Missense mutations in nuclear receptors (NR) transcription factors (TF) cause a number of genetic disorders, including PPARG mutations that result in familial partial lipodystrophy type 3 (FPLD3). Experimental assessment is essential to establish a newly identified mutation as disease-causing, as accurately predicting the effect of new mutation in silico remains challenging due to the multifunctional and modular nature of these proteins. However, deep structure-function characterisation often requires specialised and technically demanding approaches, which may not be readily available. Therefore, we established a simple and robust experimental framework, based on four complementary reporter assays that independently assess: (1) ability of the full-length receptor to activate transcription; (2) integrity of the ligand-binding domain (LBD); (3) heterodimerization potential; and (4) DNA binding capacity. As a proof-of-concept we analysed 3 uncharacterized FPLD3-associated loss-of-function (LOF) variants and two bladder cancer-associated gain-of-function (GOF) variants. Together, the four complementary assays showed unique functional phenotypes for all 5 mutants, that were further supported by co-regulator profiling. We therefore conclude that this framework provides a simple and robust first line approach to identify functional alterations in PPARγ mutants with mechanistic resolution. This framework is broadly applicable across NRs and offers a scalable path to systematic variant interpretation in both research and clinical contexts.