This study presents an extensive plant-wide model-based assessment of four alternative activated sludge (AS) configurations for biological nitrogen (N) and phosphorus (P) removal under uncertain influent loads and characteristics. Zeekoegat wastewater treatment plant (WWTP) in South Africa was chosen as case study due to its flexible design that enables operation in four different AS configurations: 3-stage Bardenpho (A2O), University of Cape Town (UCT), UCT modified (UCTM), and Johannesburg (JHB). A metamodeling based global sensitivity analysis was performed on a steady-state plant-wide simulation model using Activated Sludge Model No. 2d with the latest extension of physico-chemical processes describing the plant-wide P transformations. The simulation results showed that the predictions of effluent chemical oxygen demand (COD), N and P using the proposed approach fall within the interquartile range of measured data. The study also revealed that process configuration can affect: 1) how influent uncertainty is reflected in model predictions for effluent quality and cost related performances, and 2) the parameter rankings based on variance decomposition, particularly for effluent phosphate, sludge disposal and methane production. The results identified UCT and UCTM as more robust configurations for P removal (less propagated uncertainty and less sensitivity to N load) in the expense of incomplete denitrification. Moreover, based on the results of Monte-Carlo based scenario analysis, the balanced SRT for N and P removal is more sensitive to influent load variation/uncertainty for the A2O and JHB configurations. This gives a more operational flexibility to UCT and UCTM, where a narrow SRT range can ensure both N and P removal.