Noonan syndrome and Noonan-related syndrome
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Summary
Noonan syndrome and Noonan-related syndrome (MONDO:0020297) is a disease (an umbrella term covering 6 Mondo subtypes) caused by RRAS (GenCC Strong), with 19 cohort genes. The dominant Reactome pathway is RAF activation (8 cohort genes).
At a glance
- Causal gene: RRAS (GenCC Strong)
- Umbrella term: 6 Mondo subtypes
- Cohort genes: 19
- ClinVar variants: 557
Clinical features
No curated clinical features (Orphanet) for this disease.
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | Noonan syndrome and Noonan-related syndrome |
| Mondo ID | MONDO:0020297 |
| MeSH | C537846 |
| Orphanet | 98733 |
| UMLS | C5681679 |
| MedGen | 1826127 |
| GARD | 0019561 |
| Is cancer (heuristic) | no |
Data availability: 557 ClinVar variants · 1 GenCC gene-disease record.
Disease family
An umbrella term covering 6 Mondo subtypes.
Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › RASopathy › Noonan syndrome and Noonan-related syndrome
Related subtypes (3): neurofibromatosis-Noonan syndrome, CBL-related disorder, neurofibromatosis type 1
Subtypes (6): Noonan syndrome with multiple lentigines, Costello syndrome, Noonan syndrome-like disorder with loose anagen hair, Legius syndrome, cardiofaciocutaneous syndrome, Noonan 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
557 retrieved; paginated sample, class counts are floors:
119 conflicting classifications of pathogenicity, 103 benign, 98 uncertain significance, 76 benign/likely benign, 68 pathogenic, 39 likely benign, 35 pathogenic/likely pathogenic, 19 likely pathogenic
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 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 |
| 13976 | NM_004333.6(BRAF):c.1495A>G (p.Lys499Glu) | BRAF | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 177775 | NM_004333.6(BRAF):c.1405G>A (p.Gly469Arg) | 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 |
| 40347 | NM_004333.6(BRAF):c.735A>C (p.Leu245Phe) | BRAF | Pathogenic | reviewed by expert panel |
| 40348 | NM_004333.6(BRAF):c.735A>T (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 |
| 40383 | NM_004333.6(BRAF):c.1695T>G (p.Asp565Glu) | BRAF | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 55793 | NM_004333.6(BRAF):c.741T>G (p.Phe247Leu) | BRAF | Pathogenic | reviewed by expert panel |
| 13807 | NM_005188.4(CBL):c.1100A>C (p.Gln367Pro) | CBL | Pathogenic/Likely 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 |
| 12606 | NM_005343.4(HRAS):c.37G>T (p.Gly13Cys) | 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 |
| 35554 | NM_005343.4(HRAS):c.37G>C (p.Gly13Arg) | HRAS | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 12580 | NM_004985.5(KRAS):c.38G>A (p.Gly13Asp) | KRAS | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 12589 | NM_004985.5(KRAS):c.40G>A (p.Val14Ile) | KRAS | Pathogenic | reviewed by expert panel |
| 101038 | NM_006767.4(LZTR1):c.1397G>A (p.Arg466Gln) | LZTR1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 373089 | NM_006767.4(LZTR1):c.1234C>T (p.Arg412Cys) | LZTR1 | Pathogenic | reviewed by expert panel |
| 40744 | NM_002755.4(MAP2K1):c.371C>T (p.Pro124Leu) | MAP2K1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 44588 | NM_002755.4(MAP2K1):c.275T>G (p.Leu92Arg) | 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 |
| 177778 | NM_002524.5(NRAS):c.34G>A (p.Gly12Ser) | NRAS | Pathogenic | reviewed by expert panel |
| 219097 | NM_002524.5(NRAS):c.35G>C (p.Gly12Ala) | NRAS | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 39648 | NM_002524.5(NRAS):c.35G>A (p.Gly12Asp) | NRAS | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 4 · Orphanet: 65 · 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 |
|---|---|---|---|---|
| RRAS | Strong | Autosomal dominant | Noonan syndrome and Noonan-related syndrome | 4 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| RRAS | Orphanet:648 | Noonan syndrome |
| RRAS | 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 |
