Noonan syndrome 1

Summary

Noonan syndrome 1 (MONDO:0008104) is a disease caused by PTPN11 (GenCC Definitive), with 19 cohort genes. The dominant Reactome pathway is RAF activation (7 cohort genes).

At a glance

• Causal gene: PTPN11 (GenCC Definitive)
• Cohort genes: 19
• ClinVar variants: 413

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Noonan syndrome 1
Mondo ID	MONDO:0008104
OMIM	163950
DOID	DOID:0060578
NCIT	C75459
UMLS	C4551602
MedGen	1638960
GARD	0007223
Is cancer (heuristic)	no

Also known as: Noonan syndrome 1 · Noonan syndrome type 1 · NS1

Data availability: 413 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Noonan syndrome › Noonan syndrome 1

Related subtypes (13): Noonan syndrome 2, Noonan syndrome 3, Noonan syndrome 4, Noonan syndrome 5, Noonan syndrome 6, Noonan syndrome 7, Noonan syndrome 8, Noonan syndrome 9, Noonan syndrome 10, Noonan syndrome 14, Noonan syndrome 11, noonan syndrome 12, Noonan syndrome 13

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

413 retrieved; paginated sample, class counts are floors:

128 uncertain significance, 93 pathogenic, 45 conflicting classifications of pathogenicity, 44 pathogenic/likely pathogenic, 30 likely benign, 29 benign/likely benign, 25 likely pathogenic, 18 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
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
13979	NM_004333.6(BRAF):c.1741A>G (p.Asn581Asp)	BRAF	Pathogenic	reviewed by expert panel
13981	NM_004333.6(BRAF):c.1914T>A (p.Asp638Glu)	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
180784	NM_004333.6(BRAF):c.739T>C (p.Phe247Leu)	BRAF	Pathogenic	reviewed by expert panel
2674585	NM_004333.6(BRAF):c.741T>A (p.Phe247Leu)	BRAF	Pathogenic	no assertion criteria provided
29805	NM_004333.6(BRAF):c.722C>T (p.Thr241Met)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29806	NM_004333.6(BRAF):c.722C>G (p.Thr241Arg)	BRAF	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
29808	NM_004333.6(BRAF):c.1593G>C (p.Trp531Cys)	BRAF	Pathogenic	criteria provided, multiple submitters, no conflicts
40347	NM_004333.6(BRAF):c.735A>C (p.Leu245Phe)	BRAF	Pathogenic	reviewed by expert panel
44811	NM_004333.6(BRAF):c.1743T>A (p.Asn581Lys)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
180827	NM_005188.4(CBL):c.1111T>A (p.Tyr371Asn)	CBL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
804361	NM_004004.6(GJB2):c.205T>C (p.Phe69Leu)	GJB2	Pathogenic	criteria provided, single submitter
12602	NM_005343.4(HRAS):c.34G>A (p.Gly12Ser)	HRAS	Pathogenic	reviewed by expert panel
12587	NM_004985.5(KRAS):c.458A>T (p.Asp153Val)	KRAS	Pathogenic	reviewed by expert panel
40454	NM_004985.5(KRAS):c.101C>T (p.Pro34Leu)	KRAS	Pathogenic	reviewed by expert panel
1788221	NM_006767.4(LZTR1):c.2238del (p.Tyr747fs)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13351	NM_002755.4(MAP2K1):c.389A>G (p.Tyr130Cys)	MAP2K1	Pathogenic	reviewed by expert panel
228273	NM_002755.4(MAP2K1):c.364A>G (p.Asn122Asp)	MAP2K1	Pathogenic	reviewed by expert panel
8274	NM_030662.4(MAP2K2):c.400T>C (p.Tyr134His)	MAP2K2	Pathogenic	reviewed by expert panel
1070042	NM_002524.5(NRAS):c.173C>T (p.Thr58Ile)	NRAS	Pathogenic	reviewed by expert panel
13902	NM_002524.5(NRAS):c.149C>T (p.Thr50Ile)	NRAS	Pathogenic	reviewed by expert panel
13903	NM_002524.5(NRAS):c.179G>A (p.Gly60Glu)	NRAS	Pathogenic	reviewed by expert panel
39647	NM_002524.5(NRAS):c.101C>T (p.Pro34Leu)	NRAS	Pathogenic	no assertion criteria provided
13324	NM_002834.5(PTPN11):c.214G>T (p.Ala72Ser)	PTPN11	Pathogenic	criteria provided, multiple submitters, no conflicts
13325	NM_002834.5(PTPN11):c.215C>G (p.Ala72Gly)	PTPN11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 71 · 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
PTPN11	Definitive	Autosomal dominant	Noonan syndrome 1	19

