RRAS2

Summary

RRAS2 (RAS related 2, HGNC:17271) is a protein-coding gene on chromosome 11p15.2, encoding Ras-related protein R-Ras2 (P62070). GTP-binding protein with GTPase activity, involved in the regulation of MAPK signaling pathway and thereby controlling multiple cellular processes.

This gene encodes a member of the R-Ras subfamily of Ras-like small GTPases. The encoded protein associates with the plasma membrane and may function as a signal transducer. This protein may play an important role in activating signal transduction pathways that control cell proliferation. Mutations in this gene are associated with the growth of certain tumors. Pseudogenes of this gene are found on chromosomes 1 and 2. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 22800 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Noonan syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 18
• Clinical variants (ClinVar): 91 total — 1 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 91
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• MANE Select transcript: NM_012250

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17271
Approved symbol	RRAS2
Name	RAS related 2
Location	11p15.2
Locus type	gene with protein product
Status	Approved
Aliases	TC21
Ensembl gene	ENSG00000133818
Ensembl biotype	protein_coding
OMIM	600098
Entrez	22800

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 11 protein_coding, 2 nonsense_mediated_decay

ENST00000256196, ENST00000414023, ENST00000526063, ENST00000526717, ENST00000529237, ENST00000531421, ENST00000531807, ENST00000532814, ENST00000532950, ENST00000534746, ENST00000537760, ENST00000899694, ENST00000971491

RefSeq mRNA: 4 — MANE Select: NM_012250 NM_001102669, NM_001177314, NM_001177315, NM_012250

CCDS: CCDS44544, CCDS53603, CCDS7814

Canonical transcript exons

ENST00000256196 — 6 exons

Exon	Start	End
ENSE00001302370	14358763	14359183
ENSE00002153248	14277922	14279424
ENSE00003508390	14281602	14281720
ENSE00003550327	14294760	14294862
ENSE00003584293	14295768	14295855
ENSE00003627583	14294471	14294579

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 98.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 47.4490 / max 368.2812, expressed in 1704 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
118740	45.5250	1694
118738	1.1746	700
118739	0.3130	138
118736	0.3045	112
118737	0.1318	58

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.35	gold quality
oocyte	CL:0000023	97.99	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.21	gold quality
colonic epithelium	UBERON:0000397	95.40	gold quality
nephron tubule	UBERON:0001231	95.38	gold quality
biceps brachii	UBERON:0001507	94.80	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	94.70	gold quality
diaphragm	UBERON:0001103	94.31	gold quality
gluteal muscle	UBERON:0002000	94.02	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.96	gold quality
germinal epithelium of ovary	UBERON:0001304	93.90	gold quality
renal glomerulus	UBERON:0000074	93.89	gold quality
vastus lateralis	UBERON:0001379	93.87	gold quality
kidney epithelium	UBERON:0004819	93.71	gold quality
metanephric glomerulus	UBERON:0004736	93.66	gold quality
choroid plexus epithelium	UBERON:0003911	93.53	gold quality
quadriceps femoris	UBERON:0001377	93.43	gold quality
skeletal muscle tissue	UBERON:0001134	93.22	gold quality
placenta	UBERON:0001987	93.05	gold quality
hair follicle	UBERON:0002073	92.87	gold quality
parietal pleura	UBERON:0002400	92.84	gold quality
palpebral conjunctiva	UBERON:0001812	92.81	gold quality
deltoid	UBERON:0001476	92.28	gold quality
muscle tissue	UBERON:0002385	92.28	gold quality
muscle organ	UBERON:0001630	92.25	gold quality
skeletal muscle organ	UBERON:0014892	92.24	gold quality
islet of Langerhans	UBERON:0000006	92.16	gold quality
heart right ventricle	UBERON:0002080	92.08	gold quality
gastrocnemius	UBERON:0001388	91.87	gold quality
muscle of leg	UBERON:0001383	91.76	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	11.65
E-MTAB-8271	yes	6.95
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BCLAF1, BTF3

miRNA regulators (miRDB)

