NRAS

Summary

NRAS (NRAS proto-oncogene, GTPase, HGNC:7989) is a protein-coding gene on chromosome 1p13.2, encoding GTPase NRas (P01111). Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. In precision oncology, NRAS Mutation is associated with resistance to Panitumumab + Cetuximab in Colorectal Cancer (CIViC Level A); 63 further curated variant–drug associations are listed below.

This is an N-ras oncogene encoding a membrane protein that shuttles between the Golgi apparatus and the plasma membrane. This shuttling is regulated through palmitoylation and depalmitoylation by the ZDHHC9-GOLGA7 complex. The encoded protein, which has intrinsic GTPase activity, is activated by a guanine nucleotide-exchange factor and inactivated by a GTPase activating protein. Mutations in this gene have been associated with somatic rectal cancer, follicular thyroid cancer, autoimmune lymphoproliferative syndrome, Noonan syndrome, and juvenile myelomonocytic leukemia.

Source: NCBI Gene 4893 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Noonan syndrome (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 340 total — 10 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 244
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 64 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 22 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_002524

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7989
Approved symbol	NRAS
Name	NRAS proto-oncogene, GTPase
Location	1p13.2
Locus type	gene with protein product
Status	Approved
Aliases	N-ras
Ensembl gene	ENSG00000213281
Ensembl biotype	protein_coding
OMIM	164790
Entrez	4893

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000369535, ENST00000899430, ENST00000931009, ENST00000931010

RefSeq mRNA: 1 — MANE Select: NM_002524 NM_002524

CCDS: CCDS877

Canonical transcript exons

ENST00000369535 — 7 exons

Exon	Start	End
ENSE00000784343	114709569	114709728
ENSE00000800104	114708531	114708654
ENSE00001364464	114716658	114716771
ENSE00001365300	114708154	114708192
ENSE00001450280	114704469	114708050
ENSE00001450282	114716050	114716177
ENSE00001751295	114713800	114713978

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 96.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.5218 / max 448.9475, expressed in 1809 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13958	37.9598	1809
13959	1.5619	893

Top tissues by expression

293 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
gingival epithelium	UBERON:0001949	96.10	gold quality
epithelium of nasopharynx	UBERON:0001951	95.64	gold quality
secondary oocyte	CL:0000655	95.63	gold quality
amniotic fluid	UBERON:0000173	95.62	gold quality
colonic mucosa	UBERON:0000317	95.54	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.52	gold quality
gingiva	UBERON:0001828	95.45	gold quality
esophagus squamous epithelium	UBERON:0006920	95.20	gold quality
germinal epithelium of ovary	UBERON:0001304	95.02	gold quality
upper leg skin	UBERON:0004262	94.53	gold quality
ganglionic eminence	UBERON:0004023	93.84	gold quality
parietal pleura	UBERON:0002400	93.75	gold quality
tibia	UBERON:0000979	93.58	gold quality
visceral pleura	UBERON:0002401	93.56	gold quality
ventricular zone	UBERON:0003053	93.55	gold quality
adrenal tissue	UBERON:0018303	93.50	gold quality
oocyte	CL:0000023	93.13	gold quality
endothelial cell	CL:0000115	93.02	gold quality
cortical plate	UBERON:0005343	93.00	gold quality
trabecular bone tissue	UBERON:0002483	92.69	gold quality
islet of Langerhans	UBERON:0000006	92.65	gold quality
oral cavity	UBERON:0000167	92.57	gold quality
pleura	UBERON:0000977	92.48	gold quality
skin of hip	UBERON:0001554	92.32	gold quality
monocyte	CL:0000576	92.27	gold quality
mononuclear cell	CL:0000842	92.12	gold quality
palpebral conjunctiva	UBERON:0001812	91.97	gold quality
leukocyte	CL:0000738	91.94	gold quality
endometrium	UBERON:0001295	91.89	gold quality
mammary duct	UBERON:0001765	91.72	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.34

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, MYB, MYC, NR1H2

miRNA regulators (miRDB)

224 targeting NRAS, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Mutations were detected by using allele-specific amplification method. (PMID:11524732)
• BMECs co-expressing SV40T, hTERT and N-ras exhibited an overtly transformed phenotype; forming very large colonies with an altered morphology and generating rapidly growing tumours in vivo. (PMID:12082607)
• Regulation of Fas-mediated apoptosis by N-ras in melanoma. (PMID:12230495)
• Protein kinase C mediates mutant N-Ras-induced developmental abnormalities erythropoiesis, giving rise to phenotypic and functional abnormalities commonly observed in preleukemia. (PMID:12393454)
• role of interleukin-6 in activation of expression (PMID:12483530)
• HDL induced a potent signal through a Ras/MAPK pathway mediated by a pertussis toxin-sensitive G-protein coupled receptor to the angiogenic phenotype in HCECs. (PMID:12637339)
• high frequency of NRAS codon 61 mutations detected in primary hereditary melanomas may be the result of a hypermutability phenotype associated with a hereditary predisposition for melanoma development in patients with germline CDKN2A mutations (PMID:12783933)
• NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression (PMID:14695152)
• Acquisition of N-ras mutation is frequently associated with progression of myelodysplastic syndrome to acute myeloid leukemia (PMID:14737077)
• Mutations in N-ras gene is associated with malignant melanomas (PMID:14961576)
• Data show that Golgi-associated N-Ras is the critical Ras isoform and intracellular pool for low-grade T cell receptor signaling in Jurkat T cells. (PMID:15060167)
• Low frequency of NRAS and KRAS2 gene mutations in childhood myelodysplastic syndromes. (PMID:15474158)
• NRAS mutations are frequent in acute myeloblastic leukemia with normal karyotype. (PMID:15674343)
• oncogenic NRAS is important for avoidance of apoptosis in melanomas that harbor the codon 61 NRAS mutation (PMID:15688405)
• Although BRAF and NRAS mutations are likely to be important for the initiation and maintenance of some melanomas, other factors might be more significant for proliferation and prognosis in subgroups of aggressive melanoma (PMID:16098042)
• Overactivation of N-Ras61K induces cytoplasmic mislocalization of p27 and disrupts TGF-beta-mediated Smad nuclear translocation by activation of the Mek/Erk pathway. (PMID:16135812)
• Ras mutations do not play a significant role in the pathogenesis of multiple myeloma in the Spanish population (PMID:16142319)
• NRAS and BRAF activating mutations can coexist in the same melanoma, but are mutually exclusive at the single-cell level (PMID:16462768)
• In 239 Thai adult AML cases, 35 RAS mutations were found in 32 cases (13%) predominantly classified as M1/M2 (53%) followed by M4/M5 (38%). Ten cases were positive for NRAS codon 12, 11 for NRAS codon 61, 13 for NRAS codon 13, and one for KRAS codon 13. (PMID:16573741)
• ras may be involved in early stages of larynx carcinogenesis and may be activated by other mechanisms different from mutations, such as epigenetic events (PMID:16761621)
• NRAS mutation is associated with melanoma and melanocytic nevi. (PMID:16845322)
• The chemical properties and stucture of the membrane bound C-terminus of N-ras is reported. (PMID:16847854)
• Ras gene mutations, mostly involving the N-Ras gene, were detected in 20% of the multiple myeloma patients; Ras gene mutations are not likely to represent a master lesion in MM (PMID:17036375)
• NRAS mutations were associated with a significantly higher Clark level of invasion in melanoma tumours (PMID:17119447)
• Our data suggest that the activity of specific RAS isoforms is context-dependent and provide a possible explanation for the prevalence of NRAS mutations in melanoma. (PMID:17297468)
• patients having juvenile myelomonocytic leukemia with NRAS or KRAS2 glycine to serine substitution received no chemotherapy, but hematologic improvement was observed during a 2- to 4-year follow up (PMID:17332249)
• data indicate that both early-life UV exposure and nevus propensity contribute to occurrence of BRAF+ melanoma, whereas nevus propensity and later-life sun exposure influence the occurrence of NRAS+ melanoma (PMID:17507627)
• observations on the effects of NRAS activation indicate that RAS-inactivating drugs, such as farnesyltransferase inhibitors should be examined in human autoimmune and lymphocyte homeostasis disorders (PMID:17517660)
• Nras gene mutation might be one of the mechanisms of oncogenesis of lung adenocarcinoma. (PMID:17671710)
• No mutations in NRAS was found in pilocytic astrocytomas. (PMID:17712732)
• Ras mutations were found in 33% of the papillary thyroid carcinomas (PMID:17786355)
• CD155, at least in part, enhances the proliferation of ras-mutated cells (PMID:17893876)
• expression of RET, nuclearRAS, and ERK proteins is greatly enhanced in papillary thyroid carcinoma cells and Hashimoto’s thyroiditis oxyphil cells. (PMID:17900235)
• Frequently mutated in high hyperdiploid childhood acute lymphoblastic leukemia. (PMID:17910045)
• Data indicate that a critical component of Ras signaling is the activation of PLD. (PMID:17949898)
• 54% of childhood CBF-AML had RTKs and/or Ras mutations (PMID:17960171)
• 16k PRL inhibits cell migration by blocking the Ras-Tiam1-Rac1-Pak1 signaling pathway in endothelial cells (PMID:18006851)
• mutation of N-RAS or B-RAF, signature genetic lesions present in most MMs, potently induced the expression of cell-surface CD200, a repressor of DC function. (PMID:18008004)
• NRAS mutation is not associated with cutaneous melanoma (PMID:18227705)
• N-ras mutation is associated with familial non-medullary thyroid carcinoma (PMID:18310288)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nras	ENSDARG00000038225
mus_musculus	Nras	ENSMUSG00000027852
rattus_norvegicus	Kras	ENSRNOG00000023079

