RRAS

Summary

RRAS (RAS related, HGNC:10447) is a protein-coding gene on chromosome 19q13.33, encoding Ras-related protein R-Ras (P10301). GTP-binding protein with GTPase activity, likely involved in the regulation of MAPK signaling pathway and thereby controlling multiple cellular processes.

The protein encoded by this gene is a small GTPase involved in diverse processes including angiogenesis, vascular homeostasis and regeneration, cell adhesion, and neuronal axon guidance. Mutations in this gene are found in many invasive cancers.

Source: NCBI Gene 6237 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Noonan syndrome and Noonan-related syndrome (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 366 total — 1 likely-pathogenic
• Phenotypes (HPO): 70
• MANE Select transcript: NM_006270

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10447
Approved symbol	RRAS
Name	RAS related
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Aliases	R-Ras, RRAS1
Ensembl gene	ENSG00000126458
Ensembl biotype	protein_coding
OMIM	165090
Entrez	6237

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000246792, ENST00000601532, ENST00000928399, ENST00000962269, ENST00000962270

RefSeq mRNA: 1 — MANE Select: NM_006270 NM_006270

CCDS: CCDS12774

Canonical transcript exons

ENST00000246792 — 6 exons

Exon	Start	End
ENSE00000720889	49635734	49635852
ENSE00000720896	49636824	49636926
ENSE00000720901	49637043	49637130
ENSE00001271700	49635292	49635660
ENSE00003052781	49639946	49640143
ENSE00003628343	49636619	49636727

Expression profiles

Bgee: expression breadth ubiquitous, 242 present calls, max score 99.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 97.4850 / max 1515.2316, expressed in 1813 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
182064	95.0341	1813
182063	2.4509	946

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right coronary artery	UBERON:0001625	99.33	gold quality
popliteal artery	UBERON:0002250	99.29	gold quality
tibial artery	UBERON:0007610	99.29	gold quality
ascending aorta	UBERON:0001496	99.18	gold quality
thoracic aorta	UBERON:0001515	99.18	gold quality
descending thoracic aorta	UBERON:0002345	99.16	gold quality
aorta	UBERON:0000947	99.15	gold quality
left coronary artery	UBERON:0001626	99.07	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.04	gold quality
lower esophagus	UBERON:0013473	99.03	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.01	gold quality
mucosa of stomach	UBERON:0001199	98.94	gold quality
left uterine tube	UBERON:0001303	98.80	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.65	gold quality
right lung	UBERON:0002167	98.63	gold quality
endocervix	UBERON:0000458	98.54	gold quality
coronary artery	UBERON:0001621	98.54	gold quality
body of uterus	UBERON:0009853	98.36	gold quality
apex of heart	UBERON:0002098	98.35	gold quality
tibial nerve	UBERON:0001323	98.32	gold quality
omental fat pad	UBERON:0010414	98.09	gold quality
peritoneum	UBERON:0002358	98.02	gold quality
adipose tissue of abdominal region	UBERON:0007808	97.96	gold quality
right atrium auricular region	UBERON:0006631	97.90	gold quality
upper lobe of left lung	UBERON:0008952	97.60	gold quality
ectocervix	UBERON:0012249	97.48	gold quality
right uterine tube	UBERON:0001302	97.39	gold quality
heart left ventricle	UBERON:0002084	97.34	gold quality
upper lobe of lung	UBERON:0008948	97.21	gold quality
stromal cell of endometrium	CL:0002255	97.06	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-13	yes	886.54
E-GEOD-137537	yes	6.42
E-GEOD-75367	no	373.83
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP3

miRNA regulators (miRDB)

37 targeting RRAS, 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-190A-3P	100.00	80.35	5520
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-548AU-3P	99.70	68.22	1373
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-4519	99.48	66.10	859
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-1912-3P	99.32	67.40	936
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-5190	99.15	67.76	1234
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-1295B-5P	99.03	67.50	810
HSA-MIR-1304-5P	98.90	68.58	1054
HSA-MIR-6769B-5P	98.73	64.91	1092

Literature-anchored findings (GeneRIF, showing 34)

