RRAGC

Summary

RRAGC (Ras related GTP binding C, HGNC:19902) is a protein-coding gene on chromosome 1p34.3, encoding Ras-related GTP-binding protein C (Q9HB90). 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).

This gene encodes a member of the GTR/RAG GTP-binding protein family. The encoded protein is a monomeric guanine nucleotide-binding protein which forms a heterodimer with RRAGA and RRAGB and is primarily localized to the cytoplasm. The encoded protein promotes intracellular localization of the mTOR complex. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 64121 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Long-Olsen-Distelmaier syndrome (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 32 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 32
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• Cancer dependency (DepMap): dependent in 27.9% of screened cell lines
• MANE Select transcript: NM_022157

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19902
Approved symbol	RRAGC
Name	Ras related GTP binding C
Location	1p34.3
Locus type	gene with protein product
Status	Approved
Aliases	GTR2, FLJ13311
Ensembl gene	ENSG00000116954
Ensembl biotype	protein_coding
OMIM	608267
Entrez	64121

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000373001, ENST00000474456, ENST00000493015, ENST00000496778, ENST00000865047, ENST00000865048, ENST00000865049, ENST00000865050, ENST00000865051, ENST00000928168

RefSeq mRNA: 2 — MANE Select: NM_022157 NM_001271851, NM_022157

CCDS: CCDS430

Canonical transcript exons

ENST00000373001 — 7 exons

Exon	Start	End
ENSE00000899638	38856879	38857082
ENSE00001880684	38838198	38839704
ENSE00001899779	38859410	38859772
ENSE00003495502	38851615	38851757
ENSE00003511843	38855708	38855907
ENSE00003600439	38852374	38852488
ENSE00003650128	38845939	38846087

Expression profiles

Bgee: expression breadth ubiquitous, 177 present calls, max score 91.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.9779 / max 64.3699, expressed in 1723 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11841	5.4877	1661
11842	1.4902	1044

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	91.39	gold quality
monocyte	CL:0000576	90.90	gold quality
leukocyte	CL:0000738	90.84	gold quality
omental fat pad	UBERON:0010414	90.56	gold quality
skin of leg	UBERON:0001511	90.53	gold quality
popliteal artery	UBERON:0002250	90.48	gold quality
tibial artery	UBERON:0007610	90.48	gold quality
peritoneum	UBERON:0002358	90.43	gold quality
smooth muscle tissue	UBERON:0001135	90.42	gold quality
skin of abdomen	UBERON:0001416	90.28	gold quality
ventricular zone	UBERON:0003053	90.05	gold quality
mucosa of stomach	UBERON:0001199	89.38	gold quality
aorta	UBERON:0000947	88.85	gold quality
stromal cell of endometrium	CL:0002255	88.75	gold quality
right coronary artery	UBERON:0001625	88.75	gold quality
cortical plate	UBERON:0005343	88.53	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.38	gold quality
descending thoracic aorta	UBERON:0002345	88.37	gold quality
left coronary artery	UBERON:0001626	88.18	gold quality
lower esophagus	UBERON:0013473	88.15	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.14	gold quality
gall bladder	UBERON:0002110	88.03	gold quality
calcaneal tendon	UBERON:0003701	87.86	gold quality
adipose tissue of abdominal region	UBERON:0007808	87.84	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	87.65	gold quality
lower esophagus mucosa	UBERON:0035834	87.62	gold quality
esophagus	UBERON:0001043	87.52	gold quality
upper lobe of left lung	UBERON:0008952	87.49	gold quality
thoracic aorta	UBERON:0001515	87.29	gold quality
rectum	UBERON:0001052	87.26	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.95

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

81 targeting RRAGC, 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-4776-3P	100.00	68.73	1340
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-12129	99.72	67.45	1311

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 18)