143 targeting RRAS2, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-23A-3P	99.95	74.24	3163

Literature-anchored findings (GeneRIF, showing 17)

• TGF-beta and TC21 have roles in tumorigenesis (PMID:17656362)
• TC21 directly links antigen receptors to PI(3)K-mediated survival pathways. (PMID:19561613)
• RasGRF GEFs can activate TC21 in all sublocalizations except the Golgi complex. Farnesylated TC21 can be activated by RasGRF1 & RasGRF2, but geranylgeranylated TC21 is unresponsive to RasGRF2. (PMID:19692568)
• Suggest that TC21 promotes cell motility and metastasis by regulating the expression of E-cadherin and N-cadherin in hepatocellular carcinoma and is associated with tumor progression and poor prognosis in HCC. (PMID:20811707)
• This article is the first study demonstrating expression of TC21 in human skin malignant tumors and suggests that TC21 is more expressed in highly aggressive skin tumors. (PMID:21781067)
• R-RAS2 is overexpressed in the early stages of malignancy in tumors of the human central nervous system. (PMID:24148564)
• R-Ras2 has a role in both primary breast tumorigenesis and the late metastatic steps of cancer cells in the lung parenchyma. (PMID:24826867)
• Equilibrium dissociation constants were determined for the binding of HRAS, KRAS, NRAS and RRAS2 to the RAS binding (RB) domain of binding proteins. (PMID:27936046)
• Activating Mutations of RRAS2 Cause Noonan Syndrome. (PMID:31130282)
• Germline-Activating RRAS2 Mutations Cause Noonan Syndrome. (PMID:31130285)
• RRAS2 knockdown suppresses osteosarcoma progression by inactivating the MEK/ERK signaling pathway. (PMID:31517733)
• R-Ras subfamily proteins elicit distinct physiologic effects and phosphoproteome alterations in neurofibromin-null MPNST cells. (PMID:34530870)
• Characterization of mutant versions of the R-RAS2/TC21 GTPase found in tumors. (PMID:36476833)
• MicroRNA-23b Plays a Tumor-Suppressive Role in Cutaneous Squamous Cell Carcinoma and Targets Ras-Related Protein RRAS2. (PMID:37423552)
• The RRAS2 pathogenic variant (c.67G>T; p. Gly23Cys) produces Noonan syndrome with embryonal rhabdomyosarcoma. (PMID:37942564)
• Characterization of Three Somatic Mutations in the 3’UTR of RRAS2 and Their Inverse Correlation with Lymphocytosis in Chronic Lymphocytic Leukemia. (PMID:38067115)
• Unmutated RRAS2 emerges as a key oncogene in post-partum-associated triple negative breast cancer. (PMID:38987766)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rras2	ENSDARG00000036252
mus_musculus	Rras2	ENSMUSG00000055723
rattus_norvegicus	Rras2	ENSRNOG00000012258

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), 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), NRAS (ENSG00000213281), RASL10B (ENSG00000270885)

Protein

Protein identifiers

Ras-related protein R-Ras2 — P62070 (reviewed: P62070)

Alternative names: Ras-like protein TC21, Teratocarcinoma oncogene

All UniProt accessions (5): E9PK85, E9PQ87, E9PQC5, E9PQK5, P62070

UniProt curated annotations — full annotation on UniProt →

Function. GTP-binding protein with GTPase activity, involved in the regulation of MAPK signaling pathway and thereby controlling multiple cellular processes. Regulates craniofacial development.

Subunit / interactions. Interacts with RASSF5.

Subcellular location. Cell membrane. Golgi apparatus membrane.

Tissue specificity. Ubiquitously present in all tissues examined, with the highest levels in heart, placenta, and skeletal muscle. Moderate levels in lung and liver; low levels in brain, kidney, and pancreas.