• study of the potential contribution in generating of estrogen-independence in MCF-7 cells (PMID:12386818)
• R-Ras promotes focal adhesion formation by signaling to FAK and p130(Cas) through a novel mechanism that differs from but synergizes with the alpha2beta1 integrin. (PMID:12529399)
• the oncogene R-Ras promotes tumor growth of cervical epithelial cells and increases their migration potential over collagen through a pathway that involves PI 3-K. (PMID:12548599)
• activation of R-Ras promotes the formation of focal adhesions and a spread cell shape (PMID:12890755)
• Plexin-B1 mediates Sema4D-induced repulsive axon guidance signaling by acting as a GTPase activating protein for R-Ras (PMID:15297673)
• R-Ras plays a key role in cell migration by locally regulating the switch from Rac to Rho activity after membrane protrusion and adhesion (PMID:15525681)
• GPCRs rapidly activate R-Ras; R-Ras activation by the GPCRs is apparently directly induced by cyclic AMP-regulated Epac proteins; and activated R-Ras specifically controls GPCR-mediated phospholipase D stimulation (PMID:16754664)
• These findings show that R-Ras activity mediates inhibition of insulin signaling associated with suppression of estrogen action, implicating this GTPase in a growth-inhibitory mechanism associated with antiestrogen treatment of breast cancer. (PMID:16914723)
• R-Ras and ILK have roles upstream of GSK-3beta in the regulation of neuronal polarity (PMID:17107957)
• Notch1 ligand, Delta-like ligand-4, stimulates R-Ras-dependent alpha 5 beta 1 integrin-mediated adhesion, demonstrating the physiological relevance of this pathway. (PMID:17664272)
• results map the functional elements in the R-ras promoter sequence and suggest that the GABP may be critical for transcription of R-ras and for maintenance of normal blood vessel functions through the regulation of this gene (PMID:19011236)
• TCF8 activates R-Ras, another class of angiogenic regulator, to suppress angiogenesis by a mechanism other than a transcriptional attenuator. (PMID:19116136)
• the monomeric intracellular plexin-B1 binds R-Ras but not H-Ras. These findings suggest that the monomeric form of the intracellular region is primed for GAP activity and extend a model for plexin activation. (PMID:19843518)
• Sema3E acts on plexin D1 to initiate a two-pronged mechanism involving R-Ras inactivation and Arf6 stimulation, which affect the status of activation of integrins and their intracellular trafficking, respectively. (PMID:20385769)
• data support a model in which R-Ras functionally associates with FLNa and thereby regulates integrin-dependent migration (PMID:20585650)
• Data suggest that the RRAS gene is an important regulatory module in the pathogenesis of biliary atresia (BA), which may serve as a novel prognostic marker for BA. (PMID:21390152)
• Maintaining endothelial barrier function is dependent upon active R-Ras and association between R-Ras and FLNa. (PMID:21660952)
• These findings identify R-Ras as a critical regulator of vessel integrity and function during tumor vascularization. (PMID:22897853)
• These data suggest that pharmacological inhibition of RRAS signaling may confer therapeutic benefit in Huntington’s disease. (PMID:23209424)
• A polymorphism linked to RRAS, SCAF1, IRF3 and BCL2L12 genes is associated with cirrhosis in hepatitis C virus carriers. (PMID:24131527)
• Contradicting the positive association reported in previous studies, our results indicate that R-Ras activation may negatively regulate the transformation of breast epithelial cells. (PMID:24700169)
• Evidence is provided of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease. (PMID:24705357)
• Patients with gemistocytic astrocytomas with an RRAS deletion tend to have shorter survival rates than those without deletion. (PMID:25192052)
• phosphorylation of ORP3 controls its association with VAPA. Furthermore, ORP3-VAPA complexes stimulate R-Ras signaling. (PMID:25447204)
• Girdin regulates the trafficking of VE-cadherin in synergy with R-Ras. (PMID:25869066)
• RRAS is a key regulator of miR-34/449 promotion of actin network formation during multiciliogenesis. (PMID:26381333)
• R-Ras activation is associated melanoma tumorigenesis. (PMID:26993606)
• Suggest that R-Ras regulates angiogenic activities of endothelial cells in part via inhibition of the p38MAPK-HSP27 axis of VEGF signaling. (PMID:27029009)
• this study identified potential biochemical players involved in distant recurrence and indicates that R-Ras and Transgelin are potential post-surgical prognostic biomarkers for Stage III colorectal cancer (PMID:27270312)
• SHANK1 and SHANK3 act as integrin activation inhibitors by sequestering active Rap1 and R-Ras via the SPN domain and thus limiting their bioavailability at the plasma membrane. (PMID:28263956)
• R-Ras subfamily proteins elicit distinct physiologic effects and phosphoproteome alterations in neurofibromin-null MPNST cells. (PMID:34530870)
• METTL3/YTHDF2 m6A axis promotes the malignant progression of bladder cancer by epigenetically suppressing RRAS. (PMID:36960869)
• The ancestral type of the R-RAS protein has oncogenic potential. (PMID:38383288)
• NEDD4L-mediated RASGRP2 suppresses high-glucose and oxLDL-induced vascular endothelial cell dysfunctions by activating Rap1 and R-Ras. (PMID:39260747)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rras	ENSDARG00000006553
mus_musculus	Rras	ENSMUSG00000038387
rattus_norvegicus	Rras	ENSRNOG00000037247
drosophila_melanogaster	Ras64B	FBGN0003206
caenorhabditis_elegans		WBGENE00004310

