Tafazzin (EC 2.3.1.23) is a Phospholipid Transacylase involved in Cardiolipin 
remodeling on mitochondrial membrane and coded by TAZ gene (Cytogenetic 
Location: Xq28) in human. Its mutations cause Barth syndrome (MIM ID: 
#302060)/3-Methyl Glutaconyl Aciduria Type II, an inborn error of metabolism 
often leading to foetal or infantile fatality. Nevertheless, some mis-sense 
mutations result in mild clinical symptoms. To evaluate the rationale of mild 
symptoms and for an insight of Tafazzin active site, sequence based and 
structure based ramifications of wild and mutant Tafazzins were compared 
in-silico. Sequence based domain predictions, surface accessibilities on 
substitution & conserved catalytic sites with statistical drifts, as well as 
thermal stability changes for the mutations and the interaction analysis of 
Tafazzin were performed. Crystal structure of Tafazzin is not yet resolved 
experimentally, therefore 3D coordinates of Tafazzin and its mutants were 
spawned through homology modeling. Energetically minimized and structurally 
validated models were used for comparative docking simulations. We analyzed 
active site geometry of the models in addition to calculating overall substrate 
binding efficiencies for each of the enzyme-ligand complex deduced from binding 
energies instead of comparing only the docking scores. Also, individual binding 
energies of catalytic residues on conserved HX4D motif of Acyltransferase 
superfamily present in Tafazzins were estimated. This work elucidates the basis 
of mild symptoms in patients with mis-sense mutations, identifies the most 
pathogenic mutant among others in the study and also divulges the critical role 
of HX4D domain towards successful transacylation by Taffazin. The in-silico 
observations are in complete agreement with clinical findings reported for the 
patients with mutations.