Paralogs (35): RALA (ENSG00000006451), REM1 (ENSG00000088320), RASL10A (ENSG00000100276), RASD2 (ENSG00000100302), RASL12 (ENSG00000103710), RHEB (ENSG00000106615), RASD1 (ENSG00000108551), RERGL (ENSG00000111404), RAP1A (ENSG00000116473), RASL11A (ENSG00000122035), RAP2C (ENSG00000123728), RAP2A (ENSG00000125249), RRAS (ENSG00000126458), RAP1B (ENSG00000127314), RASL11B (ENSG00000128045), KRAS (ENSG00000133703), RRAS2 (ENSG00000133818), RERG (ENSG00000134533), REM2 (ENSG00000139890), RIT1 (ENSG00000143622), RALB (ENSG00000144118), RIT2 (ENSG00000152214), MRAS (ENSG00000158186), DIRAS3 (ENSG00000162595), GEM (ENSG00000164949), DIRAS2 (ENSG00000165023), RRAD (ENSG00000166592), RHEBL1 (ENSG00000167550), NKIRAS2 (ENSG00000168256), HRAS (ENSG00000174775), DIRAS1 (ENSG00000176490), RAP2B (ENSG00000181467), ERAS (ENSG00000187682), NKIRAS1 (ENSG00000197885), RASL10B (ENSG00000270885)

Protein

Protein identifiers

GTPase NRas — P01111 (reviewed: P01111)

Alternative names: Transforming protein N-Ras

All UniProt accessions (2): P01111, Q5U091

UniProt curated annotations — full annotation on UniProt →

Function. Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.

Subunit / interactions. Interacts (active GTP-bound form preferentially) with RGS14. Interacts (active GTP-bound form) with RASSF7. Interacts (active GTP-bound form) with both SHOC2 and PP1c (all isoforms) to form a tertiary complex; SHOC2 and PP1c preferably bind M-Ras/MRAS, but they also bind K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS.

Subcellular location. Cell membrane. Golgi apparatus membrane.

Post-translational modifications. Palmitoylated by the ZDHHC9-GOLGA7 complex. Depalmitoylated by ABHD17A, ABHD17B and ABHD17C. A continuous cycle of de- and re-palmitoylation regulates rapid exchange between plasma membrane and Golgi. Acetylation at Lys-104 prevents interaction with guanine nucleotide exchange factors (GEFs). Fatty-acylated at Lys-169 and/or Lys-170. Ubiquitinated by the BCR(LZTR1) E3 ubiquitin ligase complex at Lys-170 in a non-degradative manner, leading to inhibit Ras signaling by decreasing Ras association with membranes. Phosphorylation at Ser-89 enhances NRAS association with its downstream effectors. (Microbial infection) Glucosylated at Thr-35 by P.sordellii toxin TcsL.

Disease relevance. Leukemia, juvenile myelomonocytic (JMML) [MIM:607785] An aggressive pediatric myelodysplastic syndrome/myeloproliferative disorder characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny. Patients have splenomegaly, enlarged lymph nodes, rashes, and hemorrhages. The disease is caused by variants affecting the gene represented in this entry. Noonan syndrome 6 (NS6) [MIM:613224] A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. The disease is caused by variants affecting the gene represented in this entry. RAS-associated autoimmune leukoproliferative disorder (RALD) [MIM:614470] A disorder of apoptosis, characterized by chronic accumulation of non-malignant lymphocytes, defective lymphocyte apoptosis, and an increased risk for the development of hematologic malignancies. The disease is caused by variants affecting the gene represented in this entry. Melanocytic nevus syndrome, congenital (CMNS) [MIM:137550] A syndrome characterized by congenital pigmentary skin lesions which can occur at any site and can cover most of the body surface. These lesions may or may not be hairy. Congenital melanocytic nevi are associated with neuromelanosis (the presence of melanin-producing cells within the brain parenchyma or leptomeninges). Less commonly they are associated with malignant melanoma in childhood, both in the skin and the central nervous system. CMNS patients also tend to have a characteristic facial appearance, including wide or prominent forehead, periorbital fullness, small short nose with narrow nasal bridge, round face, full cheeks, prominent premaxilla, and everted lower lip. The disease is caused by variants affecting the gene represented in this entry. Melanosis, neurocutaneous (NCMS) [MIM:249400] A rare congenital disease characterized by the presence of giant or multiple melanocytic nevi on the skin, foci of melanin-producing cells within the brain parenchyma, and infiltration of leptomeninges by abnormal melanin deposits. Neurologic abnormalities include seizures, hydrocephalus, arachnoid cysts, tumors, and syringomyelia. Some patients may develop malignant melanoma. The disease is caused by variants affecting the gene represented in this entry. Keratinocytic non-epidermolytic nevus (KNEN) [MIM:162900] Epidermal nevi of the common, non-organoid and non-epidermolytic type are benign skin lesions and may vary in their extent from a single (usually linear) lesion to widespread and systematized involvement. They may be present at birth or develop early during childhood. The disease is caused by variants affecting the gene represented in this entry. Thyroid cancer, non-medullary, 2 (NMTC2) [MIM:188470] A form of non-medullary thyroid cancer (NMTC), a cancer characterized by tumors originating from the thyroid follicular cells. NMTCs represent approximately 95% of all cases of thyroid cancer and are classified into papillary, follicular, Hurthle cell, and anaplastic neoplasms. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Activity regulation. Alternates between an inactive form bound to GDP and an active form bound to GTP. Activated by a guanine nucleotide-exchange factor (GEF) and inactivated by a GTPase-activating protein (GAP).

