{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:08:19Z","timestamp":1785424099911,"version":"3.56.0"},"reference-count":27,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Higher Education of the Republic of Kazakhstan","award":["BR24992881"],"award-info":[{"award-number":["BR24992881"]}]},{"award":["BR24992881"],"award-info":[{"award-number":["BR24992881"]}],"id":[{"id":"https:\/\/ror.org\/05tyne317","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>The Phenylalanine Hydroxylase Gene Locus-Specific Database and BIOPKU are public databases used to track genotypes in hyperphenylalaninemia. However, the rapidly expanding databases and evolving nomenclature standards require a comprehensive characterization of the current variant landscape. We performed a descriptive statistical analysis of PAH variant allocations, allele frequencies (AF%), and phenotypic annotations using PAHvdb database. Over the period 2022\u20132026, the PAHvdb expanded by 169.26%. Of the 3409 variants studied, 75.68% of the phenotypes were not assigned. Splicing-related mutations comprised approximately 4.37% of the database, with classic phenylketonuria phenotypes represented in both donor\u2013acceptor and splice-region categories. Only 3.84% of the variants had enzymatic activity (EA%) data, which offer the most direct biochemical evidence for genotype\u2013phenotype inference. The strong Spearman\u2019s rank correlation coefficient (\u03c1) between EA% and APV (\u03c1 = 0.745, p &lt; 0.001) was consistent with the established relationship between residual PAH EA% and the severity of metabolic phenotype. The AF% distribution was markedly asymmetric and dominated by a small number of alleles that were most frequently reported in the database. These findings highlight the increasing clinical reliance on these databases. Our analysis highlights a heterogeneity of rare, uncharacterized variants of uncertain significance and underscores the need for unified, systematic reviews to standardize nomenclature and resolve phenotype\u2013genotype discrepancies.<\/jats:p>","DOI":"10.3390\/ijms27156772","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T08:16:52Z","timestamp":1785313012000},"page":"6772","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Analysis of PAH Genetic Variation and Phenotypic Diversity in the PAHvdb"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9418-7758","authenticated-orcid":false,"given":"Asylulan","family":"Amirgazin","sequence":"first","affiliation":[{"name":"Laboratory of Applied Genetics, National Center for Biotechnology, Astana 010000, Kazakhstan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bakhyt","family":"Mambetpayeva","sequence":"additional","affiliation":[{"name":"Medical Genetics and Molecular Biology Department, NCJSC \u201cAstana Medical University\u201d, Astana 010000, Kazakhstan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2206-7890","authenticated-orcid":false,"given":"Assel","family":"Akhmetova","sequence":"additional","affiliation":[{"name":"Laboratory of Applied Genetics, National Center for Biotechnology, Astana 010000, Kazakhstan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9864-2700","authenticated-orcid":false,"given":"Alma","family":"Kairzhanova","sequence":"additional","affiliation":[{"name":"Laboratory of Applied Genetics, National Center for Biotechnology, Astana 010000, Kazakhstan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0307-1053","authenticated-orcid":false,"given":"Alexandr","family":"Shevtsov","sequence":"additional","affiliation":[{"name":"Laboratory of Applied Genetics, National Center for Biotechnology, Astana 010000, Kazakhstan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"ref_1","first-page":"245","article-title":"The Phenylalanine Hydroxylating System from Mammalian Liver","volume":"Volume 35","author":"Meister","year":"1971","journal-title":"Advances in Enzymology and Related Areas of Molecular Biology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/s41572-021-00267-0","article-title":"Phenylketonuria","volume":"7","author":"Blau","year":"2021","journal-title":"Nat. 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