The scope of this paper is to give an insight into the advantages of a new, all-embracing, modeling approach of a strong ground motion scenario, by carrying out a source-to-structure analysis at regional scale, accounting explicitly for the uncertainties related to the databases and the models. To this end, a suitable case-study is represented by the 2007 Mw6.6 Niigata-Ken Ch¯ uetsu-Oki seismic sequence (west Japan), that damaged the Kashiwazaki Kariwa Nuclear Power Plant. This study describes the effect of the wave propagation path within the Earth's crust on the seismic response of nuclear reactor buildings located nearby a seismogenic source. The multiscale problem is de-coupled into three steps: (1) a parallel simulation of seismic-wave propagation throughout the Earth's crust at regional scale (≈ 60 km wide, major 3-D geological interfaces found below the nuclear site), reliable up to 5.0 Hz; (2) a mid hybridization step consisting in enriching the synthetic wave-field at high frequency (up to 30 Hz), employing an Artificial Neural Network to predict the short-period (SP) spectral ordinates; (3) a high-resolution structural dynamic analysis, introducing the hybrid broad-band synthetics as input wave-motion. A simplified stress-test is performed, ✩ Fully documented templates are available in the elsarticle package on CTAN. by simulating two small point-wise aftershocks at different source-site position. The impact of the underground 3-D geology on the structural components is finally quantified, by injecting the obtained broad-band time-histories in a Soil-Structure Interaction (SSI) model of the nuclear reactor building. The good fit obtained in terms of amplification factor at different recording stations assures the high-fidelity of the holistic philosophy endorsed.