Noonan syndrome 3
diseaseOn this page
Also known as KRAS gene related Noonan syndromeKRAS Noonan syndromeNoonan syndrome caused by mutation in KRASNoonan syndrome type 3NS3
Summary
Noonan syndrome 3 (MONDO:0012371) is a disease caused by KRAS (GenCC Definitive), with 7 cohort genes. The dominant Reactome pathway is Activated NTRK2 signals through FRS2 and FRS3 (4 cohort genes).
At a glance
- Causal gene: KRAS (GenCC Definitive)
- Cohort genes: 7
- ClinVar variants: 74
Clinical features
No curated clinical features (Orphanet) for this disease.
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | Noonan syndrome 3 |
| Mondo ID | MONDO:0012371 |
| MeSH | C537847 |
| OMIM | 609942 |
| DOID | DOID:0060581 |
| NCIT | C176931 |
| UMLS | C1860991 |
| MedGen | 349931 |
| GARD | 0009885 |
| Is cancer (heuristic) | no |
Also known as: KRAS gene related Noonan syndrome · KRAS Noonan syndrome · Noonan syndrome 3 · Noonan syndrome caused by mutation in KRAS · Noonan syndrome type 3 · NS3
Data availability: 74 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 3
Related subtypes (13): Noonan syndrome 1, Noonan syndrome 2, 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
74 retrieved; paginated sample, class counts are floors:
23 pathogenic, 15 uncertain significance, 11 pathogenic/likely pathogenic, 10 conflicting classifications of pathogenicity, 8 likely pathogenic, 4 likely benign, 2 benign/likely benign, 1 benign
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 984634 | NM_004859.4(CLTC):c.1912_1916delinsAGA (p.Ala639fs) | CLTC | Pathogenic | no assertion criteria provided |
| 12601 | NM_005343.4(HRAS):c.181C>A (p.Gln61Lys) | HRAS | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 12582 | NM_004985.5(KRAS):c.35G>A (p.Gly12Asp) | KRAS | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 12586 | NM_004985.5(KRAS):c.178G>C (p.Gly60Arg) | KRAS | Pathogenic | reviewed by expert panel |
| 12587 | NM_004985.5(KRAS):c.458A>T (p.Asp153Val) | KRAS | Pathogenic | reviewed by expert panel |
| 12588 | NM_004985.5(KRAS):c.173C>T (p.Thr58Ile) | KRAS | Pathogenic | reviewed by expert panel |
| 12589 | NM_004985.5(KRAS):c.40G>A (p.Val14Ile) | KRAS | Pathogenic | reviewed by expert panel |
| 12590 | NM_004985.5(KRAS):c.101C>G (p.Pro34Arg) | KRAS | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 12591 | NM_033360.4(KRAS):c.*9T>G | KRAS | Pathogenic | no assertion criteria provided |
| 12596 | NM_004985.5(KRAS):c.13A>G (p.Lys5Glu) | KRAS | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 12597 | NM_033360.4(KRAS):c.178G>A (p.Gly60Ser) | KRAS | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 163758 | NM_004985.5(KRAS):c.466T>A (p.Phe156Ile) | KRAS | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1695421 | NM_004985.5(KRAS):c.53C>T (p.Ala18Val) | KRAS | Pathogenic | criteria provided, single submitter |
| 1695422 | NM_004985.5(KRAS):c.194_195insGGCAATGAGGGACCAGTACAG (p.Tyr64_Ser65insArgAlaMetArgAspGlnTyr) | KRAS | Pathogenic | criteria provided, single submitter |
| 40452 | NM_004985.5(KRAS):c.65A>G (p.Gln22Arg) | KRAS | Pathogenic | reviewed by expert panel |
| 40454 | NM_004985.5(KRAS):c.101C>T (p.Pro34Leu) | KRAS | Pathogenic | reviewed by expert panel |
| 431103 | NM_033360.4(KRAS):c.440A>G (p.Lys147Arg) | KRAS | Pathogenic | criteria provided, single submitter |
| 45122 | NM_004985.5(KRAS):c.35G>C (p.Gly12Ala) | KRAS | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 637030 | NM_004985.5(KRAS):c.451-5642A>T | KRAS | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 13327 | NM_002834.5(PTPN11):c.923A>G (p.Asn308Ser) | PTPN11 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 13333 | NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys) | PTPN11 | Pathogenic | reviewed by expert panel |
