Safety factor is not applied to the payload.
Once the biggest loadcase for each component of the airframe has been defined, a safety factor is applied to these loads and the structure is sized consequently.
For example, for a standard jetliner the OEI is normally the designing case for the vertical stabiliser. Once the aerodynamic load on the vertical stabiliser has been calculated for that case, this load is multiplied by the safety factor and then used to size the structure of the vertical fin.
the weight variance with such a large aircraft will be small?
Aircraft's airframes are extremely efficient and payload is therefore not a small part of the MTOW: for an A350, payload can be as high as 68000kg with a MTOW of 316000kg i.e. some 20% of the MTOW.