ClinVar

Description

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 53 of the PAH protein (p.Arg53Ser). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAH protein function. ClinVar contains an entry for this variant (Variation ID: 1478759). This missense change has been observed in individual(s) with hyperphenylalaninemia (Invitae). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database.