Shrinkage porosities and non-metallic inclusions are common manufacturing process based defects that are present within cast materials. Conventional fatigue design recommendations, such as the FKM guideline (“Forschungskuratorium Maschinenbau”), therefore propose general safety factors for the fatigue assessment of cast structures. In fact, these factors mostly lead to oversized components and do not facilitate a lightweight design process. In this work, the effect of shrinkage porosities on the fatigue strength of defect-afflicted large-scale specimens manufactured from the cast steel G21Mn5 is studied by means of a notch stress intensity factor-based (NSIF-based) generalized Kitagawa diagram. Additionally, the mean stress sensitivity of the material is taken into account and establishes a load stress ratio enhanced diagram. Thereby, the fatigue assessment approach is performed by utilizing the defects sizes taken either from the fracture surface of the tested specimens or from non-destructive X-ray investigations. Additionally, a numerical algorithm invoking cellular automata, which enables the generation of artificial defects, is presented. Conclusively, a comparison to the results of the experimental investigations reveals a sound agreement to the generated spatial pore geometries. To sum up, the generalized Kitagawa diagram, as well as a concept utilizing artificially generated defects, is capable of assessing the local fatigue limit of cast steel G21Mn5 components and features the mapping of imperfection grades to their corresponding fatigue strength limit.