NRAS Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human NRAS — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene NRAS, list ALL gene-level database identifiers. Required: - HGNC ID and approved symbol - Ensembl gene ID (ENSG...) - NCBI Entrez Gene ID - OMIM gene/locus ID - Genomic location: chromosome, start position, end position, strand (GRCh38) ### Section 2: Transcript identifiers For human gene NRAS, list ALL transcript-level identifiers. Required: - Ensembl transcripts: ALL ENST IDs with biotype. Total count. - RefSeq transcripts: ALL NM_ mRNA accessions. Mark which is MANE Select. - CCDS IDs. - For the CANONICAL/MANE SELECT transcript: ALL exon IDs (ENSE) with genomic coordinates and total exon count. ### Section 3: Protein identifiers For human gene NRAS protein product(s), list ALL protein-level identifiers. Required: - UniProt accessions: ALL entries (reviewed and unreviewed). Mark the canonical reviewed entry. - RefSeq protein: ALL NP_ accessions. - Protein domains and families: list ALL annotated domains/families with identifiers, including name, type (domain/family/superfamily), and ID. - Antibody availability: known antibody resources for the protein. ### Section 4: Structure For human gene NRAS protein, list ALL structural data. Required: - Experimental structures: ALL PDB IDs. For each: experimental method (X-ray/NMR/Cryo-EM) and resolution. Total count. - Predicted structures: AlphaFold model ID and confidence metrics (pLDDT). ### Section 5: Cross-species orthologs For human gene NRAS, list orthologous genes in key model organisms. Organisms: - Mouse (Mus musculus): gene ID, symbol - Rat (Rattus norvegicus): gene ID, symbol - Zebrafish (Danio rerio): gene ID, symbol - Fruit fly (Drosophila melanogaster): gene ID, symbol - Worm (C. elegans): gene ID, symbol - Yeast (S. cerevisiae): gene ID, symbol ### Section 6: Clinical variants & AI predictions For human gene NRAS, summarize clinical variants and AI predictions. Clinical variant annotations (ClinVar): - Total variant count (approximate is fine) - Breakdown by classification: Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign - TOP 30 pathogenic/likely pathogenic variants with: variant ID, HGVS notation, associated condition AI-based variant effect predictions: - Splice effect predictions: total count + TOP 30 with delta scores if known - Missense pathogenicity from AlphaMissense — total count + TOP 30 likely-pathogenic with am_pathogenicity scores. ### Section 7: Pathways & Gene Ontology For human gene NRAS, list biological pathways and Gene Ontology annotations. Pathway membership: - ALL biological pathways this gene participates in, with pathway IDs and names - Total pathway count Gene Ontology: - Biological Process: count and TOP 20 terms with GO IDs - Molecular Function: count and TOP 20 terms with GO IDs - Cellular Component: count and TOP 20 terms with GO IDs ### Section 8: Protein interactions & networks For human gene NRAS protein, summarize protein interactions and networks. Protein-protein interactions (STRING, IntAct, BioGRID, etc.): - Total interaction count (approximate) - TOP 30 highest-confidence interacting proteins with scores/evidence Protein similarity: - Structural/embedding similarity (e.g. Foldseek, ESM): TOP 20 similar proteins with scores - Sequence homology: TOP 20 homologous proteins with identity/similarity ### Section 9: Transcription factor regulatory data For human gene NRAS, summarize transcription factor regulatory data. If NRAS is a transcription factor: - Downstream targets: total count + TOP 30 with regulation type (activates/represses) and evidence - DNA binding motifs from JASPAR — all known motif IDs and motif family classification. Regardless: - Upstream regulators: TFs that regulate NRAS — names with evidence type (ChIP-seq / predicted / experimentally validated) If NRAS is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene NRAS protein as a drug target, summarize pharmacology data. If NRAS is a known drug target: - Targeting molecules: total count in ChEMBL/DrugBank + TOP 30 by development phase (molecule ID, name, mechanism, highest phase) - Clinical trials: TOP 20 involving drugs targeting this gene — trial ID, phase, status, intervention - Pharmacogenomics: known drug-gene interactions affecting drug response + dosing guidelines if any If NRAS is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene NRAS, summarize expression profiles. Tissue expression (GTEx, HPA, Bgee, etc.): - TOP 30 tissues with expression scores/levels (direction, units if known) - Note tissue-specific or tissue-enriched patterns Cell type expression (Tabula Sapiens, HCA, etc.): - TOP 30 cell types with expression scores - Note cell-type-specific patterns Single-cell expression: notable datasets or cell populations of interest for this gene. ### Section 12: Disease associations For human gene NRAS, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in NRAS: disease name, disease ID (OMIM/Orphanet/Mondo), inheritance pattern, evidence level - Include all directly linked conditions Phenotype associations: - Clinical phenotypes associated with the gene (HPO terms where known) - TOP 30 phenotype terms with HPO IDs Complex-disease / GWAS: - Traits and diseases significantly associated via GWAS: trait name, variant, effect size, study where known - TOP 30 GWAS associations
Executive summary
NRAS is a proto-oncogene and established oncology drug target whose somatic mutations drive multiple cancers and whose germline variants cause RASopathy developmental syndromes. Expression is nearly ubiquitous across human tissues (present in 278 of 293 conditions; average score 82.2), with particular enrichment in epithelial, reproductive, and immune cell populations. On the disease side, germline NRAS variants cause Noonan syndrome 6 (definitive evidence, autosomal dominant) and are linked to 13 Orphanet rare diseases including cardiofaciocutaneous syndrome, juvenile myelomonocytic leukemia, and acute myeloid leukemia; phenotypic associations span cardiac defects, short stature, and lymphoproliferative disorders. In oncology, the G12C activating mutation is the primary therapeutic biomarker: two Phase 4 covalent inhibitors targeting this mutation — sotorasib and adagrasib — are approved, with roughly 100 additional molecules in active development. Pharmacogenomic guidance is mutation-specific rather than germline-based, with no formal CPIC dosing guidelines established.
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Drug & pharmacology data
NRAS as a Drug Target
NRAS is an established oncology drug target, particularly for cancers harboring KRAS/NRAS G12C mutations. The target has ~100 molecules in active development or screening across ChEMBL and related databases, with the following key compounds:
Approved Molecules (Phase 4)
| Molecule | Development Phase | Mechanism | Clinical Trials |
|---|---|---|---|
| SOTORASIB (AMG-510, Lumakras) | Phase 4 | G12C RAS inhibitor | 48 |
| ADAGRASIB (MRTX-849, Krazati) | Phase 4 | G12C RAS inhibitor | 34 |
Late-Stage Development (Phase 2–3)
| Molecule | Development Phase | Indication | Status |
|---|---|---|---|
| DIVARASIB (GDC-6036, RG-6330) | Phase 2 | KRAS G12C NSCLC, colorectal cancer | 13 trials |
Clinical Trials: TOP 20 Involving NRAS/KRAS G12C-Targeting Drugs
Adagrasib (MRTX849) trials (key active/completed):
- NCT04685135 — Phase 3: Adagrasib vs. docetaxel in KRAS G12C NSCLC | ACTIVE_NOT_RECRUITING
- NCT04793958 — Phase 3: Adagrasib + cetuximab vs. chemotherapy in KRAS G12C CRC (KRYSTAL-10) | ACTIVE_NOT_RECRUITING
- NCT04613596 — Phase 2/3: Adagrasib ± pembrolizumab in KRAS G12C (KRYSTAL-7) | RECRUITING
- NCT06875310 — Phase 3: Adagrasib + pembrolizumab + chemotherapy in untreated KRAS G12C NSCLC (KRYSTAL-4) | RECRUITING