• FLCN and its binding partners, FNIP1/2, are Rag-interacting proteins with GAP activity for RagC/D, but not RagA/B. (PMID:24095279)
• activating nature of the RRAGC mutations, their existence in the dominant clone and their stability during disease progression support their potential as an excellent candidate for therapeutic targeting (PMID:26691987)
• These findings implicate mTORC1 dysregulation through a gain-of-function mutation in RagC as a novel molecular basis for syndromic forms of pediatric heart failure, and expand genotype-phenotype correlation in RASopathy-related syndromes (PMID:27234373)
• Multiple RRAGC mutations demonstrated elevated MTOR activation. (PMID:27267853)
• 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)
• 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)
• Euchromatin histone methyltransferase II (EHMT2) regulates the expression of ras-related GTP binding C (RRAGC) protein. (PMID:32684241)
• 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)
• Cancer-secreted miRNAs regulate amino-acid-induced mTORC1 signaling and fibroblast protein synthesis. (PMID:33345445)
• TFEB Overexpression, Not mTOR Inhibition, Ameliorates RagC(S75Y) Cardiomyopathy. (PMID:34071043)
• An interdomain hydrogen bond in the Rag GTPases maintains stable mTORC1 signaling in sensing amino acids. (PMID:34116056)
• Rag GTPases suppress PRL-3 degradation and predict poor clinical diagnosis of cancer patients with low PRL-3 mRNA expression. (PMID:34482023)
• Structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex. (PMID:36697823)
• De novo missense variants in RRAGC lead to a fatal mTORopathy of early childhood. (PMID:37057673)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	rragd	ENSDARG00000006279
danio_rerio	rragca	ENSDARG00000069829
danio_rerio	rragcb	ENSDARG00000099049
mus_musculus	Rragc	ENSMUSG00000028646
rattus_norvegicus	Rragc	ENSRNOG00000017426
drosophila_melanogaster	RagC-D	FBGN0033272
caenorhabditis_elegans		WBGENE00012497

Paralogs (3): RRAGD (ENSG00000025039), RRAGB (ENSG00000083750), RRAGA (ENSG00000155876)

Protein

Protein identifiers

Ras-related GTP-binding protein C — Q9HB90 (reviewed: Q9HB90)

Alternative names: GTPase-interacting protein 2, TIB929

All UniProt accessions (1): Q9HB90

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 RagA/RRAGA or RagB/RRAGB and cycles between an inactive GTP-bound and an active GDP-bound form: RagC/RRAGC is in its active form when GDP-bound RagC/RRAGC forms a complex with GTP-bound RagA/RRAGA (or RagB/RRAGB) and in an inactive form when GTP-bound RagC/RRAGC heterodimerizes with GDP-bound RagA/RRAGA (or RagB/RRAGB). In its GDP-bound active form, promotes the recruitment of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB. This is a crucial step in the activation of the MTOR signaling cascade by amino acids. Also plays a central role in the non-canonical mTORC1 complex, which acts independently of RHEB and specifically mediates phosphorylation of MiT/TFE factors TFEB and TFE3: GDP-bound RagC/RRAGC mediates recruitment of MiT/TFE factors TFEB and TFE3.

Subunit / interactions. Forms a heterodimer with RRAGA, in a sequence-independent manner, and RRAGB. Heterodimerization stabilizes proteins of the heterodimer. The GDP-bound form of RRAGC (in complex with the GTP-bound form of RRAGA or RRAGB), interacts with RPTOR, thereby promoting recruitment of mTORC1 to the lysosomes. 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 NOL8. Interacts with SH3BP4; the interaction with this negative regulator is most probably direct, preferentially occurs with the inactive GDP-bound form of RRAGB, is negatively regulated by amino acids and prevents interaction with RPTOR. The Rag heterodimer interacts with SLC38A9; the probable amino acid sensor. Interacts with SESN1, SESN2 and SESN3. Interacts with PIP4P1. The Rag heterodimer interacts with the Ragulator complex. The GDP-bound form interacts with TFEB. The GDP-bound form interacts with TFE3.

