RRAGA

Summary

RRAGA (Ras related GTP binding A, HGNC:16963) is a protein-coding gene on chromosome 9p22.1, encoding Ras-related GTP-binding protein A (Q7L523). Guanine nucleotide-binding protein that plays a crucial role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade. It is a selective cancer dependency (DepMap: 27.9% of cell lines).

Enables several functions, including GTP binding activity; protein dimerization activity; and ubiquitin protein ligase binding activity. Involved in several processes, including cellular response to amino acid starvation; positive regulation of TORC1 signaling; and tumor necrosis factor-mediated signaling pathway. Located in GATOR1 complex; lysosome; and nucleoplasm. Part of FNIP-folliculin RagC/D GAP. Is active in lysosomal membrane.

Source: NCBI Gene 10670 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cataract (Strong, GenCC)
• Clinical variants (ClinVar): 30 total
• Cancer dependency (DepMap): dependent in 27.9% of screened cell lines
• MANE Select transcript: NM_006570

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16963
Approved symbol	RRAGA
Name	Ras related GTP binding A
Location	9p22.1
Locus type	gene with protein product
Status	Approved
Aliases	RAGA, FIP-1
Ensembl gene	ENSG00000155876
Ensembl biotype	protein_coding
OMIM	612194
Entrez	10670

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000380527

RefSeq mRNA: 1 — MANE Select: NM_006570 NM_006570

CCDS: CCDS6488

Canonical transcript exons

ENST00000380527 — 1 exons

Exon	Start	End
ENSE00001485334	19049427	19051025

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 98.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 82.1047 / max 325.6449, expressed in 1825 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
96240	81.9496	1825
205442	0.1551	43

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
paraflocculus	UBERON:0005351	98.12	gold quality
frontal pole	UBERON:0002795	98.09	gold quality
Brodmann (1909) area 10	UBERON:0013541	97.75	gold quality
prefrontal cortex	UBERON:0000451	97.61	gold quality
middle frontal gyrus	UBERON:0002702	97.59	gold quality
cerebellar vermis	UBERON:0004720	97.57	gold quality
islet of Langerhans	UBERON:0000006	97.47	gold quality
smooth muscle tissue	UBERON:0001135	97.38	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.28	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.26	gold quality
biceps brachii	UBERON:0001507	97.17	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.17	gold quality
descending thoracic aorta	UBERON:0002345	97.15	gold quality
Brodmann (1909) area 46	UBERON:0006483	97.15	gold quality
adult organism	UBERON:0007023	97.11	gold quality
cortical plate	UBERON:0005343	97.06	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.06	gold quality
frontal cortex	UBERON:0001870	97.05	gold quality
middle temporal gyrus	UBERON:0002771	97.02	gold quality
hypothalamus	UBERON:0001898	96.97	gold quality
left uterine tube	UBERON:0001303	96.93	gold quality
stromal cell of endometrium	CL:0002255	96.89	gold quality
bronchial epithelial cell	CL:0002328	96.86	gold quality
postcentral gyrus	UBERON:0002581	96.85	gold quality
quadriceps femoris	UBERON:0001377	96.83	gold quality
neocortex	UBERON:0001950	96.83	gold quality
vastus lateralis	UBERON:0001379	96.77	gold quality
thoracic aorta	UBERON:0001515	96.74	gold quality
myocardium	UBERON:0002349	96.73	gold quality
gastrocnemius	UBERON:0001388	96.71	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-100618	no	265.24
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

45 targeting RRAGA, 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-3163	100.00	77.23	8605
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-802	99.61	67.70	1254
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-122B-5P	99.46	70.81	1457
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-664A-3P	99.22	71.08	2696

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 27.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 20)