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

Protein

Protein identifiers

Ras-related protein R-Ras — P10301 (reviewed: P10301)

Alternative names: p23

All UniProt accessions (1): P10301

UniProt curated annotations — full annotation on UniProt →

Function. GTP-binding protein with GTPase activity, likely involved in the regulation of MAPK signaling pathway and thereby controlling multiple cellular processes. Regulates the organization of the actin cytoskeleton. With OSPBL3, modulates integrin beta-1 (ITGB1) activity.

Subunit / interactions. Interacts with PLCE1. Interacts (active GTP-bound form preferentially) with RGS14. Interacts with OSBPL3. Interacts with ZDHHC19.

Subcellular location. Cell membrane.

Post-translational modifications. S-palmitoylated by ZDHHC19, leading to increased association with membranes and with rafts/caveolae as well as enhanced cell viability.

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

RefSeq proteins (1): NP_006261* (*=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 (27 total): strand 6, helix 6, binding site 4, mutagenesis site 2, turn 2, chain 1, propeptide 1, lipid moiety-binding region 1, region of interest 1, short sequence motif 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2FN4	X-RAY DIFFRACTION	1.65
7S0Z	X-RAY DIFFRACTION	2.34

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10301-F1	86.79	0.69

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): 36–44; 83–87; 142–145; 172–174

Post-translational modifications (2): 215, 215

Mutagenesis-validated functional residues (2):

Position	Phenotype
38	no effect on interaction with osbpl3.
43	no effect on interaction with osbpl3.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-399955	SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion
R-HSA-416550	Sema4D mediated inhibition of cell attachment and migration
R-HSA-1266738	Developmental Biology
R-HSA-373755	Semaphorin interactions
R-HSA-400685	Sema4D in semaphorin signaling
R-HSA-422475	Axon guidance
R-HSA-9675108	Nervous system development

MSigDB gene sets: 492 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, RNGTGGGC_UNKNOWN, CREL_01, GOBP_REGULATION_OF_VASCULOGENESIS, GOBP_BODY_MORPHOGENESIS, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, PAX4_01, KEGG_MAPK_SIGNALING_PATHWAY, GOLDRATH_IMMUNE_MEMORY, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, KEGG_TIGHT_JUNCTION, GHO_ATF5_TARGETS_DN, AP2_Q3, GGAMTNNNNNTCCY_UNKNOWN, CHANDRAN_METASTASIS_DN

GO Biological Process (13): leukocyte differentiation (GO:0002521), Ras protein signal transduction (GO:0007265), positive regulation of endothelial cell migration (GO:0010595), Schwann cell migration (GO:0036135), positive regulation of angiogenesis (GO:0045766), regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051896), face morphogenesis (GO:0060325), regulation of ERK1 and ERK2 cascade (GO:0070372), negative regulation of Schwann cell migration (GO:1900148), positive regulation of endothelial cell-matrix adhesion (GO:1904906), positive regulation of vasculogenesis (GO:2001214), signal transduction (GO:0007165), cell migration (GO:0016477)