Post-translational modifications. May be post-translationally modified by both palmitoylation and polyisoprenylation. Fatty-acylation at Lys-192, Lys-194; lys-196 and Lys-197 is required for localization to the plasma membrane and activity. Defatty-acylated by SIRT6, affecting its localization to the plasma membrane.

Disease relevance. Ovarian cancer (OC) [MIM:167000] The term ovarian cancer defines malignancies originating from ovarian tissue. Although many histologic types of ovarian tumors have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. Disease susceptibility is associated with variants affecting the gene represented in this entry. Noonan syndrome 12 (NS12) [MIM:618624] 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. NS12 inheritance is autosomal dominant. There is considerable variability in severity. The disease is caused by variants affecting the gene represented in this entry.

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

Isoforms (4)

UniProt ID	Names	Canonical?
P62070-1	1	yes
P62070-2	2
P62070-3	3
P62070-4	4

RefSeq proteins (4): NP_001096139, NP_001170785, NP_001170786, NP_036382* (*=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 (42 total): sequence variant 7, lipid moiety-binding region 6, strand 6, helix 6, binding site 4, modified residue 3, splice variant 3, mutagenesis site 2, initiator methionine 1, chain 1, propeptide 1, short sequence motif 1, turn 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9B4Q	X-RAY DIFFRACTION	1.46
2ERY	X-RAY DIFFRACTION	1.7
9B4S	X-RAY DIFFRACTION	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P62070-F1	87.14	0.72

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): 21–29; 68–72; 127–130; 157–159

Post-translational modifications (9): 201, 192, 194, 196, 197, 199, 201, 2, 186

Mutagenesis-validated functional residues (2):

Position	Phenotype
192–197	strongly decreased lysine fatty-acylation.
199	does not affect lysine fatty-acylation.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-9696273	RND1 GTPase cycle
R-HSA-162582	Signal Transduction
R-HSA-194315	Signaling by Rho GTPases
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 584 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, KEGG_MAPK_SIGNALING_PATHWAY, BOYAULT_LIVER_CANCER_SUBCLASS_G2, GOBP_OSTEOBLAST_DIFFERENTIATION, KEGG_TIGHT_JUNCTION, RIZKI_TUMOR_INVASIVENESS_3D_DN, BROWNE_HCMV_INFECTION_48HR_DN, CHEN_LVAD_SUPPORT_OF_FAILING_HEART_UP, HUTTMANN_B_CLL_POOR_SURVIVAL_DN, GROSS_ELK3_TARGETS_UP, GROSS_HYPOXIA_VIA_ELK3_UP, BROWNE_HCMV_INFECTION_14HR_DN, GOBP_RAS_PROTEIN_SIGNAL_TRANSDUCTION, DACOSTA_UV_RESPONSE_VIA_ERCC3_COMMON_DN

GO Biological Process (6): osteoblast differentiation (GO:0001649), Ras protein signal transduction (GO:0007265), Schwann cell migration (GO:0036135), positive regulation of Schwann cell migration (GO:1900149), signal transduction (GO:0007165), cell migration (GO:0016477)

GO Molecular Function (7): GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), GDP binding (GO:0019003), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (8): Golgi membrane (GO:0000139), endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), focal adhesion (GO:0005925), membrane (GO:0016020), extracellular exosome (GO:0070062), Golgi apparatus (GO:0005794), endomembrane system (GO:0012505)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
RHO GTPase cycle	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signaling by Rho GTPases	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
guanyl ribonucleotide binding	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
ossification	1
cell differentiation	1
small GTPase-mediated signal transduction	1
glial cell migration	1
Schwann cell migration	1
regulation of Schwann cell migration	1
positive regulation of glial cell migration	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell motility	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
binding	1
catalytic activity	1
Golgi apparatus	1
bounding membrane of organelle	1
membrane	1
cell periphery	1
cell-substrate junction	1
extracellular vesicle	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

