The crystal structures significantly affect the electrical, optical, and mechanical properties of materials, leading to exotic physical phenomena in advanced functional materials. Solid solutions are often employed for crystal manipulation with the goal of discovering new atomic structures possessing novel properties. A practical guideline for adjusting the atomic structure symmetry of different materials is highly expected for the design of functional materials. By examining the similarity of close-packed layers in inorganic materials with different functionalities, a linear dependency between structural symmetry and composition is revealed. "Layer stacking slabs" can serve as a concise and practical pathway for structural manipulation by layer-stacking-unit rearrangement, which is promising for designing materials with various crystal symmetries and characteristics. This layer-stacking-oriented structure manipulation is further confirmed by X-ray diffraction, transmission electron microscopy imaging, and synchrotron X-ray pair distribution function analysis. Following the close-packed layer spacing guidance, a new possible thermoelectric material system of (I−V−VI 2 )−(V 2 −VI 3 ) has been experimentally synthesized in this work, thereby expanding the range of thermoelectric candidates. The layer-spacing-based structural indicator exhibits the potential for accelerating the exploration of new functional materials across different application fields.