- NCT03785249 — Phase 1/2: MRTX849 in KRAS G12C cancers (KRYSTAL-1) | ACTIVE_NOT_RECRUITING
- NCT05853575 — Phase 2: Two adagrasib dosing regimens in KRAS G12C NSCLC (KRYSTAL 21) | RECRUITING
- NCT06248606 — Phase 2: Adagrasib + stereotactic radiosurgery for brain metastases | RECRUITING
Sotorasib (AMG-510) trials (key active/completed): 8. NCT05198934 — Phase 3: Sotorasib + panitumumab vs. investigator’s choice in KRAS G12C | ACTIVE_NOT_RECRUITING 9. NCT05920356 — Phase 3: Sotorasib + platinum doublet vs. pembrolizumab doublet in NSCLC (CodeBreaK 202) | RECRUITING 10. NCT06252649 — Phase 3: Sotorasib + panitumumab + FOLFIRI vs. FOLFIRI ± bevacizumab in mCRC (CodeBreaK 201) | RECRUITING 11. NCT03600883 — Phase 1/2: Sotorasib (AMG 510) in KRAS G12C solid tumors (CodeBreaK 100) | ACTIVE_NOT_RECRUITING 12. NCT04625647 — Phase 2: Sotorasib in KRAS G12C NSCLC (Lung-MAP) | ACTIVE_NOT_RECRUITING 13. NCT04933695 — Phase 2: Sotorasib in treatment-naïve KRAS G12C NSCLC | COMPLETED 14. NCT05074810 — Phase 1/2: Avutometinib + sotorasib in KRAS G12C NSCLC | ACTIVE_NOT_RECRUITING 15. NCT05398094 — Phase 2: AMG510 in stage III unresectable KRAS G12C NSCLC | RECRUITING 16. NCT05845450 — Phase 2: Sotorasib in resectable colorectal cancer (UNICORN) | RECRUITING
Cross-drug comparison trial: 17. NCT06497556 — Phase 3: Divarasib vs. sotorasib or adagrasib in previously treated KRAS G12C NSCLC | ACTIVE_NOT_RECRUITING
Pharmacogenomics
Known Predictive Biomarkers:
- KRAS/NRAS G12C mutation status — required biomarker for sotorasib and adagrasib efficacy; confers primary sensitivity
- KRAS/NRAS wild-type or non-G12C mutations — limited response to G12C inhibitors; alternative therapies indicated
- Resistance mechanisms — emerging: secondary KRAS/NRAS mutations (e.g., G12C→G12V), pathway alterations (MAPK, PI3K), and target amplification
PharmGKB Status:
- NRAS is a VIP (high-importance) gene in PharmGKB but lacks formal CPIC dosing guidelines
- Pharmacogenomics guidance is primarily mutation-specific (G12C detection) rather than germline variant-based dosing
Clinical Implications:
- No routine pharmacogenomic dosage adjustments based on germline NRAS variants
- Tumoral G12C status is the primary treatment-selection biomarker
- Emerging correlatives: CTL019, TP53, KEAP1 mutations associated with response heterogeneity
Expression profiles
Tissue expression (Bgee)
NRAS shows ubiquitous expression across human tissues (278/293 conditions with present calls; average score 82.2; max 96.1). Expression is particularly enriched in epithelial tissues, reproductive tissues, and immune cell-related tissues.
| Rank | Tissue | Expression Score | Quality |
|---|---|---|---|
| 1 | Gingival epithelium | 96.10 | Gold |
| 2 | Epithelium of nasopharynx | 95.64 | Gold |
| 3 | Amniotic fluid | 95.62 | Gold |
| 4 | Colonic mucosa | 95.54 | Gold |
| 5 | Mucosa of sigmoid colon | 95.52 | Gold |
| 6 | Gingiva | 95.45 | Gold |
| 7 | Esophagus squamous epithelium | 95.20 | Gold |
| 8 | Germinal epithelium of ovary | 95.02 | Gold |
| 9 | Upper leg skin | 94.53 | Gold |
| 10 | Ganglionic eminence | 93.84 | Gold |
| 11 | Parietal pleura | 93.75 | Gold |
| 12 | Tibia | 93.58 | Gold |
| 13 | Visceral pleura | 93.56 | Gold |
| 14 | Ventricular zone | 93.55 | Gold |
| 15 | Adrenal tissue | 93.50 | Gold |
| 16 | Cortical plate | 93.00 | Gold |
| 17 | Trabecular bone tissue | 92.69 | Gold |
| 18 | Islet of Langerhans | 92.65 | Gold |
| 19 | Oral cavity | 92.57 | Gold |
| 20 | Pleura | 92.48 | Gold |
| 21 | Skin of hip | 92.32 | Gold |
| 22 | Palpebral conjunctiva | 91.97 | Gold |
| 23 | Endometrium | 91.89 | Gold |
| 24 | Mammary duct | 91.72 | Gold |
Tissue-specific patterns: High expression in mucosal/epithelial barriers (oral, nasopharynx, colon, esophagus); reproductive tissues (ovary, endometrium); developing neural tissues (ganglionic eminence, ventricular zone, cortical plate); immune-related tissues (adrenal, islet of Langerhans).