| SHOC2 | Orphanet:2701 | Noonan syndrome-like disorder with loose anagen hair |
| SPRED1 | Orphanet:137605 | Legius syndrome |
| LRRC56 | Orphanet:244 | Primary ciliary dyskinesia |
| 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 |
| 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 |
| LZTR1 | Orphanet:648 | Noonan syndrome |
| LZTR1 | Orphanet:93921 | Full schwannomatosis |
| MAP2K1 | Orphanet:1340 | Cardiofaciocutaneous syndrome |
| MAP2K1 | Orphanet:389 | Langerhans cell histiocytosis |
| MAP2K2 | Orphanet:1340 | Cardiofaciocutaneous syndrome |
| MAP2K2 | Orphanet:638 | Neurofibromatosis-Noonan syndrome |
| NRAS | Orphanet:146 | Differentiated thyroid carcinoma |
Cohort genes → proteins
19 cohort genes, 18 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 19 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| RRAS | HGNC:10447 | ENSG00000126458 | P10301 | Ras-related protein R-Ras | gencc |
| 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 |
| SHOC2 | HGNC:15454 | ENSG00000108061 | Q9UQ13 | Leucine-rich repeat protein SHOC-2 | clinvar |
| SPRED1 | HGNC:20249 | ENSG00000166068 | Q7Z699 | Sprouty-related, EVH1 domain-containing protein 1 | clinvar |
| LRRC56 | HGNC:25430 | ENSG00000161328 | Q8IYG6 | Leucine-rich repeat-containing protein 56 | clinvar |
| FRA11B | HGNC:3837 | fragile site, folic acid type, rare, fra(11)(q23.3) | clinvar | ||
| HRAS | HGNC:5173 | ENSG00000174775 | P01112 | GTPase HRas | 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 |
| MKRN2 | HGNC:7113 | ENSG00000075975 | Q9H000 | E3 ubiquitin-protein ligase makorin-2 | clinvar |
| NRAS | HGNC:7989 | ENSG00000213281 | P01111 | GTPase NRas | clinvar |
| PTPN11 | HGNC:9644 | ENSG00000179295 | Q06124 | Tyrosine-protein phosphatase non-receptor type 11 | clinvar |
| RAF1 | HGNC:9829 | ENSG00000132155 | P04049 | RAF proto-oncogene serine/threonine-protein kinase | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| RRAS | Ras-related protein R-Ras | GTP-binding protein with GTPase activity, likely involved in the regulation of MAPK signaling pathway and thereby controlling multiple cellular processes. |
| 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. |
| SHOC2 | Leucine-rich repeat protein SHOC-2 | Core component of the SHOC2-MRAS-PP1c (SMP) holophosphatase complex that regulates activation of the MAPK pathway. |
| SPRED1 | Sprouty-related, EVH1 domain-containing protein 1 | Tyrosine kinase substrate that inhibits growth-factor-mediated activation of MAP kinase. |
| LRRC56 | Leucine-rich repeat-containing protein 56 | Required for the assembly of dynein arms. |
| HRAS | GTPase HRas | Involved in the activation of Ras protein signal transduction. |
| 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. |
| MKRN2 | E3 ubiquitin-protein ligase makorin-2 | E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins. |
| 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… |
Protein-family classification
Druggable: 7 · Difficult: 4 · Unknown: 8 · Druggable fraction: 0.37
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× | 0.025 |
| Phosphatase | 1 | 4.4× | 0.603 |
| Scaffold/PPI | 2 | 1.8× | 0.603 |
| Enzyme (other) | 2 | 1.3× | 0.718 |
| Transcription factor | 2 | 0.9× | 0.827 |
| Other/Unknown | 8 | 0.8× | 0.924 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| RRAS | Other/Unknown | no | Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type | |
| 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 |
| SHOC2 | Other/Unknown | no | Leu-rich_rpt, Leu-rich_rpt_typical-subtyp, LRR_dom_sf | |
| SPRED1 | Other/Unknown | no | WH1/EVH1_dom, Sprouty, PH-like_dom_sf | |
| LRRC56 | Other/Unknown | no | Leu-rich_rpt, Leu-rich_rpt_4, LRR_dom_sf | |
| FRA11B | Other/Unknown | no | ||
| HRAS | Enzyme (other) | yes | 3.6.5.2 | Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type |
| 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 |
| MKRN2 | Transcription factor | no | Znf_CCCH, Znf_RING, Znf_RING/FYVE/PHD | |
| 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 |
Expression context
Cohort genes with no expression data: 1.