113 interactions, top by confidence:

A	B	Type	Score
RIN1	NRAS	psi-mi:“MI:0914”(association)	0.840
RRAS2	RIN1	psi-mi:“MI:0915”(physical association)	0.830
RIN1	RRAS2	psi-mi:“MI:0915”(physical association)	0.830
RIN1	ABL1	psi-mi:“MI:0914”(association)	0.790
Fnta	Pggt1b	psi-mi:“MI:0915”(physical association)	0.790
RABGGTB	YKT6	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
RAP1GDS1	DIRAS1	psi-mi:“MI:0914”(association)	0.640
SLC17A5	LGALS8	psi-mi:“MI:0914”(association)	0.640
Fnta	RRAS2	psi-mi:“MI:0915”(physical association)	0.590
RGL3	RRAS2	psi-mi:“MI:0915”(physical association)	0.560
RAP1GDS1	RRAS2	psi-mi:“MI:0915”(physical association)	0.560
RRAS2	RGL3	psi-mi:“MI:0915”(physical association)	0.560
RRAS2	HDAC7	psi-mi:“MI:0915”(physical association)	0.560
FNTB	YKT6	psi-mi:“MI:0914”(association)	0.530
CD53	FAM171A2	psi-mi:“MI:0914”(association)	0.530
Trim69		psi-mi:“MI:0915”(physical association)	0.400
Tubb4b	MGST3	psi-mi:“MI:0915”(physical association)	0.400
GPC1	SNAP23	psi-mi:“MI:0915”(physical association)	0.400
GPC1	GANAB	psi-mi:“MI:0915”(physical association)	0.400
RRAS2	TRAF2	psi-mi:“MI:0915”(physical association)	0.370
RRAS2	RALGDS	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (124): RRAS2 (Affinity Capture-MS), RRAS2 (Affinity Capture-MS), RRAS2 (Affinity Capture-MS), RRAS2 (Affinity Capture-MS), RRAS2 (Affinity Capture-MS), RRAS2 (Affinity Capture-MS), RRAS2 (Affinity Capture-MS), RRAS2 (Affinity Capture-MS), RRAS2 (Affinity Capture-MS), RRAS2 (Affinity Capture-MS), RRAS2 (Affinity Capture-MS), RRAS2 (Affinity Capture-MS), RRAS2 (Affinity Capture-MS), RRAS2 (Affinity Capture-MS), RRAS2 (Affinity Capture-MS)

ESM2 similar proteins: A8NU18, D3Z8L7, G4MZY8, G4N1S3, O08989, O14807, O42785, O93856, P01114, P04388, P08647, P0CQ42, P0CQ43, P10114, P10301, P10833, P22126, P22278, P22279, P22280, P28775, P32252, P32253, P32254, P34726, P38976, P51539, P61225, P61226, P61227, P62070, P62071, P70425, P70426, P87018, P97538, Q01387, Q05058, Q06AU2, Q08DI5

Diamond homologs: A1DZY4, A6QP66, A8NU18, C4YKT4, O08989, O14807, O35929, O88667, O93856, O94363, P01119, P03967, P08645, P08647, P0CY32, P10114, P10536, P11233, P11234, P15064, P17609, P22124, P22126, P22278, P22279, P22280, P28775, P32254, P36860, P36863, P48555, P59279, P61105, P61225, P61226, P61227, P62070, P62071, P63320, P63321

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
BTF3	“down-regulates quantity by repression”	RRAS2	“transcriptional regulation”
hsa-miR-23b-3p	“down-regulates quantity by repression”	RRAS2	“post transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 117 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	5	24.0×	9e-04

GO biological processes:

GO term	Partners	Fold	FDR
Ras protein signal transduction	8	19.1×	6e-06
protein modification process	5	14.2×	6e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — UCEC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	46
Likely benign	22
Benign	10

