Against this backdrop, our structural/molecular-dynamics analyses indicate that MAP2K1 (MEK1) p.R49C perturbs stabilizing interactions and protein dynamics, plausibly altering pathway output; however, actionable sensitivity to MEK/ERK inhibitors is likely to be mutation-class–dependent and remains sparsely characterized specifically in CCA, arguing that MEK/ERK-directed strategies in MAP2K1-altered or MAPK-activated iCCA should at present be prioritized within biomarker-selected clinical trials rather than routine off-label use. The gene discussed is MAP2K1; the disease is cholangiocarcinoma.