Subcellular location. Cytoplasm. Nucleus. Lysosome membrane.

Disease relevance. Long-Olsen-Distelmaier syndrome (LNGODS) [MIM:620609] An autosomal dominant syndrome characterized by lethal dilated cardiomyopathy, bilateral cataracts, mild facial dysmorphisms, and liver dysfunction. Some patients have brain abnormalities, including pachygyria, polymicrogyria, and septo-optic dysplasia. Death occurs in infancy. The disease is caused by variants affecting the gene represented in this entry. RRAGC mutations have been found in a patient with idiopathic dilated cardiomyopathy with ventricular dilation and systolic dysfunction, bilateral cataracts, and mild facial dysmorphisms.

Activity regulation. The activation of RagC/RRAGC is mediated by a GTPase activating protein (GAP). In high-amino acid conditions, activated by GTPase activating protein FLCN that stimulates RRAGC GTPase activity to turn it into its active GDP-bound form. In response to amino acid depletion, the GATOR1 complex inactivates RagC/RRAGC by securing the GTP-bound inactive form.

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

RefSeq proteins (2): NP_001258780, NP_071440* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006762	Gtr1_RagA	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR039400	RagC/D	Family

Pfam: PF04670

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (69 total): binding site 18, strand 15, helix 11, sequence variant 9, turn 5, modified residue 4, mutagenesis site 3, initiator methionine 1, chain 1, region of interest 1, sequence conflict 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
3LLU	X-RAY DIFFRACTION	1.4
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-Q9HB90-F1	70.22	0.06

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 (18): 90; 90; 94; 96; 96; 178; 179; 181; 181; 219; 220; 71 …

Post-translational modifications (4): 2, 2, 15, 96

Mutagenesis-validated functional residues (3):

Position	Phenotype
75	constitutively active mutant. increased rptor-binding.
92	promotes interaction with gator1 in the gap mode.
120	maintains gtp-bound state, leading to inactivate mtorc1. decreased rptor-binding.

Function

Pathways and Gene Ontology

Reactome pathways

19 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-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-6807070	PTEN Regulation
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
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: 316 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_REGULATION_OF_AUTOPHAGY, MYOGENIN_Q6, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOCC_VACUOLAR_MEMBRANE, GCANCTGNY_MYOD_Q6, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_POSITIVE_REGULATION_OF_TOR_SIGNALING, GOMF_GTPASE_BINDING, GOBP_CELLULAR_RESPONSE_TO_ACID_CHEMICAL, BOHN_PRIMARY_IMMUNODEFICIENCY_SYNDROM_DN, GOBP_PROTEIN_LOCALIZATION_TO_LYSOSOME, PID_MTOR_4PATHWAY, GOBP_NEGATIVE_REGULATION_OF_AUTOPHAGY, GOBP_REGULATION_OF_CATABOLIC_PROCESS

GO Biological Process (25): DNA-templated transcription (GO:0006351), apoptotic process (GO:0006915), small GTPase-mediated signal transduction (GO:0007264), intracellular protein localization (GO:0008104), RNA splicing (GO:0008380), cellular response to starvation (GO:0009267), negative regulation of autophagy (GO:0010507), cellular response to nutrient levels (GO:0031669), regulation of TOR signaling (GO:0032006), cellular response to amino acid starvation (GO:0034198), response to amino acid (GO:0043200), protein localization to lysosome (GO:0061462), cellular response to amino acid stimulus (GO:0071230), protein localization to membrane (GO:0072657), regulation of TORC1 signaling (GO:1903432), positive regulation of TORC1 signaling (GO:1904263), autophagosome assembly (GO:0000045), cytoplasmic translation (GO:0002181), lysosome organization (GO:0007040), SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146), protein destabilization (GO:0031648), TORC1 signaling (GO:0038202), negative regulation of translational initiation (GO:0045947), positive regulation of translational initiation (GO:0045948), negative regulation of protein localization to nucleus (GO:1900181)