18 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) | 18 |
| unknown | 1 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| calcaneal tendon | 3 |
| left testis | 3 |
| secondary oocyte | 3 |
| buccal mucosa cell | 2 |
| colonic epithelium | 2 |
| trigeminal ganglion | 2 |
| sural nerve | 2 |
| ventricular zone | 2 |
| right testis | 2 |
| popliteal artery | 1 |
| right coronary artery | 1 |
| tibial artery | 1 |
| leukocyte | 1 |
| monocyte | 1 |
| mononuclear cell | 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 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| RRAS | 242 | ubiquitous | marker | right coronary artery, popliteal artery, tibial artery |
| 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 |
| SHOC2 | 299 | ubiquitous | marker | calcaneal tendon, sural nerve, bone marrow |
| SPRED1 | 248 | ubiquitous | marker | ventricular zone, mucosa of sigmoid colon, calcaneal tendon |
| LRRC56 | 129 | broad | marker | right uterine tube, right testis, left testis |
| FRA11B | ||||
| HRAS | 139 | ubiquitous | marker | skin of abdomen, skin of leg, zone of skin |
| 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 |
| MKRN2 | 270 | ubiquitous | marker | secondary oocyte, left testis, sperm |
| 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 |
Protein interactions among cohort
Intra-cohort edges: 58.
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 |
|---|---|---|
| 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 | SHOC2 | string_interaction |
| BRAF | SOS1 | string_interaction |
| BRAF | SPRED1 | string_interaction |
| HRAS | LZTR1 | biogrid_interaction |
| HRAS | MAP2K1 | string_interaction |
| HRAS | MAP2K2 | string_interaction |
| HRAS | RAF1 | intact, string_interaction |
| HRAS | SHOC2 | intact, string_interaction |
| 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 | SHOC2 | intact, string_interaction |
| KRAS | SOS1 | string_interaction |
| KRAS | SOS2 | string_interaction |
| KRAS | SPRED1 | string_interaction |
| LZTR1 | NRAS | biogrid_interaction, intact, string_interaction |
| LZTR1 | RIT1 | biogrid_interaction, intact, string_interaction |
| LZTR1 | SHOC2 | 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 |
| MAP2K1 | SHOC2 | string_interaction |
| MAP2K2 | NRAS | intact, string_interaction |
| MAP2K2 | PTPN11 | string_interaction |
| MAP2K2 | RAF1 | biogrid_interaction, intact |
| MAP2K2 | SHOC2 | string_interaction |
| MAP2K2 | SOS1 | string_interaction |
| MAP2K2 | SPRED1 | string_interaction |
| MKRN2 | RAF1 | 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 |
| PTPN11 | SOS2 | string_interaction |
Structural data
PDB: 16 · AlphaFold-only: 2 · No structure: 1
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 |
| SHOC2 | Q9UQ13 | 13 |
| SOS2 | Q07890 | 11 |
| RIT1 | Q92963 | 3 |
| SPRED1 | Q7Z699 | 3 |
