Saturated organic molecules are considered to be good molecular insulators and find widespread use in studies of electronic and magnetic communication between functional molecular units. Destructive quantum interference in the s-system can further enable the design of saturated molecules where the electronic transmission is almost completely suppressed. Destructive sinterference may appear in saturated molecules when all through-bond paths in the molecular backbone have at least one gauche defect, i.e., a dihedral angle approaching 0°. However, full suppression of the single-molecule conductance is not often achieved and it is not always clear if the partial suppression is due to an interference effect. For example, the gauche conformations of simple linear alkanes have lower conductance than the trans conformations; however, clear signatures of destructive quantum interference are missing, such as sharp antiresonance dips in the electronic transmission. When s-interference effects manifest, the conductance is highly sensitive to details in the molecular geometry. Based on the extensive topological understanding of interference effects in p-systems, we expect a similar intuition should be found for s-systems. However, it is an ongoing challenge to understand the structure-property relationships for the single-molecule conductance of saturated group 14 systems. We reported a surprising chemical sensitivity of the s-interference effect. Despite the benign nature of the substituents, the electronic transmission of functionalized cyclohexane, cyclohexasilane, bicyclo[2.2.2]octane, and bicyclo[2.2.2]octasilane is systematically lower when the molecules are permethylated. This is exemplified in Figure Substituent effects are well-established for destructive quantum interference effects in conjugated molecules. The destructive p-interference effect can be systematically manipulated depending on the electron donating or withdrawing character of the substituent. Here, we examine the substituent effect on the electronic transmission of methylthiomethyl-functionalized bicyclo[2.2.2]octane (C222), bicyclo[2.2.2]octasilane, and bicyclo[2.2.2]octagermane (Ge222).