GO Molecular Function (12): magnesium ion binding (GO:0000287), GTPase activity (GO:0003924), GTP binding (GO:0005525), GDP binding (GO:0019003), protein-membrane adaptor activity (GO:0043495), protein heterodimerization activity (GO:0046982), GTPase binding (GO:0051020), molecular adaptor activity (GO:0060090), enzyme-substrate adaptor activity (GO:0140767), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (9): 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)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Signal Transduction	2
MTOR signalling	2
Autophagy	1
Transcriptional Regulation by TP53	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
PIP3 activates AKT signaling	1
Gene expression (Transcription)	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
TORC1 signaling	2
guanyl ribonucleotide binding	2
protein-macromolecule adaptor activity	2
binding	2
gene expression	1
RNA biosynthetic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
intracellular signaling cassette	1
macromolecule localization	1
RNA processing	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
TOR signaling	1
regulation of intracellular signal transduction	1
cellular response to starvation	1
response to amino acid starvation	1
response to acid chemical	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
regulation of TOR signaling	1
positive regulation of TOR 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

1326 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RRAGC	RRAGB	Q5VZM2	992
RRAGC	RRAGA	Q7L523	992
RRAGC	RPTOR	Q8N122	990
RRAGC	RRAGD	Q9NQL2	945
RRAGC	RHEB	Q15382	942
RRAGC	MTOR	P42345	901
RRAGC	LTV1	Q96GA3	894
RRAGC	FLCN	Q8NFG4	890
RRAGC	SLC36A1	Q7Z2H8	849
RRAGC	LAMTOR2	Q9Y2Q5	837
RRAGC	NOL8	Q76FK4	824
RRAGC	FNIP2	Q9P278	801
RRAGC	LARS1	Q9P2J5	801
RRAGC	MLST8	Q9BVC4	798
RRAGC	LARS2	Q15031	792

IntAct

148 interactions, top by confidence:

A	B	Type	Score
LAMTOR4	LAMTOR5	psi-mi:“MI:0914”(association)	0.960
LAMTOR5	LAMTOR4	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 (164): RRAGA (Affinity Capture-Western), RRAGB (Affinity Capture-Western), LAMTOR3 (Affinity Capture-Western), LAMTOR2 (Affinity Capture-Western), LAMTOR1 (Affinity Capture-Western), RRAGC (Affinity Capture-Western), RRAGC (Affinity Capture-Western), TSC2 (Affinity Capture-Western), TSC1 (Affinity Capture-Western), RRAGC (Affinity Capture-MS), RRAGC (Affinity Capture-MS), RRAGC (Affinity Capture-MS), RRAGC (Affinity Capture-MS), RRAGC (Affinity Capture-MS), RRAGC (Two-hybrid)

ESM2 similar proteins: A0A8I3S9V6, A0M8U1, A6NH52, E1BWM5, O35089, P13666, P86050, Q00765, Q0VCK9, Q0X0A5, Q1RLU8, Q29S14, Q2PG42, Q3KNM2, Q3ZC24, Q5BJU5, Q5M7T4, Q5R9I4, Q5R9K4, Q5RE33, Q5T4T1, Q5ZJ41, Q5ZJD7, Q6DD32, Q6GM44, Q6NYF1, Q6P360, Q6PI25, Q7TQ48, Q86TD4, Q8C407, Q8L5Y9, Q8MK44, Q8R1Z9, Q91ZQ0, Q940S0, Q96GC9, Q99K70, Q99KU0, Q9BSR8

Diamond homologs: O74544, P53290, Q7TT45, Q99K70, Q9HB90, Q9NQL2, Q3SX43, Q63486, Q7L523, Q80X95, Q9Y7Z2