| LZTR1 | Q8N653 | 3 |
| MAP2K2 | P36507 | 3 |
| RRAS | P10301 | 2 |
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| MKRN2 | Q9H000 | 71.78 |
| LRRC56 | Q8IYG6 | 56.07 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 262. Enrichment computed across 19 evidence-associated genes (15 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 15 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| RAF activation | 8 | 179.1× | 4e-15 | BRAF, SHOC2, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, RAF1 |
| Signaling by high-kinase activity BRAF mutants | 7 | 148.0× | 1e-12 | BRAF, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, RAF1 |
| MAP2K and MAPK activation | 7 | 133.2× | 2e-12 | BRAF, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, RAF1 |
| Signaling by RAF1 mutants | 7 | 130.0× | 2e-12 | BRAF, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, RAF1 |
| Negative regulation of MAPK pathway | 7 | 123.9× | 2e-12 | BRAF, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, RAF1 |
| Signaling by moderate kinase activity BRAF mutants | 7 | 118.4× | 2e-12 | BRAF, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, RAF1 |
| Paradoxical activation of RAF signaling by kinase inactive BRAF | 7 | 118.4× | 2e-12 | BRAF, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, RAF1 |
| Signaling downstream of RAS mutants | 7 | 118.4× | 2e-12 | BRAF, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, RAF1 |
| RAF/MAP kinase cascade | 9 | 36.6× | 9e-12 | BRAF, SOS1, SHOC2, SPRED1, HRAS, KRAS, MAP2K1, MAP2K2 (+1 more) |
| Signaling by BRAF and RAF1 fusions | 7 | 79.5× | 3e-11 | BRAF, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, RAF1 |
| Activated NTRK2 signals through FRS2 and FRS3 | 5 | 317.2× | 3e-11 | SOS1, HRAS, KRAS, NRAS, PTPN11 |
| FLT3 Signaling | 6 | 138.4× | 4e-11 | SOS1, CBL, HRAS, KRAS, NRAS, PTPN11 |
| Signaling by FLT3 ITD and TKD mutants | 5 | 253.8× | 1e-10 | SOS1, HRAS, KRAS, NRAS, PTPN11 |
| Constitutive Signaling by EGFRvIII | 5 | 237.9× | 2e-10 | SOS1, CBL, HRAS, KRAS, NRAS |
| Signaling by SCF-KIT | 6 | 99.3× | 3e-10 | SOS1, CBL, HRAS, KRAS, NRAS, PTPN11 |
| Tie2 Signaling | 5 | 200.3× | 3e-10 | SOS1, HRAS, KRAS, NRAS, PTPN11 |
| Negative feedback regulation of MAPK pathway | 4 | 507.6× | 4e-10 | BRAF, MAP2K1, MAP2K2, RAF1 |
| Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants | 5 | 190.3× | 4e-10 | SOS1, CBL, HRAS, KRAS, NRAS |
| FRS-mediated FGFR3 signaling | 5 | 181.3× | 5e-10 | SOS1, HRAS, KRAS, NRAS, PTPN11 |
| FRS-mediated FGFR4 signaling | 5 | 165.5× | 8e-10 | SOS1, HRAS, KRAS, NRAS, PTPN11 |
| RAS signaling downstream of NF1 loss-of-function variants | 4 | 435.1× | 8e-10 | SPRED1, HRAS, KRAS, NRAS |
| FRS-mediated FGFR1 signaling | 5 | 152.3× | 1e-09 | SOS1, HRAS, KRAS, NRAS, PTPN11 |
| FRS-mediated FGFR2 signaling | 5 | 146.4× | 1e-09 | SOS1, HRAS, KRAS, NRAS, PTPN11 |
