The AKT1 c.49G>A (p.Glu17Lys) variant resides in the pleckstrin homology (PH) domain, a critical functional domain, and lies within a statistically significant mutational hotspot where benign missense variation is notably absent (PM1_Moderate).¹ This variant is present in gnomAD v2.1 at an extremely low allele frequency of 0.0004% (1/250,006 alleles) and is absent from gnomAD v4.1, meeting the PM2 threshold for absence from population databases (PM2_Supporting).² Well-established functional studies from multiple independent laboratories demonstrate that the E17K substitution results in constitutive AKT1 kinase activation, altered lipid-binding specificity, enhanced downstream signaling, transformation in cell-based assays, and oncogenesis in murine models (PS3_Strong).³ ClinVar reports this variant as Pathogenic by 4 clinical laboratories including Labcorp Genetics/Invitae and Variantyx (PP5_Supporting).⁴ The computational in silico predictors are equivocal (REVEL 0.51, BayesDel 0.116); PP3 is not met. BS3 is contradicted by overwhelming functional evidence of a damaging gain-of-function effect. BA1 and BS1 are not met given the extremely low population frequency.⁵ Under the generic ACMG/AMP 2015 framework (PMID:25741868), the criteria met are: PS3_Strong + PM1_Moderate + PM2_Supporting + PP5_Supporting. This combination (1 Strong + 1 Moderate + 2 Supporting) meets the threshold for Likely Pathogenic per Richards et al. 2015 (1 Strong AND ≥1 Moderate AND ≥2 Supporting qualifies as Likely Pathogenic).⁶