Miscellaneous. Mutations which change AA 12, 13 or 61 activate the potential of Ras to transform cultured cells and are implicated in a variety of human tumors.

Similarity. Belongs to the small GTPase superfamily. Ras family.

RefSeq proteins (1): NP_002515* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001806	Small_GTPase	Family
IPR005225	Small_GTP-bd	Domain
IPR020849	Small_GTPase_Ras-type	Family
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00071

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (41 total): sequence variant 9, helix 8, strand 6, mutagenesis site 4, binding site 4, lipid moiety-binding region 2, chain 1, propeptide 1, glycosylation site 1, cross-link 1, region of interest 1, short sequence motif 1, turn 1, modified residue 1

Structure

Experimental structures (PDB)

35 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9BG8	X-RAY DIFFRACTION	1.2
7F68	X-RAY DIFFRACTION	1.24
9BG3	X-RAY DIFFRACTION	1.33
6ZIO	X-RAY DIFFRACTION	1.55
9Y3W	X-RAY DIFFRACTION	1.56
8TBI	X-RAY DIFFRACTION	1.59
9BG0	X-RAY DIFFRACTION	1.64
3CON	X-RAY DIFFRACTION	1.65
6WGH	X-RAY DIFFRACTION	1.65
5UHV	X-RAY DIFFRACTION	1.67
9Y1Y	X-RAY DIFFRACTION	1.7
9Y1X	X-RAY DIFFRACTION	1.72
8VM2	X-RAY DIFFRACTION	1.74
9BGD	X-RAY DIFFRACTION	1.76
6ZIZ	X-RAY DIFFRACTION	1.78
9Y0G	X-RAY DIFFRACTION	1.8
7OW4	X-RAY DIFFRACTION	1.81
9GLX	X-RAY DIFFRACTION	1.85
6ULI	X-RAY DIFFRACTION	1.88
6ULK	X-RAY DIFFRACTION	1.9
6ZIR	X-RAY DIFFRACTION	1.9
9Y1Z	X-RAY DIFFRACTION	1.92
9Y1W	X-RAY DIFFRACTION	1.95
6E6H	X-RAY DIFFRACTION	1.99
6ULN	X-RAY DIFFRACTION	2.01
9GLW	X-RAY DIFFRACTION	2.1
7OW3	X-RAY DIFFRACTION	2.46
7OW5	X-RAY DIFFRACTION	2.58
7OW6	X-RAY DIFFRACTION	2.64
9BTM	X-RAY DIFFRACTION	2.73

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01111-F1	92.56	0.81

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4): 10–18; 29–30; 57–61; 116–119

Post-translational modifications (4): 186, 170, 89, 181

Glycosylation sites (1): 35

Mutagenesis-validated functional residues (4):

Position	Phenotype
89	abolished phosphorylation by stk19.
164	loss of gtp-binding activity.
169–170	in n-ras-2kr mutant; decreased fatty-acylation.
181	loss of plasma membrane localization.

Function

Pathways and Gene Ontology

Reactome pathways

68 pathways

ID	Pathway
R-HSA-112412	SOS-mediated signalling
R-HSA-1169092	Activation of RAS in B cells
R-HSA-1236382	Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
R-HSA-1250196	SHC1 events in ERBB2 signaling
R-HSA-1250347	SHC1 events in ERBB4 signaling
R-HSA-1433557	Signaling by SCF-KIT
R-HSA-167044	Signalling to RAS
R-HSA-171007	p38MAPK events
R-HSA-179812	GRB2 events in EGFR signaling
R-HSA-180336	SHC1 events in EGFR signaling
R-HSA-186763	Downstream signal transduction
R-HSA-1963640	GRB2 events in ERBB2 signaling
R-HSA-210993	Tie2 Signaling
R-HSA-2179392	EGFR Transactivation by Gastrin
R-HSA-2424491	DAP12 signaling
R-HSA-2428933	SHC-related events triggered by IGF1R
R-HSA-2871796	FCERI mediated MAPK activation
R-HSA-375165	NCAM signaling for neurite out-growth
R-HSA-442982	Ras activation upon Ca2+ influx through NMDA receptor
R-HSA-5218921	VEGFR2 mediated cell proliferation
R-HSA-5621575	CD209 (DC-SIGN) signaling
R-HSA-5637810	Constitutive Signaling by EGFRvIII
R-HSA-5654688	SHC-mediated cascade:FGFR1
R-HSA-5654693	FRS-mediated FGFR1 signaling
R-HSA-5654699	SHC-mediated cascade:FGFR2
R-HSA-5654700	FRS-mediated FGFR2 signaling
R-HSA-5654704	SHC-mediated cascade:FGFR3
R-HSA-5654706	FRS-mediated FGFR3 signaling
R-HSA-5654712	FRS-mediated FGFR4 signaling
R-HSA-5654719	SHC-mediated cascade:FGFR4

MSigDB gene sets: 1022 (showing top): PID_SHP2_PATHWAY, RNGTGGGC_UNKNOWN, MODULE_97, RRAGTTGT_UNKNOWN, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, ACTACCT_MIR196A_MIR196B, REACTOME_INNATE_IMMUNE_SYSTEM, WWTAAGGC_UNKNOWN, HNF3ALPHA_Q6, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOCC_SECRETORY_GRANULE, HOFMANN_CELL_LYMPHOMA_UP

GO Biological Process (4): MAPK cascade (GO:0000165), positive regulation of endothelial cell proliferation (GO:0001938), Ras protein signal transduction (GO:0007265), signal transduction (GO:0007165)

GO Molecular Function (8): GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), GDP binding (GO:0019003), protein-containing complex binding (GO:0044877), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (8): Golgi membrane (GO:0000139), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), extracellular exosome (GO:0070062), tertiary granule membrane (GO:0070821)

Reactome top-level categories

Rollup of top-18 pathways:

Category	Pathways
Signaling by ERBB2	2
Signaling by EGFR	2
IRS-mediated signalling	1
Downstream signaling events of B Cell Receptor (BCR)	1
Signaling by Ligand-Responsive EGFR Variants in Cancer	1
Signaling by ERBB4	1
Signaling by Receptor Tyrosine Kinases	1
Signalling to ERKs	1
Signalling to RAS	1
Signaling by PDGF	1
Cell surface interactions at the vascular wall	1
Gastrin-CREB signalling pathway via PKC and MAPK	1
DAP12 interactions	1
IGF1R signaling cascade	1
Fc epsilon receptor (FCERI) signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
guanyl ribonucleotide binding	2
binding	2
cytoplasm	2
cellular anatomical structure	2
intracellular signaling cassette	1
endothelial cell proliferation	1
regulation of endothelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
small GTPase-mediated signal transduction	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
ribonucleoside triphosphate phosphatase activity	1
GTPase activity	1
molecular function regulator activity	1
purine ribonucleoside triphosphate binding	1
anion binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
Golgi apparatus	1
bounding membrane of organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
extracellular vesicle	1
secretory granule membrane	1
tertiary granule	1

