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Protein Phosphatase 2 Regulatory Subunit B&#8242; Delta (<i>PPP2R5D</i>)-related intellectual disability (ID) and neurodevelopmental delay results from germline de novo mutations in the <i>PPP2R5D</i> gene. This gene encodes the protein PPP2R5D (also known as the B56 delta subunit), which is an isoform of the subunit family B56 of the enzyme serine/threonine-protein phosphatase 2A (PP2A). Clinical signs include intellectual disability (ID); autism spectrum disorder (ASD); epilepsy; speech problems; behavioral challenges; and ophthalmologic, skeletal, endocrine, cardiac, and genital malformations. The association of defective PP2A activity in the brain with a wide range of severity of ID, along with its role in ASD, Alzheimer&#8217;s disease, and Parkinson&#8217;s-like symptoms, have recently generated the impetus for further research into mutations within this gene. PP2A, together with protein phosphatase 1 (PP1), accounts for more than 90% of all phospho-serine/threonine dephosphorylations in different tissues. The specificity for a wide variety of substrates is determined through nearly 100 different PP2A holoenzymes that are formed by at least 23 types of regulatory B subunits, and two isoforms each of the catalytic subunit C and the structural subunit A. In the mammalian brain, PP2A-mediated protein dephosphorylation plays an important role in learning and memory. The PPP2R5D subunit is highly expressed in the brain and the PPP2A&#8722;PPP2R5D holoenzyme plays an important role in maintaining neurons and regulating neuronal signaling. From 2015 to 2017, 25 individuals with <i>PPP2R5D</i>-related developmental disorder were diagnosed. Since then, Whole-Exome Sequencing (WES) has helped to identify more unrelated individuals clinically diagnosed with a neurodevelopmental disorder with pathological variants of <i>PPP2R5D</i>. In this review, we discuss the current understanding of the clinical and genetic aspects of the disorder in the context of the known functions of the PP2A&#8722;PPP2R5D holoenzyme in the brain, as well as the pathogenic mutations in <i>PPP2R5D</i> that lead to deficient PP2A&#8722;PPP2R5D dephosphorylation and their implications during development and in the etiology of autism, Parkinson&#8217;s disease, Alzheimer&#8217;s disease, and so forth. In the future, tools such as transgenic animals carrying pathogenic PPP2R5D mutations, and patient-derived induced pluripotent stem cell lines need to be developed in order to fully understand the effects of these mutations on different neural cell types.