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
9447	NM_012250.6(RRAS2):c.215A>T (p.Gln72Leu)	Pathogenic
1478697	NM_012250.6(RRAS2):c.212G>A (p.Gly71Glu)	Likely pathogenic
626912	NM_012250.6(RRAS2):c.208G>A (p.Ala70Thr)	Likely pathogenic

SpliceAI

1993 predictions. Top by Δscore:

Variant	Effect	Δscore
11:14294466:CTCAC:C	donor_loss	1.0000
11:14294467:TCA:T	donor_loss	1.0000
11:14294468:CA:C	donor_loss	1.0000
11:14294469:ACCT:A	donor_loss	1.0000
11:14294470:C:CT	donor_loss	1.0000
11:14294470:CCTGT:C	donor_gain	1.0000
11:14294575:CAAAA:C	acceptor_gain	1.0000
11:14294576:AAAA:A	acceptor_gain	1.0000
11:14294578:AA:A	acceptor_gain	1.0000
11:14294580:C:CC	acceptor_gain	1.0000
11:14294581:T:C	acceptor_gain	1.0000
11:14294581:T:TC	acceptor_gain	1.0000
11:14294755:CAAA:C	donor_loss	1.0000
11:14294756:AAAC:A	donor_loss	1.0000
11:14294757:AAC:A	donor_loss	1.0000
11:14294758:A:AG	donor_loss	1.0000
11:14294759:CC:C	donor_loss	1.0000
11:14294858:CAAAA:C	acceptor_gain	1.0000
11:14294859:AAAA:A	acceptor_gain	1.0000
11:14294860:AAA:A	acceptor_gain	1.0000
11:14294861:AA:A	acceptor_gain	1.0000
11:14294863:C:CC	acceptor_gain	1.0000
11:14295762:A:AC	donor_gain	1.0000
11:14295763:C:CC	donor_gain	1.0000
11:14295764:TTA:T	donor_loss	1.0000
11:14295766:A:AC	donor_gain	1.0000
11:14295766:AC:A	donor_loss	1.0000
11:14295766:ACTAT:A	donor_gain	1.0000
11:14295767:C:CC	donor_gain	1.0000
11:14295767:CT:C	donor_gain	1.0000

AlphaMissense

1343 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:14281617:A:G	L171P	1.000
11:14281625:G:C	F168L	1.000
11:14281625:G:T	F168L	1.000
11:14281627:A:G	F168L	1.000
11:14294487:A:G	L131P	1.000
11:14294495:T:A	K128N	1.000
11:14294495:T:G	K128N	1.000
11:14294496:T:A	K128I	1.000
11:14294497:T:C	K128E	1.000
11:14294498:A:C	N127K	1.000
11:14294498:A:T	N127K	1.000
11:14294502:C:T	G126D	1.000
11:14294534:C:A	K115N	1.000
11:14294534:C:G	K115N	1.000
11:14294780:A:C	F93L	1.000
11:14294780:A:T	F93L	1.000
11:14294782:A:G	F93L	1.000
11:14294790:A:G	L90P	1.000
11:14294792:G:C	F89L	1.000
11:14294792:G:T	F89L	1.000
11:14294794:A:G	F89L	1.000
11:14294796:C:T	G88D	1.000
11:14294797:C:G	G88R	1.000
11:14294834:A:C	F75L	1.000
11:14294834:A:T	F75L	1.000
11:14294835:A:C	F75C	1.000
11:14294835:A:G	F75S	1.000
11:14294836:A:G	F75L	1.000
11:14294836:A:T	F75I	1.000
11:14294847:C:A	G71V	1.000

dbSNP variants (sampled 300 via entrez): RS1000005268 (11:14364391 C>T), RS1000034384 (11:14319346 T>C), RS1000061246 (11:14313593 G>A,T), RS1000065197 (11:14346799 G>A), RS1000091911 (11:14313313 A>G), RS1000200552 (11:14357442 C>G), RS1000289880 (11:14350431 T>G), RS1000393884 (11:14319114 A>G), RS1000401380 (11:14300838 G>C), RS1000453543 (11:14301100 T>A), RS1000463775 (11:14344106 G>A), RS1000489136 (11:14357187 C>T), RS1000600461 (11:14308818 T>C), RS1000625373 (11:14352002 G>A,T), RS1000666129 (11:14345066 C>A)