Protein interactions and networks

STRING

6520 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NRAS	BRAF	P15056	973
NRAS	PIK3CA	P42336	921
NRAS	ZDHHC9	Q9Y397	901
NRAS	EGFR	P00533	900
NRAS	RAF1	P04049	900
NRAS	PTPN11	Q06124	892
NRAS	SOS1	Q07889	887
NRAS	ARAF	P07557	886
NRAS	NF1	P21359	886
NRAS	TP53	P04637	871
NRAS	PIK3CG	P48736	870
NRAS	PTEN	P60484	861
NRAS	GOLGA7	Q7Z5G4	860
NRAS	ALK	Q9UM73	854
NRAS	RALGDS	Q12967	846

IntAct

160 interactions, top by confidence:

A	B	Type	Score
RAF1	NRAS	psi-mi:“MI:0915”(physical association)	0.930
RAF1	NRAS	psi-mi:“MI:0407”(direct interaction)	0.930
NRAS	RAF1	psi-mi:“MI:0915”(physical association)	0.930
NRAS	RAF1	psi-mi:“MI:0914”(association)	0.930
NRAS	BRAF	psi-mi:“MI:0915”(physical association)	0.860
BRAF	NRAS	psi-mi:“MI:0914”(association)	0.860
BRAF	NRAS	psi-mi:“MI:0915”(physical association)	0.860
BRAF	NRAS	psi-mi:“MI:2364”(proximity)	0.860
NRAS	RIN1	psi-mi:“MI:0915”(physical association)	0.840
RIN1	NRAS	psi-mi:“MI:0914”(association)	0.840
RIN1	ABL1	psi-mi:“MI:0914”(association)	0.790
FOXP4	FOXP2	psi-mi:“MI:0914”(association)	0.770
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
RAF1	CALU	psi-mi:“MI:0914”(association)	0.640
SLC17A5	LGALS8	psi-mi:“MI:0914”(association)	0.640
FNTA	NRAS	psi-mi:“MI:0915”(physical association)	0.560
NRAS	RAP1GDS1	psi-mi:“MI:0915”(physical association)	0.560
NRAS	RGL3	psi-mi:“MI:0915”(physical association)	0.560
NRAS	ARAF	psi-mi:“MI:0915”(physical association)	0.560
PIK3R1	NRAS	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (918): RAP1GDS1 (Two-hybrid), NRAS (Affinity Capture-MS), NRAS (Affinity Capture-MS), NRAS (Affinity Capture-MS), NRAS (Affinity Capture-MS), NRAS (Affinity Capture-MS), NRAS (Affinity Capture-MS), NRAS (Affinity Capture-MS), NRAS (Affinity Capture-MS), NRAS (Affinity Capture-MS), NRAS (Affinity Capture-MS), NRAS (Affinity Capture-MS), NRAS (Affinity Capture-MS), NRAS (Affinity Capture-MS), NRAS (Affinity Capture-MS)

ESM2 similar proteins: A5A6J7, A6NIZ1, O42277, P01111, P01112, P01116, P03967, P05774, P08556, P08642, P08644, P08645, P12825, P15064, P18262, P18613, P20171, P22123, P22981, P23175, P32883, P34729, P61223, P61224, P62833, P62834, P62835, P62836, P79800, Q04970, Q05147, Q07983, Q18246, Q2MJK3, Q4R9D4, Q5EFX7, Q5F352, Q5RD87, Q5RDM6, Q5ZHX1

Diamond homologs: A5A6J7, A6NIZ1, A8NU18, B3M185, B3NZR4, B4GFJ8, B4HKC7, B4JFU8, B4LY29, B4NJ72, B4PUP5, C4YKT4, G4MZY8, O42277, O42785, O93856, P01111, P01112, P01113, P01115, P01116, P01119, P01120, P03967, P05774, P08556, P08642, P08644, P08645, P08646, P08647, P0CQ42, P0CQ43, P0CY32, P10114, P12825, P13856, P15064, P18613, P20171

SIGNOR signaling

23 interactions.

A	Effect	B	Mechanism
SOS1	“up-regulates activity”	NRAS	“guanine nucleotide exchange factor”
NRAS	up-regulates	GLI1
RASGEF1B	up-regulates	NRAS	binding
RASGEF1C	up-regulates	NRAS	binding
NRAS	up-regulates	ARAF	binding
NRAS	“up-regulates activity”	BRAF	binding
NRAS	“up-regulates activity”	PIK3CA	binding
NRAS	up-regulates	PIK3CB	binding
NRAS	up-regulates	PIK3CG	binding
NRAS	up-regulates	RAF1	relocalization
RAPGEF5	up-regulates	NRAS	“guanine nucleotide exchange factor”
RAPGEF6	up-regulates	NRAS	“guanine nucleotide exchange factor”
RASGEF1A	up-regulates	NRAS	binding
NRAS	“up-regulates activity”	PI3K	binding
AR	“down-regulates quantity by repression”	NRAS	“transcriptional regulation”
DAB2IP	“down-regulates activity”	NRAS	“gtpase-activating protein”
PTPN11	“up-regulates activity”	NRAS	dephosphorylation
GOLGA7	“up-regulates activity”	NRAS	palmitoylation
ZDHHC9	“up-regulates activity”	NRAS	palmitoylation
STK19	“up-regulates activity”	NRAS	phosphorylation
BCR-ABL	“up-regulates activity”	NRAS
MVD	“up-regulates quantity by stabilization”	NRAS

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 144 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
RAF activation	7	25.0×	7e-06
FLT3 Signaling	5	18.4×	7e-04
Negative regulation of MAPK pathway	6	16.9×	2e-04
Signaling by high-kinase activity BRAF mutants	5	16.9×	8e-04
MAP2K and MAPK activation	5	15.2×	1e-03
Signaling by RAF1 mutants	5	14.8×	1e-03
Signaling by moderate kinase activity BRAF mutants	5	13.5×	1e-03
Paradoxical activation of RAF signaling by kinase inactive BRAF	5	13.5×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of peptidyl-serine phosphorylation	5	30.4×	6e-04
Ras protein signal transduction	7	11.4×	2e-03
insulin receptor signaling pathway	6	10.6×	5e-03
MAPK cascade	7	8.5×	5e-03

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

Mutations in the RAS family of proteins have frequently been observed across cancer types. The amino acid positions G12, G13 and Q61 account for the overwhelming majority of these mutations. The isoforms, despite their raw similarity, also behave very differently when expressed in non-native tissue types, likely due to differences in the C-terminal hyper-variable regions. Mis-regulation of isoform expression has been shown to be a driving event in cancer, as well as missense mutations at the three hotspots previously mentioned. While highly recurrent in cancer, targeting these RAS mutants has also been very elusive, and has not yet become common practice in the clinic.