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PTPN11	Orphanet:2499	Metachondromatosis
PTPN11	Orphanet:500	Noonan syndrome with multiple lentigines
PTPN11	Orphanet:648	Noonan syndrome
PTPN11	Orphanet:86834	Juvenile myelomonocytic leukemia
RIT1	Orphanet:648	Noonan syndrome
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
SOS1	Orphanet:2024	Hereditary gingival fibromatosis
SOS1	Orphanet:648	Noonan syndrome
SOS2	Orphanet:648	Noonan syndrome
CBL	Orphanet:363972	Noonan syndrome-like disorder with juvenile myelomonocytic leukemia
CBL	Orphanet:648	Noonan syndrome
CBL	Orphanet:86834	Juvenile myelomonocytic leukemia
CBL	Orphanet:98850	Aggressive systemic mastocytosis
GJB2	Orphanet:166286	Porokeratotic eccrine ostial and dermal duct nevus
GJB2	Orphanet:2202	Palmoplantar keratoderma-deafness syndrome
GJB2	Orphanet:2698	Knuckle pads-leukonychia-sensorineural deafness-palmoplantar hyperkeratosis syndrome
GJB2	Orphanet:477	KID syndrome
GJB2	Orphanet:494	Keratoderma hereditarium mutilans
GJB2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GJB2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
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
NOD2	Orphanet:90340	Blau syndrome
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
LZTR1	Orphanet:251576	Gliosarcoma
LZTR1	Orphanet:251579	Giant cell glioblastoma
LZTR1	Orphanet:2678	Familial isolated café-au-lait macules

Cohort genes → proteins

19 cohort genes, 19 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	19

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PTPN11	HGNC:9644	ENSG00000179295	Q06124	Tyrosine-protein phosphatase non-receptor type 11	gencc,clinvar
RIT1	HGNC:10023	ENSG00000143622	Q92963	GTP-binding protein Rit1	clinvar
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	clinvar
SOS1	HGNC:11187	ENSG00000115904	Q07889	Son of sevenless homolog 1	clinvar
SOS2	HGNC:11188	ENSG00000100485	Q07890	Son of sevenless homolog 2	clinvar
CBL	HGNC:1541	ENSG00000110395	P22681	E3 ubiquitin-protein ligase CBL	clinvar
A2ML1	HGNC:23336	ENSG00000166535	A8K2U0	Alpha-2-macroglobulin-like protein 1	clinvar
GJB2	HGNC:4284	ENSG00000165474	P29033	Gap junction beta-2 protein	clinvar
HRAS	HGNC:5173	ENSG00000174775	P01112	GTPase HRas	clinvar
NOD2	HGNC:5331	ENSG00000167207	Q9HC29	Nucleotide-binding oligomerization domain-containing protein 2	clinvar
KRAS	HGNC:6407	ENSG00000133703	P01116	GTPase KRas	clinvar
LZTR1	HGNC:6742	ENSG00000099949	Q8N653	Leucine-zipper-like transcriptional regulator 1	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
NRAS	HGNC:7989	ENSG00000213281	P01111	GTPase NRas	clinvar
PTS	HGNC:9689	ENSG00000150787	Q03393	6-pyruvoyl tetrahydrobiopterin synthase	clinvar
RAF1	HGNC:9829	ENSG00000132155	P04049	RAF proto-oncogene serine/threonine-protein kinase	clinvar
RALA	HGNC:9839	ENSG00000006451	P11233	Ras-related protein Ral-A	clinvar
RASA2	HGNC:9872	ENSG00000155903	Q15283	Ras GTPase-activating protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
RIT1	GTP-binding protein Rit1	Plays a crucial role in coupling NGF stimulation to the activation of both EPHB2 and MAPK14 signaling pathways and in NGF-dependent neuronal differentiation.
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
SOS1	Son of sevenless homolog 1	Promotes the exchange of Ras-bound GDP by GTP.
SOS2	Son of sevenless homolog 2	Acts as guanine nucleotide exchange factor (GEF) for RAS proteins.
CBL	E3 ubiquitin-protein ligase CBL	E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors.
A2ML1	Alpha-2-macroglobulin-like protein 1	Is able to inhibit all four classes of proteinases by a unique ’trapping’ mechanism.
GJB2	Gap junction beta-2 protein	Structural component of gap junctions.
HRAS	GTPase HRas	Involved in the activation of Ras protein signal transduction.
NOD2	Nucleotide-binding oligomerization domain-containing protein 2	Pattern recognition receptor (PRR) that detects bacterial peptidoglycan fragments and other danger signals and plays an important role in gastrointestinal immunity.
KRAS	GTPase KRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
LZTR1	Leucine-zipper-like transcriptional regulator 1	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates ubiquitination of Ras (K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS).
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.
NRAS	GTPase NRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
PTS	6-pyruvoyl tetrahydrobiopterin synthase	Involved in the biosynthesis of tetrahydrobiopterin, an essential cofactor of aromatic amino acid hydroxylases.
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…
RALA	Ras-related protein Ral-A	Multifunctional GTPase involved in a variety of cellular processes including gene expression, cell migration, cell proliferation, oncogenic transformation and membrane trafficking.
RASA2	Ras GTPase-activating protein 2	Inhibitory regulator of the Ras-cyclic AMP pathway.