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 (4): plasma membrane (GO:0005886), focal adhesion (GO:0005925), extracellular exosome (GO:0070062), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Semaphorin interactions	2
Sema4D in semaphorin signaling	1
Axon guidance	1
Nervous system development	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
guanyl ribonucleotide binding	2
binding	2
hemopoiesis	1
cell differentiation	1
small GTPase-mediated signal transduction	1
regulation of endothelial cell migration	1
positive regulation of cell migration	1
endothelial cell migration	1
glial cell migration	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of intracellular signal transduction	1
anatomical structure morphogenesis	1
head morphogenesis	1
face development	1
regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
Schwann cell migration	1
regulation of Schwann cell migration	1
negative regulation of glial cell migration	1
positive regulation of cell-matrix adhesion	1
endothelial cell-matrix adhesion	1
regulation of endothelial cell-matrix adhesion	1
vasculogenesis	1
positive regulation of cell differentiation	1
regulation of vasculogenesis	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

Protein interactions and networks

STRING

3186 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RRAS	RALGDS	Q12967	986
RRAS	PLXNB1	O43157	927
RRAS	OSBPL3	Q9H4L5	922
RRAS	RND1	Q92730	885
RRAS	BCL2	P10415	875
RRAS	SEMA4D	Q92854	850
RRAS	RASA1	P20936	787
RRAS	RAF1	P04049	730
RRAS	AKT1	P31749	726
RRAS	LRPAP1	P30533	713
RRAS	TSKS	Q9UJT2	701
RRAS	BCL2L12	Q9HB09	698
RRAS	RALBP1	Q15311	691
RRAS	RASIP1	Q5U651	652
RRAS	PLXNB2	O15031	651

IntAct

73 interactions, top by confidence:

A	B	Type	Score
RIN1	NRAS	psi-mi:“MI:0914”(association)	0.840
RIN1	ABL1	psi-mi:“MI:0914”(association)	0.790
RRAS	RAP1GDS1	psi-mi:“MI:0915”(physical association)	0.560
SLC25A41	NUDT19	psi-mi:“MI:0914”(association)	0.530
BZW2	SLC27A2	psi-mi:“MI:0914”(association)	0.530
CCNL2	ZBTB43	psi-mi:“MI:0914”(association)	0.530
TMEM185A	TSPAN6	psi-mi:“MI:0914”(association)	0.530
IL36RN	UBB	psi-mi:“MI:0914”(association)	0.530
CD53	FAM171A2	psi-mi:“MI:0914”(association)	0.530
CRK	RRAS	psi-mi:“MI:0915”(physical association)	0.400
RRAS	SRC	psi-mi:“MI:0915”(physical association)	0.400
RRAS	FYN	psi-mi:“MI:0915”(physical association)	0.400
GRB2	RRAS	psi-mi:“MI:0915”(physical association)	0.400
RRAS	NCK1	psi-mi:“MI:0915”(physical association)	0.400
RRAS	PIK3R1	psi-mi:“MI:0915”(physical association)	0.400
PLCG1	RRAS	psi-mi:“MI:0915”(physical association)	0.400
RRAS	ACY3	psi-mi:“MI:0915”(physical association)	0.370
RRAS	Rassf5	psi-mi:“MI:0915”(physical association)	0.370
HMGXB4	TBCA	psi-mi:“MI:0914”(association)	0.350
Flnb	RPL22	psi-mi:“MI:0914”(association)	0.350
Ccdc77	TBC1D31	psi-mi:“MI:0914”(association)	0.350
LIMK1	SH3PXD2B	psi-mi:“MI:0914”(association)	0.350
Sesn2	CASTOR2	psi-mi:“MI:0914”(association)	0.350
Ufl1	PRSS1	psi-mi:“MI:0914”(association)	0.350
Max	PABPN1	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (83): RRAS (Affinity Capture-MS), RRAS (Affinity Capture-MS), RRAS (Affinity Capture-MS), RRAS (Affinity Capture-MS), RRAS (Affinity Capture-MS), RRAS (Affinity Capture-MS), RRAS (Affinity Capture-MS), RRAS (Affinity Capture-MS), RRAS (Affinity Capture-MS), RRAS (Affinity Capture-MS), RRAS (Affinity Capture-MS), RRAS (Affinity Capture-MS), RRAS (Affinity Capture-MS), RRAS (Affinity Capture-MS), RRAS (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: A5A6J7, A8NU18, B3M185, B3NZR4, B4GFJ8, B4HKC7, B4JFU8, B4KB60, B4LY29, B4NJ72, B4PUP5, C4YKT4, D3Z8L7, G4MZY8, O08989, O14807, O42277, O42785, O93856, P01111, P01112, P01113, P01114, P01115, P01116, P01117, P01119, P01120, P03967, P04388, P05774, P08556, P08642, P08644, P08645, P08646, P08647, P0CQ42, P0CQ43, P0CY32