• A mechanism for regulation of mTORC1 signaling by RNF152-mediated K63-linked polyubiquitination of RagA. (PMID:25936802)
• Data suugest that S-phase kinase-associated protein 2 (Skp2)-mediated Ras-related GTP-binding protein RagA ubiquitination recruits GATOR1 to restrict mTORC1 signaling upon sustained amino acid stimulation. (PMID:26051179)
• Data suggest that both microtubule-associated DYNLT (dynein light chain Tctex-type 1) and cytoplasmic DYNLT (dynein 1 intermediate chain 2 DYNC1LI2) are equally able to bind to small GTPases Rab3D (Rab3d GTPase) and RagA (Ras-related GTP binding A). (PMID:26227614)
• The data indicate that the RRAGA mutations, associated with autosomal dominant cataracts, play a role in the disease by acting through disruption of mTORC1 signaling. (PMID:27294265)
• NUDT2 is a novel complex formation enhancing factor regulating mTORC1-Rag GTPase signaling that is crucial for cell growth control. (PMID:28089905)
• The dynamic response of mTORC1 requires intersubunit communication by the Rag GTPases, providing a rationale for why they exist as a dimer and revealing a distinct mode of control for a GTP-binding protein. (PMID:29056322)
• Full-length RagA(GTP):RagC(GDP) dimer binds to regulator to activate mTORC1. (PMID:29107538)
• cryo-electron microscopy to solve structures of GATOR1 and GATOR1-RagA GTPase complexes; GATOR1 adopts an extended architecture with a cavity in the middle; NPRL2 links DEPDC5 and NPRL3, and DEPDC5 contacts the RagA GTPase heterodimer (PMID:29590090)
• Over-expression of WDR35 results in decreased phosphorylation of ribosome S6 protein in a RagA-, RagB- and RagC-dependent manner. Thus, WDR35 is associated with RagA, RagB and RagC and might negatively influence mTORC1 activity. (PMID:30570184)
• Arg-78 of Nprl2 catalyzes GATOR1-stimulated GTP hydrolysis by the Rag GTPases (PMID:30651352)
• PR137B-knockout cells exhibited defective autophagy and an expanded lysosome compartment, similar to Rag-knockout cells. Like zebrafish RagA mutants, GPR137B-mutant zebrafish had upregulated TFEB target gene expression and an expanded lysosome compartment in microglia. (PMID:31036939)
• The Raptor alpha-solenoid directly detects the nucleotide state of RagA while the Raptor “claw” threads between the GTPase domains to detect that of RagC. Mutations that disrupted Rag-Raptor binding inhibited mTORC1 lysosomal localization and signaling. (PMID:31601708)
• cryo-electron microscopy structure of RagA/RagC in complex with mTORC1 shows the details of RagA/RagC binding to the RAPTOR subunit of mTORC1 and explains why only the RagAGTP/RagCGDP nucleotide state binds mTORC1 (PMID:31601764)
• C9orf72 associates with inactive Rag GTPases and regulates mTORC1-mediated autophagosomal and lysosomal biogenesis. (PMID:32100453)
• Structural mechanism for amino acid-dependent Rag GTPase nucleotide state switching by SLC38A9. (PMID:32868926)
• The Rag GTPase Regulates the Dynamic Behavior of TSC Downstream of Both Amino Acid and Growth Factor Restriction. (PMID:32898476)
• Mitochondrial Threonyl-tRNA Synthetase TARS2 Is Required for Threonine-Sensitive mTORC1 Activation. (PMID:33340489)
• An interdomain hydrogen bond in the Rag GTPases maintains stable mTORC1 signaling in sensing amino acids. (PMID:34116056)
• Structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex. (PMID:36697823)
• RAGA prevents tumor immune evasion of LUAD by promoting CD47 lysosome degradation. (PMID:36823443)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rraga	ENSDARG00000104149
mus_musculus	Rraga	ENSMUSG00000070934
rattus_norvegicus	Rraga	ENSRNOG00000007051
drosophila_melanogaster	RagA-B	FBGN0037647
caenorhabditis_elegans		WBGENE00006414

Paralogs (3): RRAGD (ENSG00000025039), RRAGB (ENSG00000083750), RRAGC (ENSG00000116954)

Protein

Protein identifiers

Ras-related GTP-binding protein A — Q7L523 (reviewed: Q7L523)

Alternative names: Adenovirus E3 14.7 kDa-interacting protein 1, FIP-1

All UniProt accessions (1): Q7L523

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide-binding protein that plays a crucial role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade. Forms heterodimeric Rag complexes with RagC/RRAGC or RagD/RRAGD and cycles between an inactive GDP-bound and an active GTP-bound form: RagA/RRAGA is in its active form when GTP-bound RagA/RRAGA forms a complex with GDP-bound RagC/RRAGC (or RagD/RRAGD) and in an inactive form when GDP-bound RagA/RRAGA heterodimerizes with GTP-bound RagC/RRAGC (or RagD/RRAGD). In its GTP-bound active form, promotes the recruitment of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB. Involved in the RCC1/Ran-GTPase pathway. May play a direct role in a TNF signaling pathway leading to induction of cell death. (Microbial infection) May alternatively act as a cellular target for adenovirus E3-14.7K, an inhibitor of TNF functions, thereby affecting cell death.

