Single-molecule conductance measured at low bias in metal-molecule-metal junctions is generally a coherent electron transport process best described as a tunneling mechanism. The transmission through a molecule can be suppressed by destructive quantum interference; 2 a phenomenon that has been demonstrated in a variety of p-conjugated systems. In principle these molecules are ideal candidates for insulating molecular units, but when transmission through the underlying s-system is not suppressed such p-conjugated molecules cannot be more insulating than saturated molecules of equivalent length, such as alkanes. In recent work, we presented the first saturated molecule with destructive s-interference in the form of a functionalized bicyclo[2.2.2]octasilane (Si222) shown in Scheme 1. With a single-molecule conductance that is much lower than saturated molecules of the same length we consider Si222 the first quantum interference based single-molecule insulator. Given that the transmission is almost completely suppressed by destructive interference, we found that removing the insulating bicyclic part of the molecule in the simulation increases the transmission by an order of magnitude. The insulating bicyclic molecular component is, in theory, a better insulator than a gap of the same size; such is the peculiar effect of destructive s-interference. Scheme 1. Si222. Saturated s-conjugated molecules exhibit a rich variety of electronic properties, which are welldescribed for linear silanes in the literature. The strong electronic coupling through silanes make them candidates for conducting molecular wires, and an open question is how s-conjugation and s-interference effects change up or down group 14, from silicon to carbon and germanium. Wallner et al. prepared a series of mixed [2.2.2]bicyclic organosilanes, and several mixed saturated group 14 compounds have been reported. The all-carbon bicyclo[2.2.2]octane is a commonly used insulating bridge unit, for example in the original Aviram-Ratner rectifier. With the finding of the all-silicon counterpart as an extremely insulating moiety, the bicyclo[2.2.2]octane class of molecules is evidently a good place to start the search for single-molecule insulators. In this letter, we exhaust the full combined chemical space of saturated carbon, permethylated silicon, and permethylated germanium, as illustrated in Scheme 2, by using a high-throughput screening approach to asses all 771 possible molecules of the class.