An Adaptive Metamodel-Based Subset Importance Sampling (AM-SIS) approach, previously developed by the authors, is here employed to assess the (small) functional failure probability of a thermal-hydraulic (T-H) nuclear passive safety system. The approach relies on an iterative Importance Sampling (IS) scheme that efficiently couples the powerful characteristics of Subset Simulation (SS) and fast-running Artificial Neural Networks (ANNs). In particular, SS and ANNs are intelligently employed to build and progressively refine a fully nonparametric estimator of the ideal, zero-variance Importance Sampling Density (ISD), in order to: (i) increase the robustness of the failure probability estimates and (ii) decrease the number of expensive T-H simulations needed (together with the related computational burden). The performance of the approach is thoroughly compared to that of other efficient Monte Carlo (MC) techniques on a case study involving an advanced nuclear reactor cooled by helium.