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Nonsense mutations convert a sense codon into a premature termination codon (PTC), leading to premature translation termination and the production of truncated, nonfunctional proteins. This results in a loss\u2010of\u2010function phenotype in many genetic disorders, contributing to the disease's severity and progression. The molecular mechanisms of PTC formation involve various genetic alterations, including single\u2010nucleotide changes, frameshifts, and splicing mutations. The nonsense\u2010mediated mRNA decay (NMD) pathway degrades mRNAs containing premature termination codons (PTCs). In contrast, 25% of PTC mRNAs, depending on the PTC position and cellular context, can evade NMD, resulting in the synthesis of truncated proteins. A termination codon during translation is essential for proper protein synthesis, and translational readthrough\u2014a process in which the ribosome bypasses the PTC and reaches the natural stop codon\u2014may restore some level of protein function. The effectiveness of readthrough depends on the surrounding genetic context and the type of amino acid incorporated at the PTC position. This review aims to explore the molecular characteristics of nonsense\u2010related diseases (NRDs), including cystic fibrosis, hemophilia, Fabry disease, choroideremia, Usher syndrome, Shwachman\u2010Diamond syndrome, and certain hereditary neuropathies and cancers.<\/jats:p>","DOI":"10.1002\/iub.70031","type":"journal-article","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T04:08:51Z","timestamp":1749182931000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Nonsense Mutations in Rare and Ultra\u2010Rare Human Disorders: An Overview"],"prefix":"10.1002","volume":"77","author":[{"given":"Emanuele","family":"Vitale","sequence":"first","affiliation":[{"name":"Department of Biological, Chemical and Pharmaceutical Sciences and Technologies University of Palermo  Palermo 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