From intOGen — cancer-driver classification: activating (oncogene-like) across 22 cancer types — ALL, AML, ANGS, CHOL, CLLSLL, COAD, COADREAD, GBM, HCC, LGGNOS, LUAD, LUSC…(+10 more).

Clinical variants and AI predictions

ClinVar

340 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	11
Uncertain significance	156
Likely benign	90
Benign	18

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
1070042	NM_002524.5(NRAS):c.173C>T (p.Thr58Ile)	Pathogenic
13900	NM_002524.5(NRAS):c.182A>G (p.Gln61Arg)	Pathogenic
13902	NM_002524.5(NRAS):c.149C>T (p.Thr50Ile)	Pathogenic
13903	NM_002524.5(NRAS):c.179G>A (p.Gly60Glu)	Pathogenic
177778	NM_002524.5(NRAS):c.34G>A (p.Gly12Ser)	Pathogenic
280409	NM_002524.5(NRAS):c.182A>C (p.Gln61Pro)	Pathogenic
39647	NM_002524.5(NRAS):c.101C>T (p.Pro34Leu)	Pathogenic
40468	NM_002524.5(NRAS):c.34G>T (p.Gly12Cys)	Pathogenic
40469	NM_002524.5(NRAS):c.34G>C (p.Gly12Arg)	Pathogenic
40472	NM_002524.5(NRAS):c.112-1_113dup	Pathogenic
1320232	NM_002524.5(NRAS):c.449A>G (p.Gln150Arg)	Likely pathogenic
1335888	NM_002524.5(NRAS):c.108A>G (p.Ile36Met)	Likely pathogenic
13899	NM_002524.5(NRAS):c.37G>C (p.Gly13Arg)	Likely pathogenic
222971	NM_002524.5(NRAS):c.71T>A (p.Ile24Asn)	Likely pathogenic
2672090	NM_002524.5(NRAS):c.191_196dup (p.Ser65_Ala66insAspSer)	Likely pathogenic
3029607	NM_002524.5(NRAS):c.34_35delinsTT (p.Gly12Phe)	Likely pathogenic
375876	NM_002524.5(NRAS):c.38G>T (p.Gly13Val)	Likely pathogenic
4799925	NM_002524.5(NRAS):c.149C>A (p.Thr50Asn)	Likely pathogenic
561786	NM_002524.5(NRAS):c.178G>A (p.Gly60Arg)	Likely pathogenic
812886	NM_002524.5(NRAS):c.176C>A (p.Ala59Asp)	Likely pathogenic
981556	NM_002524.5(NRAS):c.204A>T (p.Arg68Ser)	Likely pathogenic

SpliceAI

577 predictions. Top by Δscore:

Variant	Effect	Δscore
1:114707945:TAAAC:T	donor_gain	1.0000
1:114708526:CTCA:C	donor_loss	1.0000
1:114708528:CACCT:C	donor_loss	1.0000
1:114708529:ACCTT:A	donor_loss	1.0000
1:114708530:C:T	donor_loss	1.0000
1:114708650:ACACC:A	acceptor_gain	1.0000
1:114708651:CACC:C	acceptor_gain	1.0000
1:114708651:CACCC:C	acceptor_gain	1.0000
1:114708652:ACC:A	acceptor_gain	1.0000
1:114708653:CC:C	acceptor_gain	1.0000
1:114708653:CCCTA:C	acceptor_gain	1.0000
1:114708654:CC:C	acceptor_gain	1.0000
1:114708655:C:CC	acceptor_gain	1.0000
1:114708655:C:T	acceptor_gain	1.0000
1:114708657:A:AC	acceptor_gain	1.0000
1:114708657:A:C	acceptor_gain	1.0000
1:114709564:CATA:C	donor_loss	1.0000
1:114709565:ATAC:A	donor_loss	1.0000
1:114709566:TA:T	donor_loss	1.0000
1:114709567:A:AC	donor_gain	1.0000
1:114709567:A:AT	donor_loss	1.0000
1:114709568:C:CC	donor_gain	1.0000
1:114709568:CCTG:C	donor_loss	1.0000
1:114709568:CCTGT:C	donor_gain	1.0000
1:114709724:GCTCC:G	acceptor_gain	1.0000
1:114709725:CTCC:C	acceptor_gain	1.0000
1:114709725:CTCCC:C	acceptor_gain	1.0000
1:114709726:TCC:T	acceptor_gain	1.0000
1:114709726:TCCC:T	acceptor_loss	1.0000
1:114709726:TCCCT:T	acceptor_gain	1.0000

AlphaMissense

1251 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:114709582:G:T	A146D	1.000
1:114709586:A:G	S145P	1.000
1:114709668:C:A	K117N	1.000
1:114709668:C:G	K117N	1.000
1:114709670:T:C	K117E	1.000
1:114709671:G:C	N116K	1.000
1:114709671:G:T	N116K	1.000
1:114709675:C:T	G115E	1.000
1:114713856:G:C	F78L	1.000
1:114713856:G:T	F78L	1.000
1:114713858:A:G	F78L	1.000
1:114713860:C:T	G77D	1.000
1:114713861:C:G	G77R	1.000
1:114713866:C:T	G75D	1.000
1:114713900:A:G	Y64H	1.000
1:114713911:C:A	G60V	1.000
1:114713911:C:T	G60E	1.000
1:114713912:C:G	G60R	1.000
1:114713912:C:T	G60R	1.000
1:114713914:G:T	A59D	1.000
1:114713917:G:A	T58I	1.000
1:114713919:A:C	D57E	1.000
1:114713919:A:T	D57E	1.000
1:114713920:T:A	D57V	1.000
1:114713920:T:C	D57G	1.000
1:114713920:T:G	D57A	1.000
1:114713921:C:A	D57Y	1.000
1:114713921:C:G	D57H	1.000
1:114713921:C:T	D57N	1.000
1:114713923:A:G	L56P	1.000

dbSNP variants (sampled 300 via entrez): RS1000164866 (1:114706754 G>A), RS1000480137 (1:114710147 C>T), RS1000829592 (1:114709919 G>A), RS1000894165 (1:114715215 C>T), RS1000946088 (1:114715491 A>G), RS1001325426 (1:114715700 T>A,C), RS1001553272 (1:114716455 C>G), RS1002003090 (1:114709305 T>C), RS1002110356 (1:114711345 C>A,T), RS1002287788 (1:114708073 A>G), RS1002323307 (1:114715584 G>A), RS1002605778 (1:114707893 C>A,T), RS1002655196 (1:114713527 G>A), RS1002720134 (1:114714422 A>G), RS1002772185 (1:114714834 T>C)

Disease associations

OMIM: gene MIM:164790 | disease phenotypes: MIM:114500, MIM:163950, MIM:613224, MIM:163200, MIM:601626, MIM:137550, MIM:162900, MIM:188470, MIM:249400, MIM:607785, MIM:614470, MIM:601518, MIM:608232

GenCC curated gene-disease

Disease	Classification	Inheritance
Noonan syndrome	Definitive	Autosomal dominant
Noonan syndrome 6	Definitive	Autosomal dominant
cardiofaciocutaneous syndrome	Strong	Autosomal dominant
Noonan syndrome with multiple lentigines	Limited	Autosomal dominant
Costello syndrome	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (4)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Costello syndrome	Limited	AD
Noonan syndrome	Definitive	AD
cardiofaciocutaneous syndrome	Limited	AD
Noonan syndrome with multiple lentigines	Limited	AD