Subunit / interactions. Can occur as a homodimer or as a heterodimer with RRAGC or RRAGD in a sequence-independent manner; heterodimerization stabilizes proteins of the heterodimer. The GTP-bound form of RRAGA (in complex with the GDP-bound form of RRAGC or RRAGD) interacts with RPTOR, thereby promoting recruitment of mTORC1 to the lysosomes. The Rag heterodimer interacts with SLC38A9; the probable amino acid sensor. The Rag heterodimer interacts with the Ragulator complex. The GTP-bound form of RRAGA interacts with NOL8. Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RagA/RRAGA or RagB/RRAGB GDP-bound, RagC/RRAGC or RagD/RRAGD GTP-bound, and Ragulator. Interacts with MiT/TFE factors MITF, TFEB and TFE3; promoting their localization to lysosomal membranes. Interacts with SH3BP4; the interaction with this negative regulator is most probably direct, preferentially occurs with the inactive GDP-bound form of RRAGA and is negatively regulated by amino acids. Interacts (polyubiquitinated) with TSC2. Interacts with SESN1, SESN2 and SESN3. Interacts with PIP4P1. Interacts with GPR137B. Interacts with WDR83; this interaction regulates the spatiotemporal localization of mTORC1 to the lysosomal surface. (Microbial infection) Interacts with adenovirus E3 14.7 kDa protein.

Subcellular location. Cytoplasm. Nucleus. Lysosome membrane.

Tissue specificity. Ubiquitously expressed with highest levels of expression in skeletal muscle, heart, and brain.

Post-translational modifications. Polybiquitinated via ‘Lys-63’-linked polyubiquitination by RNF152 in response to amino acid starvation: polyubiquitination of the GDP-bound inactive form by RNF152 promotes RRAGA inactivation and interaction with the GATOR1 complex. This does not affect RRAGA degradation.

Activity regulation. The activation of GTP-binding proteins is generally mediated by a guanine exchange factor (GEF), while inactivation through hydrolysis of bound GTP is catalyzed by a GTPase activating protein (GAP). The Ragulator complex functions as a GEF and promotes the active GTP-bound form. The GATOR1 complex functions as a GAP and stimulates RRAGA GTPase activity to turn it into its inactive GDP-bound form, preventing mTORC1 recruitment and activation.

Similarity. Belongs to the GTR/RAG GTP-binding protein family.

RefSeq proteins (1): NP_006561* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006762	Gtr1_RagA	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR039397	RagA/B	Family

Pfam: PF04670

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (81 total): binding site 23, mutagenesis site 19, strand 15, helix 12, cross-link 4, turn 4, sequence conflict 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
5X6V	X-RAY DIFFRACTION	2.02
6S6D	X-RAY DIFFRACTION	2.5
6S6A	X-RAY DIFFRACTION	2.63
6EHR	X-RAY DIFFRACTION	2.9
7UX2	ELECTRON MICROSCOPY	2.9
6U62	ELECTRON MICROSCOPY	3.18
6WJ2	ELECTRON MICROSCOPY	3.2
7UXC	ELECTRON MICROSCOPY	3.2
7UXH	ELECTRON MICROSCOPY	3.2
9ED4	ELECTRON MICROSCOPY	3.23
6ULG	ELECTRON MICROSCOPY	3.31
8DHB	ELECTRON MICROSCOPY	3.53
6NZD	ELECTRON MICROSCOPY	3.6
6WJ3	ELECTRON MICROSCOPY	3.9
7T3B	ELECTRON MICROSCOPY	3.9
9ED6	ELECTRON MICROSCOPY	3.98
6CES	ELECTRON MICROSCOPY	4
7T3A	ELECTRON MICROSCOPY	4
7T3C	ELECTRON MICROSCOPY	4
6SB0	ELECTRON MICROSCOPY	5.5
6SB2	ELECTRON MICROSCOPY	6.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7L523-F1	92.60	0.89

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 (23): 16; 21; 22; 22; 36; 36; 42; 42; 65; 127; 127; 17 …

Post-translational modifications (5): 309, 142, 220, 230, 244

Mutagenesis-validated functional residues (19):