| 13344 | NM_002834.5(PTPN11):c.1529A>C (p.Gln510Pro) | PTPN11 | Pathogenic | reviewed by expert panel |
| 164997 | NM_002834.5(PTPN11):c.206A>T (p.Glu69Val) | PTPN11 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 40488 | NM_002834.5(PTPN11):c.174C>A (p.Asn58Lys) | PTPN11 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 40494 | NM_002834.5(PTPN11):c.181G>C (p.Asp61His) | PTPN11 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 40499 | NM_002834.5(PTPN11):c.211T>C (p.Phe71Leu) | PTPN11 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 40507 | NM_002834.5(PTPN11):c.328G>A (p.Glu110Lys) | PTPN11 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 40513 | NM_002834.5(PTPN11):c.417G>C (p.Glu139Asp) | PTPN11 | Pathogenic | reviewed by expert panel |
| 40528 | NM_002834.5(PTPN11):c.853T>C (p.Phe285Leu) | PTPN11 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 40566 | NM_002834.5(PTPN11):c.1528C>G (p.Gln510Glu) | PTPN11 | Pathogenic | criteria provided, multiple submitters, no conflicts |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 17 · Orphanet: 32 · 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 |
|---|---|---|---|---|
| KRAS | Definitive | Autosomal dominant | Noonan syndrome 3 | 17 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| KRAS | Orphanet:1333 | Familial pancreatic carcinoma |
| KRAS | Orphanet:1340 | Cardiofaciocutaneous syndrome |
| KRAS | Orphanet:144 | Lynch syndrome |
| KRAS | Orphanet:146 | Differentiated thyroid carcinoma |
| KRAS | Orphanet:2396 | Encephalocraniocutaneous lipomatosis |
| KRAS | Orphanet:251615 | Pilomyxoid astrocytoma |
| KRAS | Orphanet:2612 | Linear nevus sebaceus syndrome |
| KRAS | Orphanet:268114 | RAS-associated autoimmune leukoproliferative disease |
| KRAS | Orphanet:3339 | Oculoectodermal syndrome |
| KRAS | Orphanet:648 | Noonan syndrome |
| KRAS | Orphanet:86834 | Juvenile myelomonocytic leukemia |
| SOS1 | Orphanet:2024 | Hereditary gingival fibromatosis |
| SOS1 | Orphanet:648 | Noonan syndrome |
| SHOC2 | Orphanet:2701 | Noonan syndrome-like disorder with loose anagen hair |
| CLTC | Orphanet:178342 | Inflammatory myofibroblastic tumor |
| CLTC | Orphanet:178469 | Autosomal dominant non-syndromic intellectual disability |
| CLTC | Orphanet:319308 | MiT family translocation renal cell carcinoma |
| CLTC | Orphanet:442835 | Non-specific early-onset epileptic encephalopathy |
| 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 |
| 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 |
Cohort genes → proteins
7 cohort genes, 7 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 7 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| KRAS | HGNC:6407 | ENSG00000133703 | P01116 | GTPase KRas | gencc,clinvar |
| SOS1 | HGNC:11187 | ENSG00000115904 | Q07889 | Son of sevenless homolog 1 | clinvar |
| SHOC2 | HGNC:15454 | ENSG00000108061 | Q9UQ13 | Leucine-rich repeat protein SHOC-2 | clinvar |
| CLTC | HGNC:2092 | ENSG00000141367 | Q00610 | Clathrin heavy chain 1 | clinvar |
| HRAS | HGNC:5173 | ENSG00000174775 | P01112 | GTPase HRas | 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) |
|---|---|---|
| KRAS | GTPase KRas | Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. |
| 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. |
| CLTC | Clathrin heavy chain 1 | Clathrin is the major protein of the polyhedral coat of coated pits and vesicles. |
| HRAS | GTPase HRas | Involved in the activation of Ras protein signal transduction. |
| 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: 4 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.57
Family distribution
Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.