Disease associations

OMIM: gene MIM:600098 | disease phenotypes: MIM:618624, MIM:163950

GenCC curated gene-disease

Disease	Classification	Inheritance
noonan syndrome 12	Definitive	Autosomal dominant
Noonan syndrome	Definitive	Autosomal dominant
ovarian cancer	No Known Disease Relationship	Unknown

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Noonan syndrome	Definitive	AD

Mondo (5): RASopathy (MONDO:0021060), noonan syndrome 12 (MONDO:0032839), Noonan syndrome (MONDO:0018997), ovarian neoplasm (MONDO:0021068), ovarian cancer (MONDO:0008170)

Orphanet (2): RASopathy (Orphanet:536391), Noonan syndrome (Orphanet:648)

HPO phenotypes

91 total (30 of 91 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:0000179	Thick lower lip vermilion
HP:0000218	High palate
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000391	Thickened helices
HP:0000407	Sensorineural hearing impairment
HP:0000465	Webbed neck
HP:0000474	Thickened nuchal skin fold
HP:0000476	Cystic hygroma
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000520	Proptosis
HP:0000540	Hypermetropia
HP:0000565	Esotropia
HP:0000635	Blue irides
HP:0000639	Nystagmus
HP:0000646	Amblyopia
HP:0000767	Pectus excavatum
HP:0000768	Pectus carinatum
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000878	11 pairs of ribs
HP:0000938	Osteopenia

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST001915_26	Alzheimer’s disease (cognitive decline)	7.000000e-11
GCST002602_7	Vitamin D levels	2.000000e-08
GCST002616_15	Mitochondrial DNA levels	2.000000e-06
GCST008839_549	Height	1.000000e-47
GCST009066_23	Mosaic loss of chromosome Y (Y chromosome dosage)	2.000000e-08
GCST009597_18	Multiple sclerosis	6.000000e-09
GCST010002_231	Refractive error	3.000000e-11
GCST010241_238	Apolipoprotein A1 levels	3.000000e-09
GCST010703_153	Brain morphology (MOSTest)	3.000000e-09
GCST90020025_1195	Waist-to-hip ratio adjusted for BMI	3.000000e-12
GCST90020025_1196	Waist-to-hip ratio adjusted for BMI	8.000000e-13
GCST90020026_784	Hip index	2.000000e-15
GCST90020026_785	Hip index	1.000000e-08
GCST90020027_1445	Waist-hip index	1.000000e-11
GCST90020027_1446	Waist-hip index	1.000000e-12
GCST90020028_1830	Hip circumference adjusted for BMI	1.000000e-18
GCST90020028_1831	Hip circumference adjusted for BMI	3.000000e-13
GCST90020028_1832	Hip circumference adjusted for BMI	1.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0006312	mitochondrial DNA measurement
EFO:0007783	mosaic loss of chromosome Y measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004346	neuroimaging measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
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
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4879446 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs11023197	Efficacy	3	tamoxifen	Breast Neoplasms

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11023197	RRAS2	3	1.75	1	tamoxifen