Position	Phenotype
21	reduced affinity for all nucleotides, but with preferential binding of gdp over gtp.
29	in ra3 mutant; abolished interaction with rptor without affecting gtp-binding; when associated with y-35 and a-46.
31	in ra1 mutant; abolished interaction with rptor without affecting gtp-binding. does not affect interaction with tfe3 and
35	in ra2 mutant; abolished interaction with rptor without affecting gtp-binding; when associated with a-46. does not affec
35	in ra3 mutant; abolished interaction with rptor without affecting gtp-binding; when associated with f-29 and a-46.
46	in ra2 mutant; abolished interaction with rptor without affecting gtp-binding; when associated with a-35. in ra3 mutant;
66	maintains gtp-bound state, leading to activate mtorc1.
71	abolished interaction with tfe3 and tfeb without affecting interaction with rptor.
100	abolished interaction with tfe3 and tfeb without affecting interaction with rptor.
104	abolished interaction with tfe3 and tfeb without affecting interaction with rptor.
107	abolished interaction with tfe3 and tfeb without affecting interaction with rptor.
111	abolished interaction with tfe3 and tfeb without affecting interaction with rptor.
142	prevents rraga ubiquitination and alters interaction and regulation by gator1; when associated with r-220, r-230 and r-2
151	abolished interaction with tfe3 and tfeb without affecting interaction with rptor.
153	abolished interaction with tfe3 and tfeb without affecting interaction with rptor.
154	abolished interaction with tfe3 and tfeb without affecting interaction with rptor.
220	prevents rraga ubiquitination and alters interaction and regulation by gator1; when associated with r-142, r-230 and r-2
230	prevents rraga ubiquitination and alters interaction and regulation by gator1; when associated with rr-142, r-220 and r-
244	prevents rraga ubiquitination and alters interaction and regulation by gator1; when associated with rr-142, r-220 and r-

Function

Pathways and Gene Ontology

Reactome pathways

23 pathways

ID	Pathway
R-HSA-1632852	Macroautophagy
R-HSA-165159	MTOR signalling
R-HSA-166208	mTORC1-mediated signalling
R-HSA-380972	Energy dependent regulation of mTOR by LKB1-AMPK
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-8866654	E3 ubiquitin ligases ubiquitinate target proteins
R-HSA-8943724	Regulation of PTEN gene transcription
R-HSA-9639288	Amino acids regulate mTORC1
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-162582	Signal Transduction
R-HSA-212436	Generic Transcription Pathway
R-HSA-2262752	Cellular responses to stress
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-6807070	PTEN Regulation
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8852135	Protein ubiquitination
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9006925	Intracellular signaling by second messengers
R-HSA-9612973	Autophagy
R-HSA-9711097	Cellular response to starvation

MSigDB gene sets: 212 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_RESPONSE_TO_ACID_CHEMICAL, KAAB_FAILED_HEART_ATRIUM_DN, GOBP_RESPONSE_TO_PEPTIDE, GOCC_VACUOLAR_MEMBRANE, GOBP_POSITIVE_REGULATION_OF_TOR_SIGNALING, GOBP_CELLULAR_RESPONSE_TO_ACID_CHEMICAL, GOBP_PROTEIN_LOCALIZATION_TO_LYSOSOME, EVI1_05, PID_MTOR_4PATHWAY, GOBP_NEGATIVE_REGULATION_OF_AUTOPHAGY, SMITH_TERT_TARGETS_DN, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_PROTEIN_LOCALIZATION_TO_VACUOLE

GO Biological Process (20): apoptotic process (GO:0006915), intracellular protein localization (GO:0008104), cellular response to starvation (GO:0009267), negative regulation of autophagy (GO:0010507), cellular response to nutrient levels (GO:0031669), positive regulation of TOR signaling (GO:0032008), tumor necrosis factor-mediated signaling pathway (GO:0033209), cellular response to amino acid starvation (GO:0034198), intracellular signal transduction (GO:0035556), glucose homeostasis (GO:0042593), protein localization to lysosome (GO:0061462), cellular response to amino acid stimulus (GO:0071230), protein localization to membrane (GO:0072657), positive regulation of TORC1 signaling (GO:1904263), autophagosome assembly (GO:0000045), cytoplasmic translation (GO:0002181), TORC1 signaling (GO:0038202), negative regulation of translational initiation (GO:0045947), positive regulation of translational initiation (GO:0045948), cellular response to methionine (GO:0061431)