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
SRC	“down-regulates activity”	RRAS	phosphorylation
EPHB2	“down-regulates activity”	RRAS	phosphorylation
ERK1/2	“up-regulates activity”	RRAS	phosphorylation
OSBPL3	“down-regulates activity”	RRAS	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 90 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
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	6	54.6×	2e-07
Regulation of signaling by CBL	6	52.3×	2e-07
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	5	50.1×	4e-06
Downstream signal transduction	7	46.8×	7e-08
Signaling by CSF1 (M-CSF) in myeloid cells	6	36.4×	2e-06
DAP12 signaling	5	32.3×	3e-05
FCGR3A-mediated phagocytosis	8	26.3×	2e-07
Signaling by SCF-KIT	6	26.1×	9e-06

GO biological processes:

GO term	Partners	Fold	FDR
Fc-gamma receptor signaling pathway involved in phagocytosis	5	47.4×	3e-05
ephrin receptor signaling pathway	6	27.9×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	186
Likely benign	129
Benign	11

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
521665	NM_006270.5(RRAS):c.107GCG[5] (p.Gly39dup)	Likely pathogenic

SpliceAI

614 predictions. Top by Δscore:

Variant	Effect	Δscore
19:49635757:AAAAG:A	donor_gain	1.0000
19:49635849:GGAC:G	acceptor_gain	1.0000
19:49635853:C:CA	acceptor_loss	1.0000
19:49635853:C:CC	acceptor_gain	1.0000
19:49636387:T:TA	donor_gain	1.0000
19:49636613:CCGAA:C	donor_loss	1.0000
19:49636614:CGAA:C	donor_loss	1.0000
19:49636615:GAAC:G	donor_loss	1.0000
19:49636616:AAC:A	donor_loss	1.0000
19:49636617:A:C	donor_loss	1.0000
19:49636618:C:CA	donor_loss	1.0000
19:49636723:TGAAA:T	acceptor_gain	1.0000
19:49636725:AAA:A	acceptor_gain	1.0000
19:49636726:AA:A	acceptor_gain	1.0000
19:49636726:AACT:A	acceptor_loss	1.0000
19:49636728:C:CC	acceptor_gain	1.0000
19:49636820:TCAC:T	donor_loss	1.0000
19:49636822:A:T	donor_loss	1.0000
19:49636825:T:TA	donor_gain	1.0000
19:49636922:CAGGA:C	acceptor_gain	1.0000
19:49636923:AGGA:A	acceptor_gain	1.0000
19:49636924:GGA:G	acceptor_gain	1.0000
19:49636924:GGAC:G	acceptor_loss	1.0000
19:49636925:GA:G	acceptor_gain	1.0000
19:49636927:C:CC	acceptor_gain	1.0000
19:49636927:C:T	acceptor_loss	1.0000
19:49636936:C:CT	acceptor_gain	1.0000
19:49637023:T:TA	donor_gain	1.0000
19:49637027:T:TA	donor_gain	1.0000
19:49637036:C:A	donor_gain	1.0000