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
RRAGC	up-regulates	RPTOR	binding
RRAGC	up-regulates	mTORC1	binding
RRAGC	“form complex”	RAGAC	binding
RRAGC	“form complex”	RAGBC	binding
FLCN	“up-regulates activity”	RRAGC	“gtpase-activating protein”
TFE3	“up-regulates quantity by expression”	RRAGC	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 70 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	10	95.2×	4e-16
Energy dependent regulation of mTOR by LKB1-AMPK	10	78.8×	2e-15
MTOR signalling	10	53.1×	1e-13
Amino acids regulate mTORC1	13	52.1×	3e-17
PTEN Regulation	10	45.7×	5e-13
Regulation of PTEN gene transcription	10	35.7×	6e-12
Autophagy	12	35.6×	4e-14
Cellular response to starvation	10	33.1×	1e-11

GO biological processes:

GO term	Partners	Fold	FDR
TORC1 signaling	7	90.6×	1e-10
positive regulation of TOR signaling	9	72.0×	2e-12
cellular response to amino acid stimulus	10	49.4×	2e-12
positive regulation of TORC1 signaling	8	38.1×	4e-09
cellular response to amino acid starvation	5	25.6×	1e-04
cellular response to starvation	5	15.6×	1e-03
chemotaxis	5	11.0×	4e-03

Disease & clinical

Cancer significance

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

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	21
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
2663873	NM_022157.4(RRAGC):c.269C>A (p.Thr90Asn)	Pathogenic
2663874	NM_022157.4(RRAGC):c.353C>T (p.Pro118Leu)	Pathogenic
2430326	NM_022157.4(RRAGC):c.343T>C (p.Trp115Arg)	Likely pathogenic

SpliceAI

1169 predictions. Top by Δscore:

Variant	Effect	Δscore
1:38851613:AC:A	donor_gain	1.0000
1:38851614:CC:C	donor_gain	1.0000
1:38851759:T:C	acceptor_gain	1.0000
1:38851759:T:TC	acceptor_gain	1.0000
1:38852368:A:AC	donor_gain	1.0000
1:38852369:C:CC	donor_gain	1.0000
1:38852369:CTTA:C	donor_gain	1.0000
1:38852370:TTA:T	donor_loss	1.0000
1:38852371:TA:T	donor_loss	1.0000
1:38852372:A:AC	donor_gain	1.0000
1:38852373:C:A	donor_loss	1.0000
1:38852373:C:CA	donor_gain	1.0000
1:38852373:CT:C	donor_gain	1.0000
1:38852373:CTG:C	donor_gain	1.0000
1:38852373:CTGA:C	donor_gain	1.0000
1:38852373:CTGAT:C	donor_gain	1.0000
1:38852484:AAAAG:A	acceptor_gain	1.0000
1:38852485:AAAG:A	acceptor_gain	1.0000
1:38852486:AAG:A	acceptor_gain	1.0000
1:38852486:AAGC:A	acceptor_loss	1.0000
1:38852487:AG:A	acceptor_gain	1.0000
1:38852488:GC:G	acceptor_loss	1.0000
1:38852489:C:CA	acceptor_loss	1.0000
1:38852489:C:CC	acceptor_gain	1.0000
1:38855906:TC:T	acceptor_gain	1.0000
1:38855906:TCCT:T	acceptor_loss	1.0000
1:38855907:CC:C	acceptor_gain	1.0000
1:38855907:CCTGT:C	acceptor_loss	1.0000
1:38855908:C:A	acceptor_loss	1.0000
1:38855908:C:CC	acceptor_gain	1.0000