Protein-family classification

Druggable: 9 · Difficult: 4 · Unknown: 6 · Druggable fraction: 0.47

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	5.8×	0.030
Complement	1	14.1×	0.240
Phosphatase	1	4.4×	0.363
Enzyme (other)	3	1.9×	0.363
Scaffold/PPI	2	1.8×	0.422
Transcription factor	2	0.9×	0.804
Other/Unknown	6	0.6×	0.991

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PTPN11	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, SH2
RIT1	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
SOS1	Scaffold/PPI	no		DH_dom, Ras-like_Gua-exchang_fac_N, PH_domain
SOS2	Scaffold/PPI	no		DH_dom, Ras-like_Gua-exchang_fac_N, PH_domain
CBL	Transcription factor	no	2.3.2.27	Znf_RING, Adaptor_Cbl_N_hlx, UBA-like_sf
A2ML1	Complement	yes		Macroglobln_a2, MG2, Terpenoid_cyclase/PrenylTrfase
GJB2	Other/Unknown	no		Connexin, Connexin26, Connexin_N
HRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
NOD2	Other/Unknown	no		CARD, Leu-rich_rpt, NACHT_NTPase
KRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
LZTR1	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
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
NRAS	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
PTS	Enzyme (other)	yes	4.2.3.12	6-PTP_synth/QueD, PTPS_His_AS, PTPS_Cys_AS
RAF1	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
RALA	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
RASA2	Transcription factor	no		C2_dom, Znf_Btk_motif, PH_domain

Expression context

Cohort genes with no expression data: 0.