GO Molecular Function (10): GTPase activity (GO:0003924), GTP binding (GO:0005525), ubiquitin protein ligase binding (GO:0031625), protein homodimerization activity (GO:0042803), protein-membrane adaptor activity (GO:0043495), protein heterodimerization activity (GO:0046982), phosphoprotein binding (GO:0051219), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (10): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), lysosome (GO:0005764), lysosomal membrane (GO:0005765), cytosol (GO:0005829), Gtr1-Gtr2 GTPase complex (GO:1990131), FNIP-folliculin RagC/D GAP (GO:1990877), membrane (GO:0016020), GATOR1 complex (GO:1990130)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
MTOR signalling	2
Autophagy	1
Signal Transduction	1
Transcriptional Regulation by TP53	1
Protein ubiquitination	1
PTEN Regulation	1
Cellular response to starvation	1
Intracellular signaling by second messengers	1
RNA Polymerase II Transcription	1
Cellular responses to stimuli	1
Generic Transcription Pathway	1
Metabolism of proteins	1
PIP3 activates AKT signaling	1
Gene expression (Transcription)	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
TOR signaling	2
intracellular anatomical structure	2
translational initiation	2
regulation of translational initiation	2
protein dimerization activity	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
macromolecule localization	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
autophagy	1
negative regulation of catabolic process	1
regulation of autophagy	1
response to nutrient levels	1
cellular response to stimulus	1
regulation of TOR signaling	1
positive regulation of intracellular signal transduction	1
cytokine-mediated signaling pathway	1
cellular response to tumor necrosis factor	1
cellular response to starvation	1
response to amino acid starvation	1
signal transduction	1
carbohydrate homeostasis	1
protein localization to vacuole	1
response to amino acid	1
cellular response to acid chemical	1
intracellular protein localization	1
localization within membrane	1
positive regulation of TOR signaling	1
TORC1 signaling	1
regulation of TORC1 signaling	1
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1

Protein interactions and networks

STRING

977 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RRAGA	RPTOR	Q8N122	995
RRAGA	RRAGD	Q9NQL2	992
RRAGA	RRAGC	Q9HB90	992
RRAGA	RHEB	Q15382	939
RRAGA	RRAGB	Q5VZM2	884
RRAGA	MTOR	P42345	869
RRAGA	SLC38A9	Q8NBW4	836
RRAGA	LAMTOR1	Q6IAA8	827
RRAGA	MLST8	Q9BVC4	801
RRAGA	LAMTOR4	Q0VGL1	794
RRAGA	NPRL2	Q8WTW4	776
RRAGA	FLCN	Q8NFG4	772
RRAGA	RPS6KB1	P23443	771
RRAGA	LAMTOR3	Q9UHA4	769
RRAGA	TMEM11	P17152	764

IntAct

106 interactions, top by confidence:

A	B	Type	Score
LAMTOR5	LAMTOR4	psi-mi:“MI:0914”(association)	0.960
LAMTOR4	LAMTOR5	psi-mi:“MI:0914”(association)	0.960
RRAGC	RRAGA	psi-mi:“MI:0914”(association)	0.950
RRAGC	RRAGA	psi-mi:“MI:2364”(proximity)	0.950
RRAGA	RRAGC	psi-mi:“MI:2364”(proximity)	0.950
RRAGC	RRAGA	psi-mi:“MI:0915”(physical association)	0.950
RRAGA	RRAGC	psi-mi:“MI:0915”(physical association)	0.950

BioGRID (172): RRAGA (Affinity Capture-Western), RRAGA (Affinity Capture-Western), RRAGA (Affinity Capture-Western), TSC2 (Affinity Capture-Western), TSC1 (Affinity Capture-Western), RRAGD (Affinity Capture-MS), RRAGC (Affinity Capture-MS), NPC2 (Affinity Capture-MS), CTU2 (Affinity Capture-MS), PPP1R1A (Affinity Capture-MS), RPTOR (Affinity Capture-MS), SLC38A9 (Affinity Capture-MS), RRAGC (Two-hybrid), RRAGC (Affinity Capture-Western), RRAGA (Affinity Capture-Western)

