The ability to quantify the sensitivity of QM/MM calculations with respect to parameters of the MM environment provides a natural starting point for guiding the systematic choice of the QM region. With increasing size of the QM region and approaching a full QM calculation, one can expect this sensitivity to decrease. Therefore, choosing the QM region such that the uncertainty is reduced implies that the QM/MM calculation approach those of a full QM calculation. Here, we exploit this idea by proposing a simple and efficient scheme for the systematic construction of the QM region that is guided by uncertainty quantification. This work is organized as follows. In Section 2 we recall the necessary theoretical background of QM/MM approaches (Sect. 2.1, introduce our point charge variation analysis (PCVA) for analyzing the sensitivity of QM/MM energies (Sect. 2.2, and give the computational details (Section 2.3). In Section 3, we introduce the model system used in this work and discuss the convergence of ligand charges and reaction energies for QM regions of increasing size. The sensitivity of these quantities with respect to global point charge variations is analyzed in Section 4. This is followed in by the evaluation of the energy sensitivity for single amino acids in Section 5, which are used to devise a scheme for the systematic construction of QM regions based on a PCVA. The QM regions obtained with this PCVAbased scheme are assessed for QM regions of increasing size and for atom-economical QM regions in Sections 6 and 7, respectively. Finally, conclusions and an outlook can be found in Section 8.