The NM_000277.3(PAH):c.181A>G variant in PAH is a missense variant predicted to cause substitution of asparagine to aspartic acid at amino acid 61 (p.Asn61Asp). At least one patient with this variant displayed plasma phenylalanine concentration persistently above 120umol/L (2mg/dL) AND sequencing of genes in the BH4 cofactor metabolism pathway to exclude a defect of BH4 cofactor metabolism, which is highly specific for Phenylketonuria (PMID:12501224) (PP4_Moderate). This individual was compound heterozygous for the variant and a pathogenic variant p.R261Q in unknown phase (PMID: 12501224, PM3_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.703, which is above the threshold of 0.644 but below 0.773, evidence that correlates with supporting impact to PAH function (PP3). 2 different missense variants c.182A>G (p.Asn61Ser) and c.183C>A (p.Asn61Lys) in the same codon have been classified as pathogenic/likely pathogenic for PAH deficiency by the ClinGen PAH Variant Curation Expert Panel (PM5). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Phenylketonuria VCEP: PP4_moderate, PP3, PM2_supporting, PM3_supporting, PM5 (Version 2.0, 7/16/2024).