ESM2 similar proteins: A2AGL3, A4FUD6, A4IHM6, B0LPN4, E9PZQ0, O35626, O94844, P16960, P51157, P51158, Q12829, Q15413, Q32LJ6, Q32NS2, Q3SWY9, Q3SX43, Q4R4K5, Q5E9J4, Q5F361, Q5FVD6, Q5FVJ7, Q5HYI8, Q5M8K8, Q5R8I6, Q5RCC1, Q5RFI2, Q5XGS8, Q5ZKR4, Q63486, Q66JN8, Q6GPS4, Q6NRC7, Q6TNS7, Q7L523, Q7SXV1, Q7ZUV0, Q80X95, Q8BHL5, Q8K0F1, Q91V93

Diamond homologs: O74824, Q00582, Q3SX43, Q54IK1, Q5VZM2, Q63486, Q63487, Q6NTA4, Q7L523, Q80X95, Q9SF92, O74544, P53290, Q7TT45, Q99K70, Q9HB90, Q9NQL2

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
RRAGA	“form complex”	RAGAC	binding
RRAGA	“form complex”	RAGAD	binding
RNF152	“down-regulates activity”	RRAGA	polyubiquitination
GATOR1	“down-regulates activity”	RRAGA	“gtpase-activating protein”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 31 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
mTORC1-mediated signalling	9	158.6×	3e-17
Energy dependent regulation of mTOR by LKB1-AMPK	9	131.3×	2e-16
MTOR signalling	9	88.5×	9e-15
Amino acids regulate mTORC1	11	81.6×	1e-17
PTEN Regulation	9	76.1×	3e-14
Autophagy	12	65.9×	5e-18
Regulation of PTEN gene transcription	9	59.5×	3e-13
Macroautophagy	13	55.5×	2e-18

GO biological processes:

GO term	Partners	Fold	FDR
TORC1 signaling	5	133.8×	1e-08
positive regulation of TOR signaling	8	132.2×	5e-14
cellular response to amino acid stimulus	9	91.9×	5e-14
positive regulation of TORC1 signaling	9	88.7×	5e-14
intracellular protein localization	6	20.9×	2e-05
protein transport	5	7.3×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	21
Likely benign	2
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

152 predictions. Top by Δscore:

Variant	Effect	Δscore
9:19050235:G:GT	donor_gain	0.5800
9:19050377:C:G	donor_gain	0.5700
9:19050371:TTC:T	donor_gain	0.5200
9:19050313:GT:G	acceptor_gain	0.5100
9:19050420:T:G	donor_gain	0.5000
9:19050236:A:T	donor_gain	0.4800
9:19050263:G:GT	donor_gain	0.4800
9:19050416:G:GT	donor_gain	0.4800
9:19050424:G:GT	donor_gain	0.4700
9:19050387:G:GG	donor_gain	0.4600
9:19050386:A:AG	donor_gain	0.4500
9:19050285:C:G	donor_gain	0.4300
9:19050465:ATAC:A	donor_gain	0.4300
9:19050467:AC:A	donor_gain	0.4300
9:19050469:G:GG	donor_gain	0.4300
9:19050312:A:AG	acceptor_gain	0.4100
9:19050313:G:GG	acceptor_gain	0.4100
9:19050384:GCA:G	donor_gain	0.4100
9:19050391:A:G	donor_gain	0.3900
9:19050372:TC:T	donor_gain	0.3800
9:19050466:TAC:T	donor_gain	0.3800
9:19050257:GCCGA:G	donor_gain	0.3700
9:19050376:GC:G	donor_gain	0.3600
9:19050306:A:AG	acceptor_gain	0.3500
9:19050416:G:T	donor_gain	0.3500
9:19050481:G:GA	donor_gain	0.3500
9:19050587:C:A	donor_gain	0.3500
9:19050464:AATAC:A	donor_gain	0.3400
9:19050746:A:AG	acceptor_gain	0.3400
9:19050747:G:GG	acceptor_gain	0.3400

