Pluripotent stem cells (PSCs) are a promising tool both for regenerative medicine, as well as various research fields, e.g. in vitro disease modelling. In the field of cardiogenesis, hPSCs have been used to generate cardiomyocytes for cell replacement therapy and studying various heart-related disorders. However, a major concern in the field is the frequent and spontaneous reoccurrence of a common set of large-scale genetic aberrations, e.g. gains of chromosomes 1, 12, 17, 20 and X. Such genetic changes confer PSCs with an advantage over genetically normal PSCs. These cells are known as genetically variant (GV) PSCs. For regenerative medicine particular concerns surrounding GV PSCs arise in the potential of, implanting mutated cells which could lead to the formation of cancers in patients, impacting the ability of PSCs to efficiently differentiate, as well as altering the functionality of differentiated cell types. Here we investigated the ability of WT hPSCs and variant 1q GV counterparts to differentiate to cardiomyocytes. We showed that GV hPSCs harboring 1q gain show a block in the differentiation to cardiomyocytes under the optimized conditions of their WT counterparts. Mechanistically, we demonstrated that this apparent block in differentiation is caused by aberrant Wnt signaling in GV hPSCs. By manipulating Wnt, we were able to rescue the differentiation of GV hPSCs, but the resulting cells were phenotypically and transcriptionally distinct from their wild-type counterparts.  Together, our study demonstrates that genetic changes acquired in the pluripotent state affect differentiation ability of hPSCs and the phenotype of their differentiated derivatives.