophin TRK receptor signaling pathway	3	243.1×	1e-05	SOS1, PTPN11, RAF1
myelination	4	77.4×	1e-05	HRAS, SOS1, MAP2K1, RAF1
Ras protein signal transduction	4	63.2×	2e-05	HRAS, SOS1, KRAS, NRAS
face development	3	185.2×	2e-05	BRAF, MAP2K1, RAF1
cerebellar cortex formation	2	864.2×	5e-05	MAP2K1, PTPN11
thyroid gland development	3	125.5×	5e-05	BRAF, MAP2K1, RAF1
insulin-like growth factor receptor signaling pathway	3	114.4×	6e-05	SOS1, MAP2K1, RAF1
thymus development	3	77.8×	2e-04	BRAF, MAP2K1, RAF1
fibroblast growth factor receptor signaling pathway	3	65.9×	3e-04	SOS1, SHOC2, PTPN11
positive regulation of ERK1 and ERK2 cascade	4	26.2×	3e-04	BRAF, HRAS, MAP2K1, PTPN11
epidermal growth factor receptor signaling pathway	3	57.2×	3e-04	BRAF, SOS1, PTPN11
ERBB2-ERBB3 signaling pathway	2	259.3×	4e-04	MAP2K1, RAF1
insulin receptor signaling pathway	3	51.2×	4e-04	HRAS, SOS1, RAF1
Bergmann glial cell differentiation	2	235.7×	5e-04	MAP2K1, PTPN11
regulation of long-term neuronal synaptic plasticity	2	152.5×	0.001	HRAS, KRAS
positive regulation of ruffle assembly	2	152.5×	0.001	HRAS, EPS8L2
type B pancreatic cell proliferation	2	136.4×	0.001	MAP2K1, RAF1
positive regulation of Ras protein signal transduction	2	136.4×	0.001	SHOC2, MAP2K1
regulation of neurotransmitter receptor localization to postsynaptic specialization membrane	2	136.4×	0.001	HRAS, MAP2K1
cytokine-mediated signaling pathway	3	30.1×	0.001	SOS1, KRAS, PTPN11
positive regulation of peptidyl-serine phosphorylation	2	117.8×	0.001	BRAF, RAF1
positive regulation of Rac protein signal transduction	2	99.7×	0.002	SOS1, KRAS
regulation of cell population proliferation	3	26.6×	0.002	BRAF, HRAS, SOS1
negative regulation of neuron apoptotic process	3	25.6×	0.002	BRAF, HRAS, KRAS
positive regulation of axonogenesis	2	89.4×	0.002	BRAF, MAP2K1
regulation of Rho protein signal transduction	2	78.6×	0.003	EPS8L2, RAF1
regulation of MAPK cascade	2	70.1×	0.003	SHOC2, SPRED1
homeostasis of number of cells within a tissue	2	68.2×	0.003	KRAS, PTPN11

Therapeutics

Drug target analysis

Approved (phase 4): 7 · Phase ≥3: 7 · Phased (≥1): 8 · Undrugged: 5

Druggability breadth: 9 of 13 evidence-associated genes (69%) 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
HRAS	LONAFARNIB
SOS1	IDARUBICIN
KRAS	VEMURAFENIB
MAP2K1	VEMURAFENIB
PTPN11	ESTRAMUSTINE PHOSPHATE
RAF1	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAP2K1	54	4
BRAF	48	4
RAF1	31	4
KRAS	11	4
PTPN11	8	4
SOS1	5	4
HRAS	4	4
NRAS	1	1
SHOC2	0	0
TNNT2	0	0

Drugs targeting cohort genes (top 30)

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

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
PTPN11	588	Binding:585, Functional:2, ADMET:1
SOS1	421	Binding:409, Functional:12
HRAS	48	Binding:45, Functional:3
NRAS	18	Binding:18
TNNT2	2	Binding:2

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
HRAS	3.6.5.2	small monomeric GTPase
KRAS	3.6.5.2	small monomeric GTPase
MAP2K1	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
SOS1	421
KRAS	861
MAP2K1	1,200
PTPN11	588
RAF1	839

Pharmacogenomics

Cohort genes with a PharmGKB record: 13; 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, RAF1
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF, MAP2K1
SORAFENIB	4	BRAF, MAP2K1, RAF1
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF, MAP2K1
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF, RAF1
DABRAFENIB	4	BRAF, KRAS, RAF1
COBIMETINIB	4	BRAF, MAP2K1
NILOTINIB	4	BRAF, RAF1
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF, RAF1
PAZOPANIB	4	BRAF, RAF1
DASATINIB	4	BRAF, MAP2K1, RAF1
ERLOTINIB	4	BRAF, RAF1
GEFITINIB	4	BRAF
IMATINIB	4	BRAF, RAF1
LONAFARNIB	4	HRAS, KRAS
IDARUBICIN	4	SOS1
DOXORUBICIN	4	SOS1
SOTORASIB	4	KRAS, SOS1
ADAGRASIB	4	KRAS, SOS1
SELUMETINIB	4	MAP2K1
TRAMETINIB	4	MAP2K1
BINIMETINIB	4	MAP2K1
AXITINIB	4	MAP2K1
NERATINIB	4	MAP2K1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	7	BRAF, HRAS, SOS1, KRAS, MAP2K1, PTPN11, 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	5	SHOC2, TNNT2, SPRED1, EPS8L2, LRRC56

Undrugged target profiles

5 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
SPRED1	0	RAF1
TNNT2	2	—
EPS8L2	0	—
LRRC56	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 8.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	8

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
NCT02812511	Not specified	COMPLETED	Pathophysiology Analysis of Costello Syndrome on Cellular Models
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