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10 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
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RRAGC
Ras related GTP binding C
Chromosome 1 Β· 1p34.3
NCBI Gene: 64121Ensembl: ENSG00000116954.9HGNC: HGNC:19902UniProt: B4DQ03
103PubMed Papers
21Diseases
0Drugs
4Pathogenic Variants
FUNCTIONAL ROLE
Hub Gene
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
lysosomenucleoplasmcytoplasmprotein-membrane adaptor activityLong-Olsen-Distelmaier syndromenon-Hodgkins lymphomarotator cuff tearmusculoskeletal system disease
✦AI Summary

RRAGC (Ras-related GTP-binding protein C) is a guanine nucleotide-binding protein that serves as a critical regulator of mTORC1 signaling in response to amino acid availability 12. RRAGC functions as part of a heterodimeric Rag complex with RagA or RagB, where it cycles between inactive (GTP-bound) and active (GDP-bound) conformational states 23. In its GDP-bound active form, RRAGC recruits mTORC1 to lysosomes for activation by RHEB, enabling canonical amino acid-stimulated mTORC1 signaling 12. Beyond canonical mTORC1 activation, RRAGC mediates a substrate-specific pathway controlling phosphorylation of transcription factors TFEB and TFE3, master regulators of lysosomal biogenesis and autophagy, independent of RHEB activity 45. The Rag-Ragulator complex, organized around RRAGC, serves as the central physical architecture organizing nutrient-sensing components on the lysosomal surface 6. Disease-causing de novo missense variants in RRAGC cause constitutive mTORC1 hyperactivation, resulting in early-onset mTORopathy with dilated cardiomyopathy, hepatopathy, and neurological abnormalities including pachygyria and polymicrogyria 7. Additionally, RRAGC activity is disrupted during proteotoxic stress to activate TFEB-mediated autophagy through non-canonical mechanisms 8. These findings establish RRAGC as a central hub integrating nutrient and stress signals to coordinate mTORC1-dependent cell growth with lysosomal function.

Sources cited
1
RRAGC regulates mTORC1 activation in response to amino acids through recruitment to lysosomes
PMID: 20381137
2
RRAGC forms heterodimeric Rag complexes and cycles between GTP-bound inactive and GDP-bound active forms to recruit mTORC1
PMID: 24095279
3
RRAGC nucleotide state determines active versus inactive heterodimeric Rag complex conformations
PMID: 31601708
4
RRAGC mediates substrate-specific mTORC1 phosphorylation of TFEB independent of RHEB, dependent on amino acid-activated RagC
PMID: 32612235
5
GDP-bound RRAGC recruits TFEB to mTORC1 through a RagC-dependent aspartate clamp mechanism
PMID: 36697823
6
Rag-Ragulator complex with RRAGC is the central organizer of mTORC1 nutrient-sensing architecture on lysosomes
PMID: 39163330
7
De novo RRAGC missense variants cause early-onset mTORopathy with cardiomyopathy, hepatopathy, and neurological abnormalities
PMID: 37057673
8
Proteotoxic stress disrupts RRAGC-TFEB interaction to inhibit non-canonical MTORC1 and activate TFEB
PMID: 41450115
Disease Associationsβ“˜21
Long-Olsen-Distelmaier syndromeOpen Targets
0.73Strong
non-Hodgkins lymphomaOpen Targets
0.37Weak
musculoskeletal system diseaseOpen Targets
0.32Weak
rotator cuff tearOpen Targets
0.32Weak
placenta praeviaOpen Targets
0.29Weak
genetic disorderOpen Targets
0.19Weak
menopauseOpen Targets
0.08Suggestive
cardiomyopathyOpen Targets
0.07Suggestive
mathematical abilityOpen Targets
0.07Suggestive
isolated agammaglobulinemiaOpen Targets
0.06Suggestive
severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positiveOpen Targets
0.05Suggestive
activated PI3K-delta syndromeOpen Targets
0.05Suggestive
T-B+ severe combined immunodeficiency due to JAK3 deficiencyOpen Targets
0.05Suggestive
BENTA diseaseOpen Targets
0.05Suggestive
liver diseaseOpen Targets
0.05Suggestive
autoimmune diseaseOpen Targets
0.05Suggestive
immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemiaOpen Targets
0.05Suggestive
combined immunodeficiency due to CTPS1 deficiencyOpen Targets
0.05Suggestive
hyper-IgM syndrome type 3Open Targets
0.05Suggestive
gamma chain deficiencyOpen Targets
0.05Suggestive
Long-Olsen-Distelmaier syndromeUniProt
Pathogenic Variants4
NM_022157.4(RRAGC):c.343T>C (p.Trp115Arg)Likely pathogenic
See cases|Long-Olsen-Distelmaier syndrome
β˜…β˜†β˜†β˜†2022β†’ Residue 115
NM_022157.4(RRAGC):c.269C>A (p.Thr90Asn)Pathogenic
Long-Olsen-Distelmaier syndrome
β˜†β˜†β˜†β˜†2025β†’ Residue 90
NM_022157.4(RRAGC):c.224C>A (p.Ser75Tyr)Pathogenic
Long-Olsen-Distelmaier syndrome
β˜†β˜†β˜†β˜†2025β†’ Residue 75
NM_022157.4(RRAGC):c.353C>T (p.Pro118Leu)Pathogenic
Long-Olsen-Distelmaier syndrome
β˜†β˜†β˜†β˜†2025β†’ Residue 118
View on ClinVar β†—
Related Genes
TFEBProtein interaction100%VPS39Protein interaction100%LARS2Protein interaction100%LARS1Protein interaction100%FNIP2Protein interaction100%WDR24Protein interaction100%
Tissue Expression6 tissues
Heart
100%
Bone Marrow
99%
Brain
96%
Lung
93%
Ovary
71%
Liver
63%
Gene Interaction Network
Click a node to explore
RRAGCTFEBVPS39LARS2LARS1FNIP2WDR24
PROTEIN STRUCTURE
Preparing viewer…
PDB3LLU Β· 1.40 Γ… Β· X-ray
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
0.55Moderately Constrained
pLIβ“˜
0.94Intolerant
Observed/Expected LoF0.28 [0.15–0.55]
RankingsWhere RRAGC stands among ~20K protein-coding genes
  • #4,662of 20,598
    Most Researched103 Β· top quartile
  • #3,739of 5,498
    Most Pathogenic Variants4
  • #3,470of 17,882
    Most Constrained (LOEUF)0.55 Β· top quartile
Genes detectedRRAGC
Sources retrieved10 papers
Response timeβ€”
πŸ“„ Sources
10β–Ό
1
Lipotoxicity-induced STING1 activation stimulates MTORC1 and restricts hepatic lipophagy.
PMID: 34382907
Autophagy Β· 2022
1.00
2
Structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex.
PMID: 36697823
Nature Β· 2023
0.90
3
A substrate-specific mTORC1 pathway underlies Birt-Hogg-DubΓ© syndrome.
PMID: 32612235
Nature Β· 2020
0.80
4
The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1.
PMID: 18497260
Science Β· 2008
0.70
5
Rag-Ragulator is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway.
PMID: 39163330
Proc Natl Acad Sci U S A Β· 2024
0.60