NM_000157.4:c.1279G>A (p.Glu427Lys) is a missense variant in exon 9 of GBA1, located within the catalytic domain of glucocerebrosidase.¹ This variant is present at very low frequency in population databases: gnomAD v2.1 AF=0.0159% (45/282,860 alleles) and gnomAD v4.1 AF=0.0193% (311/1,614,180 alleles), with no homozygotes observed (PM2_Supporting).² The variant is located within the well-characterized catalytic domain of GBA1 where multiple pathogenic missense variants cluster (PM1_Supporting).³ This variant has been reported in ClinVar as Uncertain significance by 7 clinical laboratories (ClinVar Variation ID: 493050), with no expert panel classification available.⁴ In silico predictors are mixed: REVEL score is 0.579 (intermediate), BayesDel is 0.107 (benign-leaning), and SpliceAI predicts no splicing impact (max delta 0.07). Multiple lines of computational evidence do not consistently support a pathogenic or benign interpretation (PP3 not met, BP4 not met).⁵ Exploratory literature review identified potential functional evidence (PMID:10079102, PMID:15300782) reporting severely reduced glucocerebrosidase activity for E427K, and potential co-segregation evidence (PMID:9375849). However, full-text verification was not available in this case to confirm exact variant-specific data (PS3 and PP1 not assessed pending full-text review). Applying generic ACMG/AMP 2015 combination rules: PM1_Supporting + PM2_Supporting = 2 supporting pathogenic criteria. No benign criteria are met. This is consistent with a final classification of Variant of Uncertain Significance (VUS).⁶