NM_181523.2:c.1355A>G (p.Tyr452Cys) in PIK3R1 is extremely rare in population databases (gnomAD v4.1 allele frequency 6.47e-7, 1 heterozygous allele among 1,544,610 alleles), meeting PM2_Supporting per Antibody Deficiencies VCEP specifications.¹ The variant is absent from ClinVar and has not been reported in any germline patient cohort, precluding assessment of PS4, PP1, PP4, or de novo criteria (PS2).² No functional data are available for this specific variant in any VCEP-approved assay (AKT kinase, lipid kinase, protein binding, conformational dynamics, knock-in mouse, or the PMID:40543502 screen); PS3 and BS3 cannot be assessed.³ Computational predictors are indeterminate: REVEL 0.55 is intermediate between VCEP PP3 (≥0.644) and BP4 (≤0.290) thresholds, and SpliceAI predicts no splicing impact (max delta 0.00).⁴ Under the Bayesian point-based framework adopted by the Antibody Deficiencies VCEP (≥10 = Pathogenic, 6-9 = Likely Pathogenic, 0-5 = VUS, -6 to -1 = Likely Benign, ≤-7 = Benign), the single PM2_Supporting assignment yields 1 point, classifying this variant as a Variant of Uncertain Significance.⁵