19 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)	19
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	3
gingival epithelium	3
secondary oocyte	3
leukocyte	2
monocyte	2
mononuclear cell	2
colonic epithelium	2
trigeminal ganglion	2
gingiva	2
epithelium of nasopharynx	2
dorsal motor nucleus of vagus nerve	1
globus pallidus	1
medial globus pallidus	1
calcaneal tendon	1
jejunal mucosa	1
tendon of biceps brachii	1
biceps brachii	1
vastus lateralis	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PTPN11	295	ubiquitous	marker	medial globus pallidus, dorsal motor nucleus of vagus nerve, globus pallidus
RIT1	268	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon
SOS1	289	ubiquitous	marker	colonic epithelium, jejunal mucosa, tendon of biceps brachii
SOS2	298	ubiquitous	marker	vastus lateralis, biceps brachii, buccal mucosa cell
CBL	271	ubiquitous	marker	primordial germ cell in gonad, trigeminal ganglion, male germ line stem cell (sensu Vertebrata) in testis
A2ML1	176	tissue_specific	marker	lower esophagus mucosa, gingiva, gingival epithelium
GJB2	196	broad	marker	gingival epithelium, gingiva, penis
HRAS	139	ubiquitous	marker	skin of abdomen, skin of leg, zone of skin
NOD2	189	broad	marker	monocyte, mononuclear cell, leukocyte
KRAS	298	ubiquitous	marker	trigeminal ganglion, pylorus, nipple
LZTR1	134	ubiquitous	marker	sural nerve, pituitary gland, adenohypophysis
MAP2K1	298	ubiquitous	marker	secondary oocyte, oocyte, orbitofrontal cortex
MAP2K2	291	ubiquitous	marker	mucosa of transverse colon, right testis, left testis
NRAS	278	ubiquitous	marker	gingival epithelium, epithelium of nasopharynx, secondary oocyte
PTS	298	ubiquitous	marker	adrenal tissue, right adrenal gland, left adrenal gland cortex
RAF1	299	ubiquitous	marker	gastrocnemius, muscle of leg, ventricular zone
RALA	286	ubiquitous	marker	esophagus squamous epithelium, secondary oocyte, buccal mucosa cell
RASA2	269	ubiquitous	marker	epithelium of nasopharynx, superficial temporal artery, trabecular bone tissue

Protein interactions among cohort

Intra-cohort edges: 49.

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
CBL	4,575
MAP2K2	3,789
SOS1	3,625

Intra-cohort edges

A	B	Sources
A2ML1	LZTR1	string_interaction
A2ML1	RASA2	string_interaction
A2ML1	RIT1	string_interaction
BRAF	HRAS	intact, string_interaction
BRAF	KRAS	biogrid_interaction, intact, string_interaction
BRAF	MAP2K1	biogrid_interaction, intact, string_interaction
BRAF	MAP2K2	biogrid_interaction, intact, string_interaction
BRAF	NRAS	biogrid_interaction, intact, string_interaction
BRAF	RAF1	biogrid_interaction, intact, string_interaction
BRAF	SOS1	string_interaction
HRAS	LZTR1	biogrid_interaction
HRAS	MAP2K1	string_interaction
HRAS	MAP2K2	string_interaction
HRAS	RAF1	intact, string_interaction
HRAS	RALA	intact
HRAS	SOS1	intact, string_interaction
HRAS	SOS2	string_interaction
KRAS	LZTR1	string_interaction
KRAS	MAP2K1	biogrid_interaction, string_interaction
KRAS	MAP2K2	string_interaction
KRAS	NRAS	intact
KRAS	RAF1	intact, string_interaction
KRAS	SOS1	string_interaction
KRAS	SOS2	string_interaction
LZTR1	NRAS	biogrid_interaction, intact, string_interaction
LZTR1	RASA2	string_interaction
LZTR1	RIT1	biogrid_interaction, intact, string_interaction
LZTR1	SOS1	string_interaction
LZTR1	SOS2	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
MAP2K2	RASA2	string_interaction
MAP2K2	SOS1	string_interaction
NRAS	PTPN11	string_interaction
NRAS	RAF1	biogrid_interaction, intact, string_interaction
NRAS	RALA	intact
NRAS	RASA2	string_interaction
NRAS	SOS1	string_interaction
PTPN11	RASA2	string_interaction
PTPN11	SOS1	biogrid_interaction, string_interaction
PTPN11	SOS2	string_interaction
RAF1	SOS1	string_interaction
RASA2	SOS1	string_interaction
RASA2	SOS2	string_interaction

