The PAH variant c.707-1G>A (IVS6-1G>A) is a null variant (acceptor site) located in exon number 7 of the PAH gene. Loss of function in the PAH gene is a known mechanism of disease. Eleven null variants in exon 7 of the PAH gene have been reported. This variant causes exon skipping that results in the removal of more than 10% of the transcript. This variant is predicted to disrupt the reading frame, altering regions critical to protein function (63 pathogenic non-nonsense variants in skipped exons have been reported). The mRNA transcript is predicted to undergo NMD. According to TraP in silico splicing prediction, this alteration is probably damaging (TraP score 0.572). HSF (-31.55% variation) and MaxEnt (-114.25% variation) agree that this alteration of the WT acceptor site most probably affects splicing. The PAH variant c.707-1G>A (IVS6-1G>A) was identified in three alleles from Chinese patients with classical PKU. The patients had a plasma Phe level above 120 μmol/L. DHPR activity, biopterin, and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 28754886, 30747360). The PAH variant c.707-1G>A (IVS6-1G>A) was detected in two Chinese patients with classic PKU (cPKU Phe more than 1200 μmol/L). These two patients were identified with the likely pathogenic PAH variant c.1285C>A (p.Gln429Lys) (ClinVar ID: 551555) and with the pathogenic PAH variant c.526C>T (p.Arg176Ter) (ClinVar ID: 102723) Pathogenic PM3 Points: 0.75 (Supporting) (PMID: 28754886) This variant is absent in the gnomAD, ExAC , and PAGE population databases. In summary, this variant meets the criteria to be classified as pathogenic. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Supporting, PP4_Moderate, PVS1.