| SOS-mediated signalling | 4 | 380.7× | 1e-09 | SOS1, HRAS, KRAS, NRAS |
| Activated NTRK3 signals through RAS | 4 | 338.4× | 3e-09 | SOS1, HRAS, KRAS, NRAS |
| Downstream signal transduction | 5 | 126.9× | 3e-09 | SOS1, HRAS, KRAS, NRAS, PTPN11 |
| EGFR Transactivation by Gastrin | 4 | 304.5× | 4e-09 | SOS1, HRAS, KRAS, NRAS |
| SHC-related events triggered by IGF1R | 4 | 304.5× | 4e-09 | SOS1, HRAS, KRAS, NRAS |
| Activated NTRK2 signals through RAS | 4 | 304.5× | 4e-09 | SOS1, HRAS, KRAS, NRAS |
| MET activates RAS signaling | 4 | 276.9× | 6e-09 | 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 18 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| Ras protein signal transduction | 7 | 79.9× | 4e-10 | RIT1, RRAS, SOS1, SOS2, HRAS, KRAS, NRAS |
| Schwann cell development | 5 | 292.6× | 5e-10 | SOS1, HRAS, MAP2K1, MAP2K2, RAF1 |
| MAPK cascade | 7 | 59.6× | 1e-09 | BRAF, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, RAF1 |
| face development | 4 | 178.3× | 4e-07 | BRAF, MAP2K1, MAP2K2, RAF1 |
| myelination | 5 | 69.9× | 4e-07 | SOS1, HRAS, MAP2K1, MAP2K2, RAF1 |
| thyroid gland development | 4 | 120.8× | 1e-06 | BRAF, MAP2K1, MAP2K2, RAF1 |
| insulin-like growth factor receptor signaling pathway | 4 | 110.1× | 2e-06 | SOS1, MAP2K1, MAP2K2, RAF1 |
| ERBB2-ERBB3 signaling pathway | 3 | 280.9× | 4e-06 | MAP2K1, MAP2K2, RAF1 |
| thymus development | 4 | 74.9× | 6e-06 | BRAF, MAP2K1, MAP2K2, RAF1 |
| neurotrophin TRK receptor signaling pathway | 3 | 175.5× | 2e-05 | SOS1, PTPN11, RAF1 |
| insulin receptor signaling pathway | 4 | 49.3× | 3e-05 | SOS1, SOS2, HRAS, RAF1 |
| cerebellar cortex formation | 2 | 624.1× | 8e-05 | MAP2K1, PTPN11 |
| positive regulation of axonogenesis | 3 | 96.8× | 8e-05 | BRAF, MAP2K1, MAP2K2 |
| regulation of Golgi inheritance | 2 | 468.1× | 1e-04 | MAP2K1, MAP2K2 |
| cytokine-mediated signaling pathway | 4 | 29.0× | 2e-04 | SOS1, CBL, KRAS, PTPN11 |
| epithelial cell proliferation involved in lung morphogenesis | 2 | 374.5× | 2e-04 | MAP2K1, MAP2K2 |
| regulation of pro-B cell differentiation | 2 | 374.5× | 2e-04 | SOS1, SOS2 |
| regulation of T cell differentiation in thymus | 2 | 267.5× | 3e-04 | SOS1, SOS2 |
| regulation of axon regeneration | 2 | 267.5× | 3e-04 | MAP2K1, MAP2K2 |
| trachea formation | 2 | 267.5× | 3e-04 | MAP2K1, MAP2K2 |
| ERK1 and ERK2 cascade | 3 | 53.0× | 3e-04 | BRAF, MAP2K1, MAP2K2 |
| regulation of early endosome to late endosome transport | 2 | 234.1× | 4e-04 | MAP2K1, MAP2K2 |
| fibroblast growth factor receptor signaling pathway | 3 | 47.6× | 4e-04 | SOS1, SHOC2, PTPN11 |
| regulation of stress-activated MAPK cascade | 2 | 208.1× | 5e-04 | MAP2K1, MAP2K2 |
| epidermal growth factor receptor signaling pathway | 3 | 41.3× | 5e-04 | BRAF, SOS1, PTPN11 |