Structural data

PDB: 17 · AlphaFold-only: 2 · 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
CBL	P22681	33
GJB2	P29033	24
RALA	P11233	16
SOS2	Q07890	11
A2ML1	A8K2U0	5
RIT1	Q92963	3
LZTR1	Q8N653	3
MAP2K2	P36507	3
PTS	Q03393	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NOD2	Q9HC29	84.76
RASA2	Q15283	83.63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 269. Enrichment computed across 19 evidence-associated genes (17 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 17 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	138.3×	4e-12	BRAF, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, RAF1
Signaling by high-kinase activity BRAF mutants	7	130.6×	4e-12	BRAF, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, RAF1
MAP2K and MAPK activation	7	117.6×	6e-12	BRAF, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, RAF1
Signaling by RAF1 mutants	7	114.7×	6e-12	BRAF, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, RAF1
Negative regulation of MAPK pathway	7	109.4×	6e-12	BRAF, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, RAF1
Signaling by moderate kinase activity BRAF mutants	7	104.5×	6e-12	BRAF, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, RAF1
Paradoxical activation of RAF signaling by kinase inactive BRAF	7	104.5×	6e-12	BRAF, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, RAF1
Signaling downstream of RAS mutants	7	104.5×	6e-12	BRAF, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, RAF1
Activated NTRK2 signals through FRS2 and FRS3	5	279.9×	9e-11	PTPN11, SOS1, HRAS, KRAS, NRAS
Signaling by BRAF and RAF1 fusions	7	70.2×	9e-11	BRAF, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, RAF1
FLT3 Signaling	6	122.1×	1e-10	PTPN11, SOS1, CBL, HRAS, KRAS, NRAS
Signaling by FLT3 ITD and TKD mutants	5	223.9×	3e-10	PTPN11, SOS1, HRAS, KRAS, NRAS
Constitutive Signaling by EGFRvIII	5	209.9×	3e-10	SOS1, CBL, HRAS, KRAS, NRAS
Signaling by SCF-KIT	6	87.6×	7e-10	PTPN11, SOS1, CBL, HRAS, KRAS, NRAS
Tie2 Signaling	5	176.8×	8e-10	PTPN11, SOS1, HRAS, KRAS, NRAS
Negative feedback regulation of MAPK pathway	4	447.8×	8e-10	BRAF, MAP2K1, MAP2K2, RAF1
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	5	167.9×	9e-10	SOS1, CBL, HRAS, KRAS, NRAS
FRS-mediated FGFR3 signaling	5	159.9×	1e-09	PTPN11, SOS1, HRAS, KRAS, NRAS
FRS-mediated FGFR4 signaling	5	146.0×	2e-09	PTPN11, SOS1, HRAS, KRAS, NRAS
FRS-mediated FGFR1 signaling	5	134.3×	3e-09	PTPN11, SOS1, HRAS, KRAS, NRAS
SOS-mediated signalling	4	335.9×	3e-09	SOS1, HRAS, KRAS, NRAS
FRS-mediated FGFR2 signaling	5	129.2×	3e-09	PTPN11, SOS1, HRAS, KRAS, NRAS
Activated NTRK3 signals through RAS	4	298.6×	5e-09	SOS1, HRAS, KRAS, NRAS
Downstream signal transduction	5	112.0×	6e-09	PTPN11, SOS1, HRAS, KRAS, NRAS
