RGL1 (Ral guanine nucleotide dissociation stimulator like 1) is a RAS effector protein that functions as a guanine nucleotide exchange factor (GEF) for Ral GTPases 1. RGL1 activates Ral GTPase by stimulating nucleotide exchange through its conserved RAS-association (RA) domain, which achieves optimal RAS binding through unique structural features including notably large distances between the RAS α1 helix and effector α1 helix (21.7-22.2 Å) compared to other RAS-effector complexes 2. The oncogenic KRAS G12V mutation increases intermolecular correlations within the KRAS-RGL1 complex, forming a more compact structure that enhances binding stability 3. Clinically, RGL1 is implicated in multiple cancers. In colorectal cancer, RGL1 overexpression promotes metastasis by activating the CDC42/RAC1 complex to facilitate motile focal adhesion formation, with expression significantly elevated in metastatic versus non-metastatic tumors 4. RGL1 is also associated with metastasis risk in Group 3 medulloblastoma and linked to worst overall survival 5. In the RAS-signaling axis, RGL1 and RGL2 act as key RalGEFs downstream of active RAS to promote RalB-dependent invasion and metastasis 1. Additionally, RGL1 expression is downregulated in duck hepatocytes infected with duck hepatitis B virus, suggesting involvement in viral pathogenesis 6. RGL1 is widely expressed across tissues including heart, brain, kidney, and spleen 7.