| Family | Genes | Fold | FDR |
|---|---|---|---|
| Phosphatase | 1 | 12.0× | 0.275 |
| Enzyme (other) | 2 | 3.4× | 0.275 |
| Kinase | 1 | 4.0× | 0.378 |
| Scaffold/PPI | 1 | 2.5× | 0.426 |
| Other/Unknown | 2 | 0.5× | 0.968 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| KRAS | 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 | |
| CLTC | Other/Unknown | no | Clathrin_H-chain/VPS_repeat, TPR-like_helical_dom_sf, Clathrin_H-chain_linker_core | |
| HRAS | Enzyme (other) | yes | 3.6.5.2 | 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: 0.
7 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) | 7 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| nipple | 1 |
| pylorus | 1 |
| trigeminal ganglion | 1 |
| colonic epithelium | 1 |
| jejunal mucosa | 1 |
| tendon of biceps brachii | 1 |
| bone marrow | 1 |
| calcaneal tendon | 1 |
| sural nerve | 1 |
| Brodmann (1909) area 46 | 1 |
| lateral nuclear group of thalamus | 1 |
| pons | 1 |
| skin of abdomen | 1 |
| skin of leg | 1 |
| zone of skin | 1 |
| dorsal motor nucleus of vagus nerve | 1 |
| globus pallidus | 1 |
| medial globus pallidus | 1 |
| gastrocnemius | 1 |
| muscle of leg | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| KRAS | 298 | ubiquitous | marker | trigeminal ganglion, pylorus, nipple |
| SOS1 | 289 | ubiquitous | marker | colonic epithelium, jejunal mucosa, tendon of biceps brachii |
| SHOC2 | 299 | ubiquitous | marker | calcaneal tendon, sural nerve, bone marrow |
| CLTC | 305 | ubiquitous | marker | pons, lateral nuclear group of thalamus, Brodmann (1909) area 46 |
| HRAS | 139 | ubiquitous | marker | skin of abdomen, skin of leg, zone of skin |
| 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: 11.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| KRAS | 14,509 |
| HRAS | 8,064 |
| RAF1 | 6,574 |
| PTPN11 | 6,009 |
| CLTC | 5,550 |
| SOS1 | 3,625 |
| SHOC2 | 2,149 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| HRAS | RAF1 | intact, string_interaction |
| HRAS | SHOC2 | intact, string_interaction |
| HRAS | SOS1 | intact, string_interaction |
| KRAS | RAF1 | intact, string_interaction |
| KRAS | SHOC2 | intact, string_interaction |
| KRAS | SOS1 | string_interaction |
| PTPN11 | SHOC2 | string_interaction |
| PTPN11 | SOS1 | biogrid_interaction, string_interaction |
| RAF1 | SHOC2 | biogrid_interaction |
| RAF1 | SOS1 | string_interaction |
| SHOC2 | SOS1 | string_interaction |
Structural data
PDB: 7 · AlphaFold-only: 0 · No structure: 0
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| KRAS | P01116 | 511 |
| HRAS | P01112 | 246 |
| PTPN11 | Q06124 | 115 |
| SOS1 | Q07889 | 91 |
| RAF1 | P04049 | 76 |
| SHOC2 | Q9UQ13 | 13 |