AlphaMissense

2099 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:19049691:T:A	L11Q	1.000
9:19049691:T:C	L11P	1.000
9:19049694:T:A	L12Q	1.000
9:19049694:T:C	L12P	1.000
9:19049699:G:A	G14R	1.000
9:19049699:G:C	G14R	1.000
9:19049699:G:T	G14W	1.000
9:19049700:G:A	G14E	1.000
9:19049700:G:C	G14A	1.000
9:19049700:G:T	G14V	1.000
9:19049709:G:A	G17E	1.000
9:19049714:G:A	G19R	1.000
9:19049714:G:C	G19R	1.000
9:19049714:G:T	G19W	1.000
9:19049715:G:A	G19E	1.000
9:19049715:G:C	G19A	1.000
9:19049715:G:T	G19V	1.000
9:19049717:A:C	K20Q	1.000
9:19049717:A:G	K20E	1.000
9:19049718:A:T	K20M	1.000
9:19049719:G:C	K20N	1.000
9:19049719:G:T	K20N	1.000
9:19049720:A:C	T21P	1.000
9:19049721:C:A	T21N	1.000
9:19049721:C:T	T21I	1.000
9:19049723:A:C	S22R	1.000
9:19049724:G:A	S22N	1.000
9:19049724:G:T	S22I	1.000
9:19049725:C:A	S22R	1.000
9:19049725:C:G	S22R	1.000

dbSNP variants (sampled 300 via entrez): RS1001019171 (9:19049467 C>G), RS1001410344 (9:19049302 T>G), RS1002087753 (9:19047734 C>G), RS1002199098 (9:19050252 T>C), RS1003521795 (9:19048590 T>C), RS1003628160 (9:19049175 G>A,C), RS1003765205 (9:19048842 T>C,G), RS1004827098 (9:19048771 A>G), RS1004988891 (9:19049428 T>C,G), RS1006433011 (9:19049435 C>A,G,T), RS1008524777 (9:19048252 T>C,G), RS1009077070 (9:19047987 A>C), RS1010903340 (9:19049197 C>G,T), RS1011216915 (9:19047608 A>T), RS1012527205 (9:19049731 G>A)

Disease associations

OMIM: gene MIM:612194 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
cataract	Strong	Autosomal dominant

Mondo (1): cataract (MONDO:0005129)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D002386	Cataract	C11.510.245

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects expression, increases abundance, decreases expression	2
Valproic Acid	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
nuciferine	affects binding, decreases reaction	1
resorcinol	increases expression	1
di-n-butylphosphoric acid	affects expression	1
chloropicrin	affects expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
picoxystrobin	increases expression	1
Temozolomide	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases expression	1
Catechin	affects cotreatment, increases expression	1
Cyclophosphamide	decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	increases expression	1
Ozone	affects expression, increases abundance	1
Rotenone	increases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
Vitamin E	increases expression	1
Sodium Selenite	increases expression	1
Antirheumatic Agents	increases expression	1
Copper Sulfate	decreases expression	1
Phenol	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Cellosaurus cell lines