AlphaMissense

1407 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:49635788:G:T	A173D	1.000
19:49636643:C:A	K143N	1.000
19:49636643:C:G	K143N	1.000
19:49636645:T:C	K143E	1.000
19:49636646:G:C	N142K	1.000
19:49636646:G:T	N142K	1.000
19:49636856:G:C	F104L	1.000
19:49636856:G:T	F104L	1.000
19:49636858:A:G	F104L	1.000
19:49636860:C:T	G103D	1.000
19:49636898:G:C	F90L	1.000
19:49636898:G:T	F90L	1.000
19:49636900:A:G	F90L	1.000
19:49636911:C:T	G86D	1.000
19:49636912:C:G	G86R	1.000
19:49636917:G:A	T84I	1.000
19:49636919:G:C	D83E	1.000
19:49636919:G:T	D83E	1.000
19:49636920:T:A	D83V	1.000
19:49636920:T:C	D83G	1.000
19:49636920:T:G	D83A	1.000
19:49636921:C:A	D83Y	1.000
19:49636921:C:G	D83H	1.000
19:49636921:C:T	D83N	1.000
19:49636923:A:G	L82P	1.000
19:49636926:A:T	I81N	1.000
19:49637093:T:G	D64A	1.000
19:49637094:C:G	D64H	1.000
19:49637099:A:T	I62N	1.000
19:49637108:T:C	D59G	1.000

dbSNP variants (sampled 300 via entrez): RS1000205836 (19:49637785 C>T), RS1001974225 (19:49635937 T>C), RS1002145706 (19:49641908 C>T), RS1002712238 (19:49640737 G>A,T), RS1002735963 (19:49640495 C>T), RS1002818648 (19:49635174 A>G), RS1002969158 (19:49634943 C>T), RS1003119006 (19:49640651 G>A), RS1003320524 (19:49639348 C>A), RS1003558210 (19:49640438 G>C), RS1003700331 (19:49639657 G>C), RS1004296821 (19:49638206 C>A,G,T), RS1006976014 (19:49641343 T>A), RS1007125344 (19:49635393 G>A), RS1007465332 (19:49639748 G>A)

Disease associations

OMIM: gene MIM:165090 | disease phenotypes: MIM:163950

GenCC curated gene-disease

Disease	Classification	Inheritance
Noonan syndrome and Noonan-related syndrome	Strong	Autosomal dominant
Noonan syndrome	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Noonan syndrome	Limited	AD

Mondo (2): Noonan syndrome (MONDO:0018997), Noonan syndrome and Noonan-related syndrome (MONDO:0020297)

Orphanet (1): Noonan syndrome (Orphanet:648)

HPO phenotypes

70 total (30 of 70 shown, HPO-id order):

HPO	Term
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:0000635	Blue irides
HP:0000639	Nystagmus
HP:0000767	Pectus excavatum
HP:0000768	Pectus carinatum
HP:0000938	Osteopenia
HP:0000978	Bruising susceptibility
HP:0000995	Melanocytic nevus
HP:0001004	Lymphedema
HP:0001156	Brachydactyly
HP:0001249	Intellectual disability
HP:0001252	Hypotonia

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002539_91	Schizophrenia	5.000000e-08
GCST006021_2	Systolic blood pressure	8.000000e-08
GCST006022_15	Pulse pressure	3.000000e-07
GCST006803_99	Schizophrenia	4.000000e-11
GCST008058_300	Estimated glomerular filtration rate	3.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0005763	pulse pressure measurement

