The c.614A>C variant in PAH is a missense variant predicted to cause substitution of glutamic acid by alanine at amino acid 205 (p.Glu205Ala). At least one patient with this variant displayed plasma phenylalanine concentration persistently above 120umol/L (2mg/dL) without analysis of urine pterins, DHPR activity, or sequencing to exclude defects of BH4 cofactor metabolism, which is highly specific for PAH deficiency (PP4_Supporting, PMID: 11180595). This individual was compound heterozygous for the variant and a pathogenic variant (phase unknown, PM3_supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.969, which meets the threshold of 0.932, evidence that correlates with strong impact to PAH function (PP3_Strong). Another missense variant c.613G>A (p.Glu205Lys) [ClinVar Variation ID: 102759] in the same codon has been classified as likely pathogenic for PAH deficiency by the ClinGen PAH Variant Curation Expert Panel (PM5_Supporting). 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 PAH Variant Curation Expert Panel: PP3_strong, PP4, PM2_supporting, PM3_supporting, PM5_supporting (PAH VCEP specifications version 2.0.0; approved July 16, 2024).