An extensively studied cancer and Autism Spectrum Disorders (ASD) gene PTEN provided an exclusive opportunity to map its mutational-landscape, compare and establish plausible genotypic predictors of ASD-associated phenotypic outcomes. Our exhaustive in silico analysis on 4252 SNPs using >30 tools identified increased mutational-density in exon7. Phosphatase domain, although evolutionarily conserved, had the most nsSNPs localised within signature regions. The evolutionarily variable C-terminal contained the highest truncating-SNPs outside signature regions of C2 domain and highest PTMs within C-tail that displayed maximum intolerance to polymorphisms, permitting benign but destabilising nsSNPs that enhanced its intrinsically-disordered nature. ASD-associated SNPs localised within ATP-binding motifs and Nuclear-Localising-Sequences were the most potent triggers of ASD manifestation. These, along with variations within P, WPD and TI loops, M1 within phosphatase domain, M2 and MoRFs of C2 domain, caused severe long-range conformational fluctuations altering PTEN’s dynamic stability- not observed in variations outside signature regions. 3’UTR-SNPs affected 44 strong miRNA brain-specific targets; several 5′ UTR-SNPs targeted transcription-factor POLR2A and 10 pathogenic Splice-Affecting-Variants were identified.Copyright © 2020. Published by Elsevier Inc.