AlphaMissense

2677 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:38839669:C:G	A362P	1.000
1:38839688:G:C	N355K	1.000
1:38839688:G:T	N355K	1.000
1:38845972:A:G	C339R	1.000
1:38845977:A:G	L337P	1.000
1:38846028:A:G	L320P	1.000
1:38851621:A:T	I298K	1.000
1:38851628:A:G	S296P	1.000
1:38851642:A:T	V291D	1.000
1:38851659:G:C	C285W	1.000
1:38851663:A:G	L284P	1.000
1:38851697:C:G	D273H	1.000
1:38851702:G:T	A271E	1.000
1:38851703:C:G	A271P	1.000
1:38851713:T:A	K267N	1.000
1:38851713:T:G	K267N	1.000
1:38851714:T:A	K267I	1.000
1:38851715:T:C	K267E	1.000
1:38851716:G:C	S266R	1.000
1:38851716:G:T	S266R	1.000
1:38851718:T:G	S266R	1.000
1:38851732:A:C	L261R	1.000
1:38851732:A:G	L261P	1.000
1:38851732:A:T	L261H	1.000
1:38851734:A:C	F260L	1.000
1:38851734:A:T	F260L	1.000
1:38851736:A:G	F260L	1.000
1:38851754:A:G	S254P	1.000
1:38852393:A:G	L246P	1.000
1:38852423:A:G	L236P	1.000

dbSNP variants (sampled 300 via entrez): RS1000113969 (1:38851542 T>C), RS1000159960 (1:38855483 T>A,C), RS1000175760 (1:38845169 C>A,T), RS1000326502 (1:38859334 G>A), RS1000357057 (1:38853339 A>T), RS1000444607 (1:38851917 T>C), RS1000452089 (1:38853073 G>C,T), RS1000554985 (1:38856583 CTAT>C), RS1000593392 (1:38859593 C>A,G,T), RS1000788611 (1:38854130 C>T), RS1000854903 (1:38842153 T>C), RS1000862113 (1:38839195 T>A), RS1001046929 (1:38850516 A>T), RS1001054153 (1:38842427 C>T), RS1001061116 (1:38860195 T>C)

Disease associations

OMIM: gene MIM:608267 | disease phenotypes: MIM:620609

GenCC curated gene-disease

Disease	Classification	Inheritance
Long-Olsen-Distelmaier syndrome	Strong	Autosomal dominant

Mondo (1): Long-Olsen-Distelmaier syndrome (MONDO:0957960)

Orphanet (0):

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000256	Macrocephaly
HP:0000316	Hypertelorism
HP:0000369	Low-set ears
HP:0000494	Downslanted palpebral fissures
HP:0000518	Cataract
HP:0000609	Optic nerve hypoplasia
HP:0001302	Pachygyria
HP:0001508	Failure to thrive
HP:0001629	Ventricular septal defect
HP:0001635	Congestive heart failure
HP:0001640	Cardiomegaly
HP:0001644	Dilated cardiomyopathy
HP:0001684	Secundum atrial septal defect
HP:0001788	Premature rupture of membranes
HP:0001790	Nonimmune hydrops fetalis
HP:0001943	Hypoglycemia
HP:0001987	Hyperammonemia
HP:0002126	Polymicrogyria
HP:0002151	Increased circulating lactate concentration
HP:0002389	Cavum septum pellucidum
HP:0002416	Subependymal cysts
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0003819	Death in childhood
HP:0011220	Prominent forehead
HP:0011968	Feeding difficulties
HP:0012666	Severely reduced left ventricular ejection fraction
HP:0030961	Microspherophakia
HP:0031956	Elevated circulating aspartate aminotransferase concentration

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003475_2	Beard thickness	8.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, decreases methylation	4
bisphenol A	increases expression	2
cobaltous chloride	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Plant Extracts	affects cotreatment, increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
nuciferine	affects binding, decreases reaction	1
trichostatin A	affects expression	1
dodecyldimethylamine oxide	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	increases expression	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, increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
apatinib	affects cotreatment, increases expression	1
7-(benzylamino)-1,3,4,8-tetrahydropyrrolo(4,3,2-de)quinolin-8(1H)-one	increases expression	1
NSC 689534	affects binding, increases expression	1
Resveratrol	affects cotreatment, increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2E7	Abcam HeLa RRAGC KO	Cancer cell line	Female

Clinical trials (associated diseases)

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