A quantitative and predictive microscopic theoretical framework that can describe reactions induced by $\alpha$ particles ($^4$He nuclei) and heavier projectiles is currently lacking. Such a framework would contribute to reducing uncertainty in the modeling of stellar evolution and nucleosynthesis and provide the basis for achieving a comprehensive understanding of the phenomenon of nuclear clustering (the organization of protons and neutrons into distinct substructures within a nucleus). We have developed an efficient and general configuration-interaction framework for the description of low-energy reactions and clustering in light nuclei. The new formalism takes full advantage of powerful second-quantization techniques, enabling the description of $\alpha$-$\alpha$ scattering and an exploration of clustering in the exotic $^{12}$Be nucleus. We find that the $^4$He($\alpha$, $\alpha$)$^4$He differential cross section computed with non-locally regulated chiral interactions is in good agreement with experimental data. Our results for $^{12}$Be indicate the presence of strongly mixed helium-cluster states consistent with a molecular-like picture surviving far above the $^6$He+$^6$He threshold, and reveal the strong influence of neutron decay in both the $^{12}$Be spectrum and in the $^6$He($^6$He,$\alpha$)$^8$He cross section. We expect that this approach will enable the description of helium burning cross sections and provide insight on how three-nucleon forces influence the emergence of clustering in nuclei.