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
C537846	Noonan like syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	3
Valproic Acid	affects expression, increases expression, increases methylation	3
bisphenol F	increases expression, affects cotreatment	2
bisphenol A	affects cotreatment, increases expression	2
sodium arsenite	decreases expression, increases expression	2
cobaltous chloride	decreases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, increases expression	2
Copper	affects binding, increases expression	2
Estradiol	affects cotreatment, increases expression, decreases expression	2
Smoke	decreases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Aflatoxin B1	increases expression	2
aristolochic acid I	decreases expression	1
alpha phellandrene	increases expression	1
titanium dioxide	affects binding, increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
ochratoxin A	affects binding	1
potassium chromate(VI)	decreases expression	1
ochratoxin B	affects binding	1
di-n-butylphosphoric acid	affects expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	increases expression	1
NSC 689534	increases expression	1
(+)-JQ1 compound	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1616	OC 314	Cancer cell line	Female
CVCL_1618	OC 316	Cancer cell line	Female
CVCL_B2E8	Abcam HeLa RRAS KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00452725	PHASE3	COMPLETED	Effect of MAXOMAT ® on the Growth of Small Children to NOONAN’s Syndrome
NCT01529840	PHASE3	COMPLETED	Somatropin Effect on Linear Growth and Final Height in Subjects With Noonan Syndrome
NCT01529944	PHASE3	COMPLETED	Genetic Testing of Noonan Subjects Previously Treated With Norditropin®. An Extension to Trial GHNOO-1658
NCT01927861	PHASE3	COMPLETED	Investigating the Long-term Efficacy and Safety of Two Doses of NN-220 (Somatropin) in Short Stature Due to Noonan Syndrome
NCT02713945	PHASE3	COMPLETED	Treatment With HMG-COA Reductase Inhibitor of Growth and Bone Abnormalities in Children With Noonan Syndrome
NCT05723835	PHASE3	ACTIVE_NOT_RECRUITING	A Research Study Looking at How Safe Somapacitan is and How Well it Works in Children Who Need Help to Grow - REAL 9
NCT00351221	PHASE2	TERMINATED	Research Study Using Recombinant Human Insulin-Like Growth Factor-1/Recombinant Human Insulin-Like Growth Factor Binding Protein-3 for Children With Noonan Syndrome
NCT06555237	PHASE2	RECRUITING	MEK Inhibitors for the Treatment of Hypertrophic Cardiomyopathy in Patients With RASopathies
NCT06668805	PHASE2	RECRUITING	A Study of Vosoritide in Children With Noonan Syndrome With Inadequate Growth During or After Human Growth Hormone Treatment
NCT00960128	Not specified	COMPLETED	Observational Prospective Study on Patients Treated With Norditropin®
NCT02486731	Not specified	COMPLETED	Hormonal Sensitivity in Patients With Noonan and LEOPARD Syndromes
NCT03435627	Not specified	COMPLETED	Post Marketing Surveillance on Long-term Use With Norditropin® (Short Stature Due to Noonan Syndrome)
NCT04395495	Not specified	RECRUITING	RASopathy Biorepository
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT04888936	Not specified	RECRUITING	Clinical, Genetic, and Epidemiologic Study of Children and Adults With RASopathies
NCT05202210	Not specified	RECRUITING	Constitution of a Biological Collection to Study the Pathophysiology in Noonan Syndrome
NCT05308927	Not specified	ENROLLING_BY_INVITATION	French Registry of Children Treated With Norditropin® for Short Stature Associated With Noonan Syndrome
NCT05361811	Not specified	RECRUITING	Acceptance and Commitment Therapy for Caregivers of Children With a RASopathy: An Internal Pilot Feasibility Study and Follow-up Randomized Controlled Trial
NCT05761314	Not specified	RECRUITING	Solid Tumors in RASopathies
NCT06267807	Not specified	COMPLETED	Lymphatic Phenotype in Noonan Syndrome Spectrum Disorders
NCT06331117	Not specified	UNKNOWN	Effect of RAS/MAPK Pathway Hyperactivation on Growth’ and Bone’ Profile of the RASopathies
NCT06355622	Not specified	UNKNOWN	Prevalence and Characterization of Pain in RASopathies
NCT06550635	Not specified	COMPLETED	Joint and Hematologic Disorders of Noonan Syndrome: French Descriptive Cross-sectional Study
NCT06938542	Not specified	ENROLLING_BY_INVITATION	Palliative Care Needs of Children With Rare Diseases and Their Families
NCT07259135	Not specified	NOT_YET_RECRUITING	Link Between Abnormal Bleeding and Coagulation Disorders in Noonan Syndromes
NCT07336394	Not specified	RECRUITING	Precision Diagnosis and Risk Stratification of Rare Cardiomyopathies Based on Novel Cardiac Magnetic Resonance Techniques
NCT07464821	Not specified	RECRUITING	National Multicentre Study on Lipid Profile in Noonan Syndrome and Related Disorders: Trends by Age, Gender and Genotype