Mondo (26): RASopathy (MONDO:0021060), neurodevelopmental disorder (MONDO:0700092), colorectal cancer (MONDO:0005575), Noonan syndrome 1 (MONDO:0008104), Noonan syndrome (MONDO:0018997), Noonan syndrome and Noonan-related syndrome (MONDO:0020297), Noonan syndrome 6 (MONDO:0013186), colon carcinoma (MONDO:0002032), linear nevus sebaceous syndrome (MONDO:0008097), acute myeloid leukemia (MONDO:0018874), large congenital melanocytic nevus (MONDO:0044792), non-small cell lung carcinoma (MONDO:0005233), nevus, epidermal (MONDO:0008093), thyroid cancer, nonmedullary, 2 (MONDO:0008566), neurocutaneous melanocytosis (MONDO:0009578)

Orphanet (15): RASopathy (Orphanet:536391), Noonan syndrome (Orphanet:648), 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), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667), NON RARE IN EUROPE: Non-small cell lung cancer (Orphanet:488201)

HPO phenotypes

244 total (30 of 244 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000078	Abnormality of the genital system
HP:0000085	Horseshoe kidney
HP:0000155	Oral ulcer
HP:0000179	Thick lower lip vermilion
HP:0000194	Open mouth
HP:0000218	High palate
HP:0000232	Everted lower lip vermilion
HP:0000238	Hydrocephalus
HP:0000256	Macrocephaly
HP:0000267	Cranial asymmetry
HP:0000269	Prominent occiput
HP:0000286	Epicanthus
HP:0000293	Full cheeks
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry
HP:0000325	Triangular face
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000391	Thickened helices
HP:0000407	Sensorineural hearing impairment
HP:0000418	Narrow nasal ridge

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002268_1	Autism	3.000000e-08
GCST002268_10	Autism	4.000000e-08
GCST002268_2	Autism	9.000000e-08
GCST010988_251	Adult body size	7.000000e-10

MeSH disease descriptors (16)

Descriptor	Name	Tree numbers
D000740	Anemia	C15.378.050
D002289	Carcinoma, Non-Small-Cell Lung	C04.588.894.797.520.109.220.249; C08.381.540.140.500; C08.785.520.100.220.500
D056685	Costello Syndrome	C05.660.207.219; C16.131.077.256; C16.320.188
D017789	Granuloma, Pyogenic	C23.550.382.937
D044542	LEOPARD Syndrome	C05.660.207.525; C14.240.400.695; C14.280.400.695; C14.280.484.716.525; C16.131.077.525; C16.131.240.400.685; C16.131.621.207.525; C17.800.621.430.530.550.525
D015470	Leukemia, Myeloid, Acute	C04.557.337.539.275; C15.378.508.539.275
D054429	Leukemia, Myelomonocytic, Juvenile	C04.557.337.539.525; C15.378.190.615.520; C15.378.508.539.525
D065886	Neurodevelopmental Disorders	F03.625
D009634	Noonan Syndrome	C05.660.207.690; C14.240.400.787; C14.280.400.787; C16.131.240.400.784; C16.131.621.207.690; C17.300.690
D054079	Vascular Malformations	C14.240.850; C16.131.240.850
C535579	Cardiofaciocutaneous syndrome (supp.)
C580062	Epidermal Nevus (supp.)
C537387	Neurocutaneous melanosis (supp.)
C548084	Noonan Syndrome 6 (supp.)
C537846	Noonan like syndrome (supp.)
C572845	Thyroid cancer, follicular (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL2079845 (SINGLE PROTEIN), CHEMBL4524006 (PROTEIN FAMILY), CHEMBL6193817 (PROTEIN-PROTEIN INTERACTION), CHEMBL6195563 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 324 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL279433	L-778123 FREE BASE	1	324

Clinical evidence (CIViC)

Drug × variant × indication: 64 predictive associations from 77 curated evidence items; also 9 prognostic, 2 diagnostic, 2 predisposing.

Variant	Therapy	Indication	Effect	Level	CIViC
NRAS Mutation	Panitumumab + Cetuximab	Colorectal Cancer	Resistance	CIViC A	EID5344
NRAS Mutation	Binimetinib	Skin Melanoma	Sensitivity/Response	CIViC B	EID1472 +1
NRAS Q61K	Dactolisib	Colorectal Cancer	Sensitivity/Response	CIViC B	EID2194 +1
BRAF V600E OR NRAS Mutation OR HRAS Mutation OR KRAS Mutation OR NF1 Inactivating Mutation	Selumetinib	Cancer	Sensitivity/Response	CIViC B	EID11696
BRAF V600E OR NRAS Mutation OR HRAS Mutation OR KRAS Mutation OR NF1 Mutation	Selumetinib	Cancer	Sensitivity/Response	CIViC B	EID11681
NRAS Mutation	Binimetinib	Solid Tumor	Sensitivity/Response	CIViC B	EID11674
NRAS Mutation	Docetaxel + Trametinib	Skin Melanoma	Sensitivity/Response	CIViC B	EID1225
NRAS Mutation	Trametinib	Melanoma	Sensitivity/Response	CIViC B	EID1227
NRAS Mutation	Ribociclib + Binimetinib	Skin Melanoma	Sensitivity/Response	CIViC B	EID2931
NRAS Mutation	Belvarafenib	Melanoma	Sensitivity/Response	CIViC B	EID7452
NRAS Q61	Binimetinib	Skin Melanoma	Sensitivity/Response	CIViC B	EID1226
NRAS Q61H	Ipilimumab	Melanoma	Sensitivity/Response	CIViC B	EID7333
NRAS G12D	Cetuximab	Colorectal Cancer	Resistance	CIViC B	EID3693 +2
NRAS Q61K	Cetuximab	Colorectal Cancer	Resistance	CIViC B	EID3833 +1
NRAS Mutation	Cetuximab + Chemotherapy	Colorectal Cancer	Resistance	CIViC B	EID2210
NRAS Mutation	Vemurafenib + Dabrafenib	Melanoma	Resistance	CIViC B	EID6263
NRAS Q179*	Cetuximab	Colorectal Cancer	Resistance	CIViC B	EID4785
NRAS Q61	Cetuximab	Colorectal Cancer	Resistance	CIViC B	EID124
NRAS Q61	Vemurafenib	Melanoma	Resistance	CIViC B	EID14
NRAS Q61	Cetuximab + Chemotherapy	Colorectal Cancer	Resistance	CIViC B	EID36
NRAS Q61K	Trametinib + Dabrafenib	Melanoma	Resistance	CIViC B	EID7678
NRAS G13D	Tanespimycin	Melanoma	Sensitivity/Response	CIViC C	EID21
NRAS Q61	Selumetinib	Skin Melanoma	Sensitivity/Response	CIViC C	EID1473
NRAS Q61K	Trametinib	Ovary Serous Adenocarcinoma	Sensitivity/Response	CIViC C	EID8933
NRAS Q61L	Temozolomide	Melanoma	Sensitivity/Response	CIViC C	EID22
NRAS Q61R	Temozolomide	Melanoma	Sensitivity/Response	CIViC C	EID23
NRAS Q61K	Vemurafenib	Melanoma	Resistance	CIViC C	EID2191 +3
NRAS G13R	Vemurafenib	Melanoma	Resistance	CIViC C	EID3843 +1
NRAS Q61L	Vemurafenib	Melanoma	Resistance	CIViC C	EID3825 +1
NRAS Q61R	Vemurafenib	Melanoma	Resistance	CIViC C	EID3829 +1

+34 more predictive associations (showing top 30 by evidence level).