| positive regulation of ERK1 and ERK2 cascade | 4 | 18.9× | 5e-04 | BRAF, HRAS, MAP2K1, PTPN11 |
| Bergmann glial cell differentiation | 2 | 170.2× | 6e-04 | MAP2K1, PTPN11 |
| positive regulation of protein serine/threonine kinase activity | 2 | 144.0× | 8e-04 | MAP2K1, MAP2K2 |
| regulation of T cell proliferation | 2 | 117.0× | 0.001 | SOS1, SOS2 |
| regulation of long-term neuronal synaptic plasticity | 2 | 110.1× | 0.001 | HRAS, KRAS |
Therapeutics
Drug target analysis
Approved (phase 4): 9 · Phase ≥3: 9 · Phased (≥1): 10 · Undrugged: 9
Druggability breadth: 11 of 19 evidence-associated genes (58%) 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 |
| SOS1 | IDARUBICIN |
| SOS2 | TACRINE |
| HRAS | LONAFARNIB |
| KRAS | VEMURAFENIB |
| MAP2K1 | VEMURAFENIB |
| MAP2K2 | VEMURAFENIB |
| PTPN11 | ESTRAMUSTINE PHOSPHATE |
| 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 |
| SOS1 | 5 | 4 |
| HRAS | 4 | 4 |
| SOS2 | 1 | 4 |
| NRAS | 1 | 1 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| 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 |
| IMATINIB | 4 | BRAF, RAF1 |
| IDARUBICIN | 4 | SOS1 |
| DOXORUBICIN | 4 | SOS1 |
| SOTORASIB | 4 | KRAS, SOS1 |
| ADAGRASIB | 4 | KRAS, SOS1 |
| TACRINE | 4 | SOS2 |
| LONAFARNIB | 4 | HRAS, KRAS |
| SELUMETINIB | 4 | MAP2K1, MAP2K2 |
| TRAMETINIB | 4 | MAP2K1, MAP2K2 |
| BINIMETINIB | 4 | MAP2K1, MAP2K2 |
| AXITINIB | 4 | MAP2K1, MAP2K2 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 8.
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 |
| HRAS | 48 | Binding:45, Functional:3 |
| NRAS | 18 | Binding:18 |
| SOS2 | 10 | Binding:10 |
| CBL | 4 | Binding:2, Toxicity: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 |
| 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 |
| 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 |
| MAP2K2 | 615 |
| PTPN11 | 588 |
| RAF1 | 839 |
Pharmacogenomics
Cohort genes with a PharmGKB record: 18; 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, 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 |
| IMATINIB | 4 | BRAF, RAF1 |
| IDARUBICIN | 4 | SOS1 |
| DOXORUBICIN | 4 | SOS1 |
| SOTORASIB | 4 | KRAS, SOS1 |
| ADAGRASIB | 4 | KRAS, SOS1 |
| TACRINE | 4 | SOS2 |
| LONAFARNIB | 4 | HRAS, KRAS |
| SELUMETINIB | 4 | MAP2K1, MAP2K2 |
| TRAMETINIB | 4 | MAP2K1, MAP2K2 |
| BINIMETINIB | 4 | MAP2K1, MAP2K2 |
| AXITINIB | 4 | MAP2K1, MAP2K2 |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 9 | BRAF, SOS1, SOS2, HRAS, KRAS, MAP2K1, MAP2K2, 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 | 9 | RRAS, RIT1, CBL, SHOC2, SPRED1, LRRC56, FRA11B, LZTR1, MKRN2 |
Undrugged target profiles
9 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 |
| RRAS | 0 | — |
| RIT1 | 0 | — |
| CBL | 4 | — |
| LRRC56 | 0 | — |
| FRA11B | 0 | — |
| LZTR1 | 0 | — |
| MKRN2 | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 0.