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases methylation, decreases expression, increases expression, affects expression	5
sodium arsenite	decreases expression, increases expression	4
Cyclosporine	affects cotreatment, increases expression, decreases expression	3
Benzo(a)pyrene	affects methylation, increases expression	2
Carbamazepine	affects expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	affects expression, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
afimoxifene	affects response to substance	1
cobaltous chloride	increases expression	1
doxifluridine	decreases response to substance	1
ochratoxin A	affects binding	1
1-UFT protocol	decreases response to substance	1
ochratoxin B	affects binding	1
nefazodone	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
2-chloromethylpyridine	increases expression	1
U 0126	affects expression, affects reaction	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
obeticholic acid	increases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4827256	Binding	Inhibition of RRAS2 transcriptional activity in human KMS-11 cells assessed as reduction in H3K36 methylation at 10 uM measured after 72 hrs by chip q-PCR analysis	5-Aminonaphthalene derivatives as selective nonnucleoside nuclear receptor binding SET domain-protein 2 (NSD2) inhibitors for the treatment of multiple myeloma. — Eur J Med Chem

Cellosaurus cell lines

100 cell lines: 68 cancer cell line, 31 spontaneously immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0134	A2780	Cancer cell line	Female
CVCL_0135	A2780/CP70	Cancer cell line	Female
CVCL_1110	CAL-51	Cancer cell line	Female
CVCL_1941	A2780ADR	Cancer cell line	Female
CVCL_1942	A2780cis	Cancer cell line	Female
CVCL_1F93	A2780-TC1	Cancer cell line	Female
CVCL_4862	A2780/R	Cancer cell line	Female
CVCL_4863	A2780/S	Cancer cell line	Female
CVCL_4T95	A2780-DX1	Cancer cell line	Female
CVCL_4T96	A2780-DX2	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00727961	PHASE4	COMPLETED	A Study to Evaluate Efficacy and Tolerance of Caelyx in Patients With Epithelial Ovarian Cancer. (Study P04072)(COMPLETED)
NCT00740116	PHASE4	COMPLETED	Tranexamic Acid in Surgery of Advanced Ovarian Cancer
NCT00817479	PHASE4	COMPLETED	Tumor Gene Expression in Women With Ovarian Cancer
NCT01432015	PHASE4	COMPLETED	Fosaprepitant Versus Aprepitant in the Prevention of Chemotherapy Induced Nausea and Vomiting
NCT01706120	PHASE4	UNKNOWN	Study of Clinical and Biological Prognostic Factors in Patients With Ovarian Cancer Receiving Carboplatin +Paclitaxel With Bevacizumab
NCT01932125	PHASE4	COMPLETED	An Interventional Study of Avastin (Bevacizumab) in Patients With Advanced/Metastatic Epithelial Ovarian Cancer, Fallopian Tube Cancer or Primary Peritoneal Cancer
NCT01953107	PHASE4	COMPLETED	Oral Iron vs. Placebo in Newly Diagnosed Gynecologic Oncology Patients Who Are Surgical Candidates.
NCT02035345	PHASE4	TERMINATED	Slowed Carboplatin Infusion for Ovarian Cancer Patients Receiving Carboplatin Re-Treatment
NCT02243059	PHASE4	WITHDRAWN	Magnetic Resonance Imaging for Lymph Node Staging in Ovarian Cancer
NCT03164980	PHASE4	TERMINATED	QoL-Comparison Between Trabectedin/PLD and Pt-based Therapy in Patients With Pt-sensitive Recurrent Ovarian Cancer
NCT03384511	PHASE4	COMPLETED	The Use of 18F-ALF-NOTA-PRGD2 PET/CT Scan to Predict the Efficacy and Adverse Events of Apatinib in Malignancies.
NCT03543462	PHASE4	COMPLETED	Diaphragmatic Resection And Gynecological Ovarian Neoplasm