4 cell lines: 2 cancer cell line, 1 transformed cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B3GA	Abcam HEK293T RRAGA KO	Transformed cell line	Female
CVCL_C1T6	GIBHi002-A-5	Induced pluripotent stem cell	Female
CVCL_TJ76	HAP1 RRAGA (-) 1	Cancer cell line	Male
CVCL_XS29	HAP1 RRAGA (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00273221	PHASE4	UNKNOWN	Combined Phacotube vs Phacotrabeculectomy:A Randomized Controlled Trial
NCT00312299	PHASE4	COMPLETED	Posterior Capsule Opacification Study
NCT00345046	PHASE4	COMPLETED	A Comparison of Three Different Formulations of Prednisolone Acetate 1%
NCT00347243	PHASE4	COMPLETED	Wavefront Analisys and Contrast Sensitivity of Spherical and Aspherical Intraocular Lenses
NCT00347503	PHASE4	COMPLETED	Aqueous Concentrations and PGE2 Inhibition of Ketorolac 0.4% vs. Bromfenac 0.09% in Cataract Patients
NCT00348244	PHASE4	COMPLETED	Ketorolac vs. Steroid in the Prevention of CME
NCT00348270	PHASE4	COMPLETED	Comparison of the Quality of Vision Provided by AMO Tecnis Z9000 and Alcon Laboratories MA60 Acrysof Posterior Chamber Intraocular Lenses
NCT00348582	PHASE4	COMPLETED	Acular LS vs. Nevanac in Post op Inflammation Following Cataract Surgery
NCT00348621	PHASE4	COMPLETED	A Study of Interventions to Reduce Disability From Visual Loss in Nursing Home Residents
NCT00349583	PHASE4	COMPLETED	Efficacy of Topical Cyclosporine Versus Tears for Improving Visual Outcomes Following Multifocal IOL Implantation
NCT00355446	PHASE4	COMPLETED	Bioavailability of Bimatoprost Ophthalmic Solution in Human Aqueous.
NCT00386438	PHASE4	COMPLETED	Efficacy of Honan Balloon in Intraocular Pressure Reduction Before Phacoemulsification
NCT00392275	PHASE4	COMPLETED	Penetrance of Third Generation Fluoroquinolones in Eyes With Functioning Filtering Blebs
NCT00428363	PHASE4	COMPLETED	Effect of Optic Edge Design in a Silicone Intraocular Lens on Posterior Capsule Opacification
NCT00449267	PHASE4	COMPLETED	Aurolab Hydrophobic Foldable Intraocular Lens Study
NCT00459303	PHASE4	COMPLETED	Comparison of Functional Vision Provided by AMO Tecnis Z9000 and Alcon SA60AT Acrysof
NCT00469690	PHASE4	COMPLETED	Aqueous Concentrations and PGE2 Inhibition of Ketorolac 0.4% vs. Bromfenac 0.09% in Cataract Patients: Trough Drug Effects
NCT00576485	PHASE4	COMPLETED	Spherical Aberration and Contrast Sensitivity in IOLs
NCT00612729	PHASE4	COMPLETED	Light Filters in Intraocular Lenses (IOLs) and Its Influence on Colour and Contrast Vision.
NCT00612781	PHASE4	COMPLETED	Yellow Versus White Study
NCT00630019	PHASE4	COMPLETED	Ocular Tissue Levels of 1.5% Levofloxacin Ophthalmic Solution Compared to an Active Comparator
NCT00673803	PHASE4	COMPLETED	Influence of Two Different Preloaded Intraocular Lens (IOLs) on Posterior Capsule Opacification
NCT00684138	PHASE4	COMPLETED	ACRYSOF® ReSTOR® Aspheric +3.0 D Add Power Intraocular Lens (IOL)
NCT00698724	PHASE4	COMPLETED	Comparing Optical Coherence Tomography (OCT) and Visual Acuity Outcomes in Subjects Undergoing Cataract Surgery, Who Receive Xibrom Ophthalmic Solution and Standard Presurgical Care vs. Xibrom Ophthalmic Solution Plus Prednisolone Acetate 1% and Standard Presurgical Care
NCT00710905	PHASE4	TERMINATED	Visual Function With Contralateral AcrySof® ReSTOR® Aspheric SN6AD1 and SN6AD3
NCT00710931	PHASE4	COMPLETED	Visual Function With Bilateral AcrySof® ReSTOR® Aspheric SN6AD1
NCT00711347	PHASE4	COMPLETED	Intraoperative Floppy Iris Syndrome
NCT00712244	PHASE4	COMPLETED	DisCoVisc Versus DuoVisc, Healon5 and AmVisc Plus
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00719732	PHASE4	COMPLETED	Visual Function After Implantation of Bilateral AcrySof ReSTOR Aspheric +3
NCT00721253	PHASE4	COMPLETED	Visual Outcomes of Subjects Bilaterally Implanted With ReSTOR Aspheric +4 vs. Tecnis or Acri.LISA
NCT00731640	PHASE4	COMPLETED	Contralateral ReSTOR / Monofocal or Phakic Eye
NCT00732030	PHASE4	COMPLETED	Low Cylinder Toric
NCT00758199	PHASE4	COMPLETED	Determination of Optimum Duration of Treatment With Bromfenac (Xibrom) Eyedrops Following Cataract Surgery
NCT00760058	PHASE4	WITHDRAWN	Visual Outcome and Visual Quality After Bilateral Implantation of the AcrySof® IQ IOL Compared to MI60® and Tecnis® IOL
NCT00760487	PHASE4	COMPLETED	Visual Function After Implantation of Bilateral AcrySof® Toric Natural Intraocular Lens
NCT00761488	PHASE4	WITHDRAWN	Recommendations for Monitoring Clinical Experience Following Implantation of the AcrySof® Toric
NCT00763360	PHASE4	COMPLETED	To Compare the Ability of DiscoVisc® OVD to Protect the Corneal Endothelium and Maintain Anterior Chamber Space With Healon® and Amvisc® PLUS During Cataract Surgery.
NCT00786370	PHASE4	COMPLETED	Dexmedetomidine vs. Propofol for Cataract Surgery
NCT00786565	PHASE4	COMPLETED	Clinical Evaluation of a New Aspheric Intraocular Lens.