EGFR Transactivation by Gastrin	4	268.7×	7e-09	SOS1, HRAS, KRAS, NRAS
SHC-related events triggered by IGF1R	4	268.7×	7e-09	SOS1, HRAS, KRAS, NRAS
Activated NTRK2 signals through RAS	4	268.7×	7e-09	SOS1, HRAS, KRAS, NRAS
MET activates RAS signaling	4	244.3×	1e-08	SOS1, HRAS, KRAS, NRAS
Signaling by FGFR4 in disease	4	223.9×	1e-08	SOS1, HRAS, KRAS, NRAS
Constitutive Signaling by Overexpressed ERBB2	4	223.9×	1e-08	SOS1, HRAS, 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 19 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	5	277.2×	7e-10	SOS1, HRAS, MAP2K1, MAP2K2, RAF1
Ras protein signal transduction	7	75.7×	7e-10	RIT1, SOS1, SOS2, HRAS, KRAS, NRAS, RALA
MAPK cascade	7	56.4×	2e-09	BRAF, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, RAF1
face development	4	168.9×	5e-07	BRAF, MAP2K1, MAP2K2, RAF1
myelination	5	66.2×	6e-07	SOS1, HRAS, MAP2K1, MAP2K2, RAF1
thyroid gland development	4	114.4×	2e-06	BRAF, MAP2K1, MAP2K2, RAF1
insulin-like growth factor receptor signaling pathway	4	104.3×	2e-06	SOS1, MAP2K1, MAP2K2, RAF1
ERBB2-ERBB3 signaling pathway	3	266.1×	6e-06	MAP2K1, MAP2K2, RAF1
thymus development	4	71.0×	9e-06	BRAF, MAP2K1, MAP2K2, RAF1
neurotrophin TRK receptor signaling pathway	3	166.3×	2e-05	PTPN11, SOS1, RAF1
insulin receptor signaling pathway	4	46.7×	4e-05	SOS1, SOS2, HRAS, RAF1
positive regulation of ERK1 and ERK2 cascade	5	22.4×	6e-05	PTPN11, BRAF, HRAS, NOD2, MAP2K1
cerebellar cortex formation	2	591.3×	9e-05	PTPN11, MAP2K1
positive regulation of axonogenesis	3	91.8×	1e-04	BRAF, MAP2K1, MAP2K2
regulation of Golgi inheritance	2	443.5×	1e-04	MAP2K1, MAP2K2
positive regulation of epidermal growth factor receptor signaling pathway	3	78.3×	1e-04	SOS1, CBL, RALA
signal transduction	8	6.8×	2e-04	RIT1, SOS1, CBL, HRAS, MAP2K1, RAF1, RALA, RASA2
epithelial cell proliferation involved in lung morphogenesis	2	354.8×	2e-04	MAP2K1, MAP2K2
regulation of pro-B cell differentiation	2	354.8×	2e-04	SOS1, SOS2
cytokine-mediated signaling pathway	4	27.5×	2e-04	PTPN11, SOS1, CBL, KRAS
regulation of T cell differentiation in thymus	2	253.4×	3e-04	SOS1, SOS2
regulation of axon regeneration	2	253.4×	3e-04	MAP2K1, MAP2K2
trachea formation	2	253.4×	3e-04	MAP2K1, MAP2K2
ERK1 and ERK2 cascade	3	50.2×	4e-04	BRAF, MAP2K1, MAP2K2
regulation of early endosome to late endosome transport	2	221.7×	4e-04	MAP2K1, MAP2K2
regulation of stress-activated MAPK cascade	2	197.1×	5e-04	MAP2K1, MAP2K2
epidermal growth factor receptor signaling pathway	3	39.1×	7e-04	PTPN11, BRAF, SOS1
Bergmann glial cell differentiation	2	161.3×	7e-04	PTPN11, MAP2K1
positive regulation of protein serine/threonine kinase activity	2	136.4×	0.001	MAP2K1, MAP2K2
regulation of T cell proliferation	2	110.9×	0.001	SOS1, SOS2