| CLTC | Q00610 | 10 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 224. Enrichment computed across 7 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| Activated NTRK2 signals through FRS2 and FRS3 | 4 | 543.8× | 5e-09 | KRAS, SOS1, HRAS, PTPN11 |
| Signaling by FLT3 ITD and TKD mutants | 4 | 435.1× | 8e-09 | KRAS, SOS1, HRAS, PTPN11 |
| Tie2 Signaling | 4 | 343.5× | 1e-08 | KRAS, SOS1, HRAS, PTPN11 |
| FRS-mediated FGFR3 signaling | 4 | 310.8× | 2e-08 | KRAS, SOS1, HRAS, PTPN11 |
| FRS-mediated FGFR4 signaling | 4 | 283.7× | 2e-08 | KRAS, SOS1, HRAS, PTPN11 |
| FRS-mediated FGFR1 signaling | 4 | 261.0× | 2e-08 | KRAS, SOS1, HRAS, PTPN11 |
| FRS-mediated FGFR2 signaling | 4 | 251.0× | 2e-08 | KRAS, SOS1, HRAS, PTPN11 |
| Downstream signal transduction | 4 | 217.5× | 4e-08 | KRAS, SOS1, HRAS, PTPN11 |
| FLT3 Signaling | 4 | 197.8× | 5e-08 | KRAS, SOS1, HRAS, PTPN11 |
| RAF activation | 4 | 191.9× | 5e-08 | KRAS, SHOC2, HRAS, RAF1 |
| SOS-mediated signalling | 3 | 611.8× | 1e-07 | KRAS, SOS1, HRAS |
| Signaling by SCF-KIT | 4 | 141.9× | 1e-07 | KRAS, SOS1, HRAS, PTPN11 |
| Activated NTRK3 signals through RAS | 3 | 543.8× | 2e-07 | KRAS, SOS1, HRAS |
| EGFR Transactivation by Gastrin | 3 | 489.4× | 2e-07 | KRAS, SOS1, HRAS |
| SHC-related events triggered by IGF1R | 3 | 489.4× | 2e-07 | KRAS, SOS1, HRAS |
| Activated NTRK2 signals through RAS | 3 | 489.4× | 2e-07 | KRAS, SOS1, HRAS |
| MET activates RAS signaling | 3 | 444.9× | 3e-07 | KRAS, SOS1, HRAS |
| Signaling by FGFR4 in disease | 3 | 407.9× | 4e-07 | KRAS, SOS1, HRAS |
| Constitutive Signaling by Overexpressed ERBB2 | 3 | 407.9× | 4e-07 | KRAS, SOS1, HRAS |
| Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants | 3 | 376.5× | 4e-07 | KRAS, SOS1, HRAS |
| Signaling by PDGFRA extracellular domain mutants | 3 | 376.5× | 4e-07 | KRAS, SOS1, HRAS |
| GRB2 events in EGFR signaling | 3 | 326.3× | 6e-07 | KRAS, SOS1, HRAS |
| Erythropoietin activates RAS | 3 | 326.3× | 6e-07 | KRAS, SOS1, HRAS |
| SHC1 events in ERBB4 signaling | 3 | 305.9× | 7e-07 | KRAS, SOS1, HRAS |
| SHC1 events in EGFR signaling | 3 | 305.9× | 7e-07 | KRAS, SOS1, HRAS |
| Constitutive Signaling by EGFRvIII | 3 | 305.9× | 7e-07 | KRAS, SOS1, HRAS |
| Signalling to RAS | 3 | 287.9× | 7e-07 | KRAS, SOS1, HRAS |
| Insulin receptor signalling cascade | 3 | 287.9× | 7e-07 | KRAS, SOS1, HRAS |
| Signaling by ERBB2 ECD mutants | 3 | 287.9× | 7e-07 | KRAS, SOS1, HRAS |
| GRB2 events in ERBB2 signaling | 3 | 271.9× | 9e-07 | KRAS, SOS1, HRAS |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 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 | 3 | 451.4× | 2e-06 | SOS1, HRAS, RAF1 |
| neurotrophin TRK receptor signaling pathway | 3 | 451.4× | 2e-06 | SOS1, PTPN11, RAF1 |
