Isometric pyrochlore, A(2)B(2)O(7), with compositions in the Y-2(Ti,Sn,Zr)(2)O-7 ternary system, are of particular interest because there are dramatic changes in properties, such as ionic conductivity, and response to radiation damage, as a function of disordering of the A- and B-site cations and oxygen vacancies. First-principles calculations using density functional theory and the plane-wave pseudopotential method, predict lattice constants (1.0049-1.0463 nm), atomic coordinates, and bulk moduli (176-205 GPa) that are linearly dependent on the B-site cation radius (0.062-0.072 nm). However, the energetics for the formation of cation-antisite (0-2 eV) and Frenkel-pair (4-11 eV) defects do not correlate with cation size, underscoring the importance of the specific electronic configuration of the B-site cation. The greater degree of covalent bonding between as compared with or results in defect formation energies otherwise unexpected solely due to the radius ratios of the cation species. Y2Sn2O7 shows 2-4 eV greater defect formation energies than otherwise predicted through mean B-site cation sizes. Relaxed calculations on coupled cation-antisite and Frenkel-pair defects show that cation-antisite reactions likely drive the oxygen-Frenkel pair defect formation process that ultimately leads to increased oxygen mobility and completely aperiodic structures. Total charge and partial density of states calculations show strikingly different behavior of oxygen on two different crystallographic positions, emphasizing the need for a full account of the electronic structure.