Therapeutics

Drug target analysis

Approved (phase 4): 11 · Phase ≥3: 11 · Phased (≥1): 12 · Undrugged: 7

Druggability breadth: 15 of 19 evidence-associated genes (79%) 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
PTPN11	ESTRAMUSTINE PHOSPHATE
BRAF	VEMURAFENIB
SOS1	IDARUBICIN
SOS2	TACRINE
GJB2	KANAMYCIN
HRAS	LONAFARNIB
NOD2	PACLITAXEL
KRAS	VEMURAFENIB
MAP2K1	VEMURAFENIB
MAP2K2	VEMURAFENIB
RAF1	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAP2K1	54	4
MAP2K2	52	4
BRAF	48	4
RAF1	31	4
KRAS	11	4
PTPN11	8	4
NOD2	6	4
SOS1	5	4
HRAS	4	4
SOS2	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ESTRAMUSTINE PHOSPHATE	4	PTPN11
VEMURAFENIB	4	BRAF, KRAS, MAP2K1, MAP2K2, RAF1
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF, MAP2K1, MAP2K2
SORAFENIB	4	BRAF, MAP2K1, RAF1
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF, MAP2K1, MAP2K2
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF, RAF1
DABRAFENIB	4	BRAF, KRAS, RAF1
COBIMETINIB	4	BRAF, MAP2K1, MAP2K2
NILOTINIB	4	BRAF, RAF1
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF, RAF1
PAZOPANIB	4	BRAF, RAF1
DASATINIB	4	BRAF, MAP2K1, MAP2K2, RAF1
ERLOTINIB	4	BRAF, RAF1
GEFITINIB	4	BRAF, NOD2
IMATINIB	4	BRAF, RAF1
IDARUBICIN	4	SOS1
DOXORUBICIN	4	SOS1
SOTORASIB	4	KRAS, SOS1
ADAGRASIB	4	KRAS, SOS1
TACRINE	4	SOS2
KANAMYCIN	4	GJB2
LONAFARNIB	4	HRAS, KRAS
PACLITAXEL	4	NOD2
DOCETAXEL ANHYDROUS	4	NOD2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 9.

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

Symbol	Assays	Type breakdown
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
MAP2K1	1,200	Binding:1150, Functional:47, ADMET:3
KRAS	861	Binding:829, Functional:32
RAF1	839	Binding:803, Functional:31, ADMET:5
MAP2K2	615	Binding:581, Functional:33, ADMET:1
PTPN11	588	Binding:585, Functional:2, ADMET:1
SOS1	421	Binding:409, Functional:12
NOD2	126	Binding:121, Functional:5
HRAS	48	Binding:45, Functional:3
NRAS	18	Binding:18
SOS2	10	Binding:10
GJB2	5	Binding:5
CBL	4	Binding:2, Toxicity:2
RALA	2	Binding:2
PTS	1	ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PTPN11	3.1.3.48	protein-tyrosine-phosphatase
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
CBL	2.3.2.27	RING-type E3 ubiquitin transferase
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
MAP2K2	2.7.12.2	mitogen-activated protein kinase kinase
PTS	4.2.3.12	6-pyruvoyltetrahydropterin synthase
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
PTPN11	588
BRAF	1,442
SOS1	421
NOD2	126
KRAS	861
MAP2K1	1,200
MAP2K2	615
RAF1	839

Pharmacogenomics

Cohort genes with a PharmGKB record: 19; 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)
ESTRAMUSTINE PHOSPHATE	4	PTPN11
VEMURAFENIB	4	BRAF, KRAS, MAP2K1, MAP2K2, RAF1
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF, MAP2K1, MAP2K2
SORAFENIB	4	BRAF, MAP2K1, RAF1
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF, MAP2K1, MAP2K2
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF, RAF1
DABRAFENIB	4	BRAF, KRAS, RAF1
COBIMETINIB	4	BRAF, MAP2K1, MAP2K2
NILOTINIB	4	BRAF, RAF1
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF, RAF1
PAZOPANIB	4	BRAF, RAF1
DASATINIB	4	BRAF, MAP2K1, MAP2K2, RAF1
ERLOTINIB	4	BRAF, RAF1
GEFITINIB	4	BRAF, NOD2
IMATINIB	4	BRAF, RAF1
IDARUBICIN	4	SOS1
DOXORUBICIN	4	SOS1
SOTORASIB	4	KRAS, SOS1
ADAGRASIB	4	KRAS, SOS1
TACRINE	4	SOS2
KANAMYCIN	4	GJB2
LONAFARNIB	4	HRAS, KRAS
PACLITAXEL	4	NOD2
DOCETAXEL ANHYDROUS	4	NOD2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	11	PTPN11, BRAF, SOS1, SOS2, GJB2, HRAS, NOD2, KRAS, MAP2K1, MAP2K2 (+1 more)
B	Phased (≥1) drug, not yet approved	1	NRAS
C	Druggable family + PDB, no drug	2	A2ML1, PTS
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	RIT1, CBL, LZTR1, RALA, RASA2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RASA2	0	SOS1, SOS2
RIT1	0	—
CBL	4	—
A2ML1	0	—
LZTR1	0	—
PTS	1	—
RALA	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.