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1065634	Efficacy	3	carboplatin;cisplatin;gemcitabine	Non-Small Cell Lung Carcinoma

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1065634	CSDE1, NRAS	3	2.75	1	carboplatin;cisplatin;gemcitabine

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — RAS subfamily

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
lonafarnib	Inhibition	8.55	pIC50

Binding affinities (BindingDB)

10 measured of 10 human assays (10 total across all organisms); most potent 10 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
NCGC 00371858	IC50	2 nM	US-11254667: Substituted imidazo[1,2-A]pyridines as IRAK 1/4 and flt3 inhibitors
NCGC 00371852	IC50	3720 nM	US-11254667: Substituted imidazo[1,2-A]pyridines as IRAK 1/4 and flt3 inhibitors
NCGC 00371484	IC50	4430 nM	US-11254667: Substituted imidazo[1,2-A]pyridines as IRAK 1/4 and flt3 inhibitors
NCGC 00371485	IC50	9350 nM	US-11254667: Substituted imidazo[1,2-A]pyridines as IRAK 1/4 and flt3 inhibitors
NCGC 00371482	IC50	15700 nM	US-11254667: Substituted imidazo[1,2-A]pyridines as IRAK 1/4 and flt3 inhibitors
NCGC 00371487	IC50	16600 nM	US-11254667: Substituted imidazo[1,2-A]pyridines as IRAK 1/4 and flt3 inhibitors
NCGC 00371857	IC50	16600 nM	US-11254667: Substituted imidazo[1,2-A]pyridines as IRAK 1/4 and flt3 inhibitors
NCGC 00371958	IC50	17600 nM	US-11254667: Substituted imidazo[1,2-A]pyridines as IRAK 1/4 and flt3 inhibitors
NCGC 00371853	IC50	29800 nM	US-11254667: Substituted imidazo[1,2-A]pyridines as IRAK 1/4 and flt3 inhibitors
NCGC 00262327	IC50	33200 nM	US-11254667: Substituted imidazo[1,2-A]pyridines as IRAK 1/4 and flt3 inhibitors

ChEMBL bioactivities

336 potent at pChembl≥5 of 359 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.52	Ki	0.3	nM	L-778123 FREE BASE
8.70	IC50	2	nM	CHEMBL6038112
7.26	IC50	55	nM	CHEMBL5863589
7.26	IC50	55	nM	CHEMBL5805515
7.26	IC50	55	nM	CHEMBL5750957
7.26	IC50	55	nM	CHEMBL5901194
7.26	IC50	55	nM	CHEMBL5906199
7.26	IC50	55	nM	CHEMBL5916613
7.26	IC50	55	nM	CHEMBL5792114
7.26	IC50	55	nM	CHEMBL6042397
7.26	IC50	55	nM	CHEMBL5935060
7.26	IC50	55	nM	CHEMBL5877158
7.26	IC50	55	nM	CHEMBL5946158
7.26	IC50	55	nM	CHEMBL5753950
7.26	IC50	55	nM	CHEMBL6056472
7.26	IC50	55	nM	CHEMBL6007436
7.26	IC50	55	nM	CHEMBL5750007
7.26	IC50	55	nM	CHEMBL5981374
7.26	IC50	55	nM	CHEMBL6018688
7.26	IC50	55	nM	CHEMBL6008925
7.26	IC50	55	nM	CHEMBL5828567
7.26	IC50	55	nM	CHEMBL5746155
7.26	IC50	55	nM	CHEMBL5990708
7.26	IC50	55	nM	CHEMBL6008715
7.26	IC50	55	nM	CHEMBL5824251
7.26	IC50	55	nM	CHEMBL6033993
7.26	IC50	55	nM	CHEMBL5831167
7.26	IC50	55	nM	CHEMBL5979311
7.26	IC50	55	nM	CHEMBL5936777
7.26	IC50	55	nM	CHEMBL6044428
7.26	IC50	55	nM	CHEMBL6023023
7.26	IC50	55	nM	CHEMBL6052700
7.26	IC50	55	nM	CHEMBL5867756
7.26	IC50	55	nM	CHEMBL6043630
7.26	IC50	55	nM	CHEMBL5856243
7.26	IC50	55	nM	CHEMBL5840072
7.26	IC50	55	nM	CHEMBL5841454
7.26	IC50	55	nM	CHEMBL5991616
7.26	IC50	55	nM	CHEMBL5757361
7.26	IC50	55	nM	CHEMBL5887007
7.26	IC50	55	nM	CHEMBL5966197
7.26	IC50	55	nM	CHEMBL5873051
7.26	IC50	55	nM	CHEMBL5895869
7.26	IC50	55	nM	CHEMBL5829698
7.26	IC50	55	nM	CHEMBL6037737
7.26	IC50	55	nM	CHEMBL6043222
7.26	IC50	55	nM	CHEMBL5784621
7.26	IC50	55	nM	CHEMBL5915901
7.26	IC50	55	nM	CHEMBL5835747
7.26	IC50	55	nM	CHEMBL5956737

PubChem BioAssay actives

2 with measured affinity, of 8 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-[[5-[[4-(3-chlorophenyl)-3-oxopiperazin-1-yl]methyl]imidazol-1-yl]methyl]benzonitrile	1893893: Binding affinity to NRAS (unknown origin) assessed as inhibition constant	ki	0.0003	uM
4-(hydroxyamino)-N-(2-naphthalen-2-yloxyethyl)-N-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]benzenesulfonamide	682552: Inhibition of N-Ras expressed in Escherichia coli using [3H]GDP and [3H]GTP assessed as inhibition of intrinsic nucleotide exchange by scintillation counting	ic50	0.5000	uM

CTD chemical–gene interactions

71 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation	4
sodium arsenite	decreases expression, increases expression	2
Copper	affects binding, increases expression, decreases expression	2
Nickel	increases expression	2
Quercetin	decreases expression	2
Tobacco Smoke Pollution	increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	affects cotreatment, affects expression	1
moringin	affects cotreatment, decreases expression	1
BI-2852	affects binding	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
methylparaben	increases expression	1
perfluorooctanoic acid	affects cotreatment, affects expression	1
ochratoxin A	affects binding	1
hydroquinone	decreases expression	1
mitomycin C-DNA adduct	decreases expression	1
cyanoginosin LR	increases expression	1
10-decarbamoylmitomycin C	decreases expression	1
perfluorooctane sulfonic acid	affects expression, affects cotreatment	1
L 744832	decreases prenylation, increases reaction	1
deguelin	decreases expression	1
emamectin benzoate	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
GGTI 2147	decreases prenylation, increases reaction	1
perfluorobutanesulfonic acid	affects expression, affects cotreatment	1
asparanin A	decreases expression	1
AC 93253	decreases expression	1