NCT03752216	PHASE4	COMPLETED	NIraparib and Quality of LifE is a Longitudinal Study Evaluating in Real Life the Tolerability of Niraparib.
NCT03858166	PHASE4	TERMINATED	Efficacy and Safety of PEG-rhG-CSF Secondary Prophylaxis vs. Therapeutic Administration in Patients With Ovarian Cancer
NCT04024254	PHASE4	COMPLETED	A Study of Serum Folate Levels in Patients Treated With Olaparib
NCT04330040	PHASE4	COMPLETED	Prospective Multicentre Phase-IV Clinical Trial of Olaparib in Indian Patients With Ovarian and Metastatic Breast Cancer
NCT04352439	PHASE4	COMPLETED	Aspirin for Prevention of Venous Thromboembolism Among Ovarian Cancer Patients Receiving Neoadjuvant Chemotherapy
NCT05187208	PHASE4	UNKNOWN	PARP Inhibitor Oral Maintenance in Low-Risk Ovarian Cancer
NCT05606692	PHASE4	RECRUITING	Influences of Propofol and Sevoflurane Anesthesia in Ovarian Cancer (Anesthetics)
NCT05926336	PHASE4	RECRUITING	The Effects of Using Different Anesthetics on the Prognosis of Primary Tumors and Its Mechanism of Action
NCT06412120	PHASE4	RECRUITING	Study Evaluating Safety, Tolerability, and Metabolism of Niraparib
NCT06871787	PHASE4	NOT_YET_RECRUITING	Near-Infrared Fluorescence Imaging With Indocyanine Green to Evaluate Bowel Anastomoses in Gynecologic Oncology Surgery
NCT06887933	PHASE4	NOT_YET_RECRUITING	A Trial to Evaluate the Safety of Niraparib Tablets in Adult Female Participants With Advanced or Relapsed Epithelial Ovarian Cancer
NCT07469202	PHASE4	NOT_YET_RECRUITING	CYTALUX Dose Extension Study
NCT00001806	PHASE3	COMPLETED	Methods in Education for Breast Cancer Genetics
NCT00002477	PHASE3	UNKNOWN	Adjuvant Chemotherapy Compared With Observation in Treating Patients With Resected Early Stage Ovarian Epithelial Cancer
NCT00002568	PHASE3	COMPLETED	Combination Chemotherapy With or Without Surgery in Treating Patients With Stage III Ovarian Epithelial Cancer
NCT00002641	PHASE3	COMPLETED	Surgery With or Without Chemotherapy in Treating Patients With Soft Tissue Sarcoma
NCT00002717	PHASE3	COMPLETED	Paclitaxel and Cisplatin in Treating Patients With Stage III or Stage IV Ovarian Cancer or Primary Peritoneal Cancer
NCT00002764	PHASE3	COMPLETED	Surgery With or Without Combination Chemotherapy in Treating Patients With Lung Metastases From Soft Tissue Sarcoma
NCT00002819	PHASE3	TERMINATED	Chemotherapy With or Without Peripheral Stem Cell Transplantation in Treating Patients With Persistent Ovarian Epithelial Cancer
NCT00002894	PHASE3	COMPLETED	Platinum-based Chemotherapy With or Without Paclitaxel in Treating Patients With Relapsed Ovarian Cancer
NCT00002895	PHASE3	COMPLETED	Early Chemotherapy Based on CA 125 Level Alone Compared With Delayed Chemotherapy in Treating Patients With Recurrent Ovarian Epithelial , Fallopian Tube, or Primary Peritoneal Cancer
NCT00003120	PHASE3	COMPLETED	S9701 Paclitaxel in Treating Patients With Advanced Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Remission
NCT00003214	PHASE3	COMPLETED	Chemosensitivity Testing to Assign Treatment for Patients With Stage III or Stage IV Ovarian Cancer
NCT00003322	PHASE3	COMPLETED	Combination Chemotherapy in Treating Patients With Primary Peritoneal or Stage III Epithelial Ovarian Cancer
NCT00003636	PHASE3	COMPLETED	Chemotherapy Plus Surgery in Treating Patients With Stage III or Stage IV Ovarian, Peritoneal, or Fallopian Tube Cancer
NCT00003644	PHASE3	COMPLETED	Carboplatin Plus Paclitaxel With or Without Continued Low-Dose Paclitaxel in Treating Patients With Early-Stage Ovarian Cancer