Precisely manipulating asymmetric coordination configurations and examining electronic effects enable to tunethe intrinsic oxygen reduction reaction (ORR) activity of single-atom catalysts (SACs). However, the lackof a definite relationship between coordination asymmetry and catalytic activity makes the rational design of SACs ambiguous. Here, we propose a concept of "asymmetry degree" to quantify asymmetric coordination configurations and assess the effectiveness of active moieties in Fe-based SACs. A theoretical framework is established, elucidating the volcanic relationship between asymmetry degree and ORR activity by constructing a series of Fe-based SAC models doped with non-metal atoms (B, P, S, Se, and Te) in the first or second coordination sphere, which aligns with Sabatier principle. The predicted ORR activity of Fe asymmetric active moieties is then experimentally validated using asymmetry degree. The combined computational and experimental results suggest that single-atom moiety with a moderate asymmetry degree exhibits optimal intrinsic ORR activity, because breaking the square-planar symmetry of FeN