| fibroblast growth factor receptor signaling pathway | 3 | 122.4× | 9e-05 | SOS1, SHOC2, PTPN11 |
| myelination | 3 | 107.8× | 1e-04 | SOS1, HRAS, RAF1 |
| insulin receptor signaling pathway | 3 | 95.0× | 1e-04 | SOS1, HRAS, RAF1 |
| Ras protein signal transduction | 3 | 88.1× | 1e-04 | KRAS, SOS1, HRAS |
| MAPK cascade | 3 | 65.7× | 3e-04 | KRAS, HRAS, RAF1 |
| cytokine-mediated signaling pathway | 3 | 56.0× | 4e-04 | KRAS, SOS1, PTPN11 |
| regulation of long-term neuronal synaptic plasticity | 2 | 283.2× | 4e-04 | KRAS, HRAS |
| positive regulation of Rac protein signal transduction | 2 | 185.2× | 9e-04 | KRAS, SOS1 |
| insulin-like growth factor receptor signaling pathway | 2 | 141.6× | 0.001 | SOS1, RAF1 |
| homeostasis of number of cells within a tissue | 2 | 126.7× | 0.002 | KRAS, PTPN11 |
| response to mineralocorticoid | 1 | 2407.4× | 0.005 | KRAS |
| negative regulation of cortisol secretion | 1 | 2407.4× | 0.005 | PTPN11 |
| negative regulation of growth hormone secretion | 1 | 2407.4× | 0.005 | PTPN11 |
| cellular response to growth hormone stimulus | 1 | 2407.4× | 0.005 | SHOC2 |
| epidermal growth factor receptor signaling pathway | 2 | 70.8× | 0.005 | SOS1, PTPN11 |
| neuron apoptotic process | 2 | 52.9× | 0.006 | KRAS, HRAS |
| microvillus organization | 1 | 1203.7× | 0.008 | PTPN11 |
| intestinal epithelial cell migration | 1 | 1203.7× | 0.008 | PTPN11 |
| death-inducing signaling complex assembly | 1 | 1203.7× | 0.008 | RAF1 |
| multicellular organism growth | 2 | 39.1× | 0.009 | SOS1, PTPN11 |
| cerebellar cortex formation | 1 | 802.5× | 0.010 | PTPN11 |
| forebrain astrocyte development | 1 | 802.5× | 0.010 | KRAS |
| positive regulation of miRNA metabolic process | 1 | 802.5× | 0.010 | HRAS |
| response to isolation stress | 1 | 601.9× | 0.010 | KRAS |
| regulation of type I interferon-mediated signaling pathway | 1 | 601.9× | 0.010 | PTPN11 |
| clathrin coat disassembly | 1 | 601.9× | 0.010 | CLTC |
| negative regulation of hyaluronan biosynthetic process | 1 | 601.9× | 0.010 | CLTC |
| midbrain morphogenesis | 1 | 601.9× | 0.010 | SOS1 |
Therapeutics
Drug target analysis
Approved (phase 4): 5 · Phase ≥3: 5 · Phased (≥1): 5 · Undrugged: 2
Druggability breadth: 6 of 7 evidence-associated genes (86%) 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 |
|---|---|
| KRAS | VEMURAFENIB |
| SOS1 | IDARUBICIN |
| HRAS | LONAFARNIB |
| PTPN11 | ESTRAMUSTINE PHOSPHATE |
| RAF1 | VEMURAFENIB |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| RAF1 | 31 | 4 |
| KRAS | 11 | 4 |
| PTPN11 | 8 | 4 |
| SOS1 | 5 | 4 |
| HRAS | 4 | 4 |
| SHOC2 | 0 | 0 |
| CLTC | 0 | 0 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| VEMURAFENIB | 4 | KRAS, RAF1 |
