The NM_000152.5:c.4G>T (p.Gly2Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Of note, SpliceAI predicts the possible activation of a cryptic donor splice site 2 bp upstream from the variant which, if used could result in the loss of the remainder of exon 2, including the signal sequence; there is no experimental evidence in normal tissue or minigene to confirm that impact. The highest population minor allele frequency in gnomAD v4.1.0. is 0.000001697 (2/1178586 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). To our knowledge, this variant has not been reported in individuals with Pompe disease in the literature and functional studies are unavailable. There is a ClinVar entry for this variant (Variation ID: 560377). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, July 21, 2026)