ChEMBL screening assays

18 unique, capped per target: 18 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2089526	Binding	Inhibition of N-Ras expressed in Escherichia coli using [3H]GDP and [3H]GTP assessed as inhibition of intrinsic nucleotide exchange by scintillation counting	Ras inhibition via direct Ras binding–is there a path forward? — Bioorg Med Chem Lett

Cellosaurus cell lines

1,627 cell lines: 1,591 cancer cell line, 22 transformed cell line, 8 induced pluripotent stem cell, 4 spontaneously immortalized cell line, 2 undefined cell line type

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0002	HL-60	Cancer cell line	Female
CVCL_0006	THP-1	Cancer cell line	Male
CVCL_0013	MOLT-4	Cancer cell line	Male
CVCL_0027	Hep-G2	Cancer cell line	Male
CVCL_0039	SK-MEL-30	Cancer cell line	Male
CVCL_0060	NCI-H1299	Cancer cell line	Male
CVCL_0069	SK-MEL-2	Cancer cell line	Male
CVCL_0092	NALM-6	Cancer cell line	Male
CVCL_0115	2fTGH	Cancer cell line	Male
CVCL_0195	C8166/45	Transformed cell line	Male

Clinical trials (associated diseases)

323 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00114829	PHASE4	UNKNOWN	Preoperative Assessment of Colon Tumor
NCT00114842	PHASE4	COMPLETED	Magnetic Resonance (MR) Colonography With Fecal Tagging
NCT00114946	PHASE4	TERMINATED	A Study to Compare Two Avastin-Based Treatment Regimens for the Treatment of Metastatic Colorectal Cancer
NCT00122720	PHASE4	COMPLETED	The Effect of Darbepoetin Upon Rehabilitation for Colorectal Cancer Surgery
NCT00129870	PHASE4	TERMINATED	CONCEPT: Comparison of Oxaliplatin vs Conventional Methods With Calcium/Magnesium in First-Line Metastatic Colorectal Cancer
NCT00138060	PHASE4	COMPLETED	Toxicity/Benefit Ratio Optimization of Chemotherapy in Colorectal Cancer (CRC) Patients by Determination of Individual Genotypic Determinants
NCT00216424	PHASE4	TERMINATED	Capecitabine (Xeloda) and Radiation for Patients With Rectosigmoid Carcinoma
NCT00327093	PHASE4	TERMINATED	Elaboration of a Model for Predicting Efficacy of Monoclonal Antibodies (Cetuximab and Bevacizumab) in Patients With Colorectal Cancer and Liver Metastases
NCT00332943	PHASE4	COMPLETED	MR Colonography With Fecal Tagging. Barium vs. BariumFerumoxsil
NCT00441311	PHASE4	COMPLETED	Dissemination of Colorectal Cancer Screening to Primary Care Physicians
NCT00460837	PHASE4	WITHDRAWN	Comparison of Bowel Preparation in Virtual Colonoscopy (VC) - Patient Experience
NCT00473980	PHASE4	COMPLETED	Preoperative Non-steroidal Anti-inflammatory Drugs(NSAID) to Colorectal Cancer Patients
NCT00488904	PHASE4	COMPLETED	Omega-3 Fatty Acids and Postoperative Complications After Colorectal Surgery
NCT00496678	PHASE4	COMPLETED	Trial of Patient Navigation-Activation
NCT00502671	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) as Adjuvant Monotherapy in Patients With Colon Cancer.
NCT00559676	PHASE4	COMPLETED	Study of Biomarkers in Patients Undergoing Chemotherapy for Metastatic Colorectal Cancer
NCT00577031	PHASE4	COMPLETED	OBELIX Study: A Study of Avastin (Bevacizumab) in Combination With XELOX in Patients With Metastatic Cancer of the Colon or Rectum.
NCT00626054	PHASE4	COMPLETED	Comparison of Two Methods of Administration of a PEG Solution
NCT00812864	PHASE4	COMPLETED	Pharmacokinetic Study of Capecitabine in Elderly Cancer Patient (≥ 75 Years)
NCT00868569	PHASE4	UNKNOWN	Transhepatic Arterial Chemotherapy (TAC) Versus Transcatheter Arterial Chemoembolization (TACE) Plus Folfox4 as the Treatment of Unresectable Liver Metastasis of Colorectal Cancer
NCT00868816	PHASE4	COMPLETED	Oxaliplatine Based Adjuvant Chemotherapy for Stage II/III Colorectal Cancer: 8 Cycles Versus 12 Cycles
NCT00874406	PHASE4	UNKNOWN	Preoperative Transhepatic Arterial Chemotherapy (TAC) in the Treatment of Liver Metastasis of Resectable Colorectal Cancer
NCT00928928	PHASE4	COMPLETED	Oxidative Stress Markers in Open and Laparoscopic Colectomy for Cancer
NCT00942461	PHASE4	COMPLETED	Inflammatory Response in Laparoscopic and Open Colectomy
NCT01023633	PHASE4	UNKNOWN	OPTIMOX1 in Chinese mCRC Patients
NCT01271582	PHASE4	UNKNOWN	Investigation of Association Between UGT1A1 Polymorphisms and Irinotecan Toxicity in Korean Patients
NCT01315990	PHASE4	UNKNOWN	FOLFIRI in Combination With Cetuximab in the First-line Treatment of Metastatic Colorectal Cancer Including a Regular Dermal Prophylaxis to Prevent Acneiforme Follicular Exanthema
NCT01493713	PHASE4	COMPLETED	Correlation Between RECIST, Morphologic Response by CT- Histopathologic Response in Hepatic Metastasis Secondary to Colorectal Cancer
NCT01609660	PHASE4	COMPLETED	Impact of Probiotics on the Intestinal Microbiota
NCT01641458	PHASE4	COMPLETED	Pharmacology-driven Dosing of Fluoropyrimidines in Cancer Patients
NCT01689792	PHASE4	COMPLETED	A Multi-centre Study Comparing the Polyp Detection Rate of Two Different Types of Bowel Preparation: a 2-litre Solution (MOVIPREP®) Versus a Hyperosmotic and Stimulant Combined Low Volume Bowel Preparation (Sodium Picosulfate and Magnesium Citrate)
NCT01695772	PHASE4	COMPLETED	A Study of Bevacizumab Plus 5-Flurouracil (5-FU) Based Doublet Chemotherapy as Neoadjuvant Therapy for Participants With Previously Untreated Unresectable Liver-Only Metastases From Colorectal Cancer
NCT01695863	PHASE4	COMPLETED	Efficacy and Patient Satisfaction of Miralax and Gatorade Versus Movi Prep
NCT01706822	PHASE4	TERMINATED	Radial Reload Laparoscopic LAR Case Series
NCT01740947	PHASE4	TERMINATED	Does Administration of Antibiotics in Patients Undergoing Surgery for Colorectal Cancer Result in Less Complications and Better Prognosis?
NCT01831310	PHASE4	COMPLETED	Nutrition for Colorectal Cancer Patients and Neutrophil Functions
NCT01841294	PHASE4	UNKNOWN	NK Activity Modulation Induced by Intravenous Lidocaine During Colorectal Laparoscopic Surgery
NCT01959061	PHASE4	UNKNOWN	Efficacy and Safety of Raltitrexed-based Transarterial Chemoembolisation(TACE)for Colorectal Cancer Liver Metastases