Cell type expression (Bgee)
| Cell Type | Expression Score | Quality |
|---|---|---|
| Secondary oocyte | 95.63 | Gold |
| Oocyte | 93.13 | Gold |
| Endothelial cell | 93.02 | Gold |
| Monocyte | 92.27 | Gold |
| Mononuclear cell | 92.12 | Gold |
| Leukocyte | 91.94 | Gold |
Cell-type patterns: NRAS is expressed in oocytes and reproductive cells; endothelial cells; and multiple immune cell populations (monocytes, leukocytes, mononuclear cells), consistent with its role in cell proliferation and differentiation signaling.
Single-cell expression datasets
E-MTAB-6819 (Single Cell Expression Atlas):
- Description: Single-cell RNA-seq of naive and primed human embryonic stem cells
- Cells: 1,344
- Cell types: Embryonic stem cells
- Tissue source: Inner cell mass
- NRAS status: Identified as expressed gene; marker gene in cluster 3 (log fold change 2.64)
Summary: NRAS demonstrates constitutive, nearly ubiquitous expression across human tissues with mild enrichment in epithelial tissues, immune cells, and reproductive tissues, consistent with its function as a proto-oncogene regulating cell proliferation and differentiation.
Disease associations
Mendelian / monogenic disease
| Disease | Disease ID | Inheritance Pattern | Evidence Level |
|---|---|---|---|
| Noonan syndrome 6 | OMIM:613224 | Autosomal dominant | Definitive |
| Cardiofaciocutaneous syndrome | MONDO:0015280 | Autosomal dominant | Strong |
| Noonan syndrome | ORPHANET:648 | Autosomal dominant | Supportive |
Additional Orphanet-curated rare disease associations (13 total):
- RASopathy (ORPHANET:536391)
- Noonan syndrome and Noonan-related syndrome (ORPHANET:98733)
- Linear nevus sebaceus syndrome (ORPHANET:2612)
- Acute myeloid leukemia (ORPHANET:519)
- Large/giant congenital melanocytic nevus (ORPHANET:626)
- Neurocutaneous melanocytosis (ORPHANET:2481)
- Woolly hair nevus (ORPHANET:79414)
- RAS-associated autoimmune leukoproliferative disease (ORPHANET:268114)
- Juvenile myelomonocytic leukemia (ORPHANET:86834)
- Acute megakaryoblastic leukemia in children with Down syndrome (ORPHANET:99887)
- Familial prostate cancer (ORPHANET:1331)
- Chronic myeloid leukemia (ORPHANET:521)
Phenotype associations
Top 30 HPO terms associated with NRAS:
- HP:0000006 - Autosomal dominant inheritance
- HP:0000256 - Macrocephaly
- HP:0000311 - Round face
- HP:0000324 - Facial asymmetry
- HP:0000365 - Hearing impairment
- HP:0000465 - Webbed neck
- HP:0000474 - Thickened nuchal skin fold
- HP:0001249 - Intellectual disability
- HP:0001263 - Global developmental delay
- HP:0001382 - Joint hypermobility
- HP:0001510 - Growth delay
- HP:0001548 - Overgrowth
- HP:0001631 - Atrial septal defect
- HP:0001639 - Hypertrophic cardiomyopathy
- HP:0001642 - Pulmonic stenosis
- HP:0001873 - Thrombocytopenia
- HP:0001909 - Leukemia
- HP:0002007 - Frontal bossing
- HP:0002240 - Hepatomegaly
- HP:0002716 - Lymphadenopathy
- HP:0004322 - Short stature
- HP:0005523 - Lymphoproliferative disorder
- HP:0006699 - Premature atrial contractions
- HP:0012209 - Juvenile myelomonocytic leukemia
- HP:0030680 - Abnormal cardiovascular system morphology
- HP:0100555 - Asymmetric growth
- HP:0100763 - Abnormality of the lymphatic system
- HP:0001442 - Typified by somatic mosaicism
- HP:0001528 - Hemihypertrophy
- HP:0001482 - Subcutaneous nodule
Complex-disease / GWAS
GWAS associations for NRAS:
| Trait | Variant(s) | P-value | Study |
|---|---|---|---|
| Adult body size | NRAS | 7.0 × 10⁻¹⁰ | GCST010988 |
| Autism | CSDE1; AMPD1 - RN7SL432P | 3.0 × 10⁻⁸ - 9.0 × 10⁻⁸ | GCST002268 |
Note: NRAS shows limited direct GWAS associations in current databases. The primary associations are with monogenic RASopathy syndromes through exon variants, particularly for developmental and cardiac phenotypes.