| DABRAFENIB | 4 | KRAS, RAF1 |
| LONAFARNIB | 4 | HRAS, KRAS |
| SOTORASIB | 4 | KRAS, SOS1 |
| ADAGRASIB | 4 | KRAS, SOS1 |
| IDARUBICIN | 4 | SOS1 |
| DOXORUBICIN | 4 | SOS1 |
| ESTRAMUSTINE PHOSPHATE | 4 | PTPN11 |
| SORAFENIB | 4 | RAF1 |
| REGORAFENIB | 4 | RAF1 |
| NILOTINIB | 4 | RAF1 |
| TOVORAFENIB | 4 | RAF1 |
| PAZOPANIB | 4 | RAF1 |
| DASATINIB | 4 | RAF1 |
| ERLOTINIB | 4 | RAF1 |
| IMATINIB | 4 | RAF1 |
| OPNURASIB | 3 | KRAS |
| PLINABULIN | 3 | RAF1 |
| AVUTOMETINIB | 3 | RAF1 |
| NAPORAFENIB | 3 | RAF1 |
| MOTESANIB | 3 | RAF1 |
| DIVARASIB | 2 | KRAS |
| GLECIRASIB | 2 | KRAS |
| STALLIMYCIN | 2 | HRAS |
| ENOXOLONE | 2 | PTPN11 |
| CEFSULODIN | 2 | PTPN11 |
| BATOPROTAFIB | 2 | PTPN11 |
| VOCIPROTAFIB | 2 | PTPN11 |
| DORAMAPIMOD | 2 | RAF1 |
| CI-1040 | 2 | RAF1 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 4.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| 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 |
| CLTC | 8 | Binding:8 |
Cohort enzymes (BRENDA EC)
| Symbol | EC numbers | Names |
|---|---|---|
| KRAS | 3.6.5.2 | small monomeric GTPase |
| HRAS | 3.6.5.2 | small monomeric GTPase |
| 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 |
|---|---|
| KRAS | 861 |
| SOS1 | 421 |
| PTPN11 | 588 |
| RAF1 | 839 |
Pharmacogenomics
Cohort genes with a PharmGKB record: 7; 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 | KRAS, RAF1 |
| DABRAFENIB | 4 | KRAS, RAF1 |
| LONAFARNIB | 4 | HRAS, KRAS |
| SOTORASIB | 4 | KRAS, SOS1 |
| ADAGRASIB | 4 | KRAS, SOS1 |
| IDARUBICIN | 4 | SOS1 |
| DOXORUBICIN | 4 | SOS1 |
| ESTRAMUSTINE PHOSPHATE | 4 | PTPN11 |
| SORAFENIB | 4 | RAF1 |
| REGORAFENIB | 4 | RAF1 |
| NILOTINIB | 4 | RAF1 |
| TOVORAFENIB | 4 | RAF1 |
| PAZOPANIB | 4 | RAF1 |
| DASATINIB | 4 | RAF1 |
| ERLOTINIB | 4 | RAF1 |
| IMATINIB | 4 | RAF1 |
| OPNURASIB | 3 | KRAS |
| PLINABULIN | 3 | RAF1 |
| AVUTOMETINIB | 3 | RAF1 |
| NAPORAFENIB | 3 | RAF1 |
| MOTESANIB | 3 | RAF1 |
| DIVARASIB | 2 | KRAS |
| GLECIRASIB | 2 | KRAS |
| STALLIMYCIN | 2 | HRAS |
| ENOXOLONE | 2 | PTPN11 |
| CEFSULODIN | 2 | PTPN11 |
| BATOPROTAFIB | 2 | PTPN11 |
| VOCIPROTAFIB | 2 | PTPN11 |
| DORAMAPIMOD | 2 | RAF1 |
| CI-1040 | 2 | RAF1 |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 5 | KRAS, SOS1, HRAS, PTPN11, RAF1 |
| B | Phased (≥1) drug, not yet approved | 0 | |
| C | Druggable family + PDB, no drug | 0 | |
| D | Druggable family + AlphaFold only, no drug | 0 | |
| E | Difficult family or no structure, no drug | 2 | SHOC2, CLTC |
Undrugged target profiles
2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| SHOC2 | 0 | SOS1 |
| CLTC | 8 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 0.