NM_181523.2:c.1345_1347del (p.Leu449del) is an in-frame deletion of a single amino acid in exon 11 of PIK3R1, which encodes the p85-alpha regulatory subunit of PI3K. The variant has not been reported in ClinVar and is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2_Supporting under the Antibody Deficiencies VCEP framework (total AF = 0; threshold <0.00000132).¹ The variant has been observed in somatic cancers (COSMIC COSV57127217, n=5) and is annotated as Likely Oncogenic / Likely Loss-of-function by OncoKB. However, no variant-specific germline functional data are available from VCEP-approved assays (lipid kinase activity, AKT kinase activity, protein binding, conformational dynamics, mouse knock-in, or pS6/pAKT T-cell enrichment assay). PS3 and BS3 are not met.² PVS1, PS1, PM1, PM5, PM6, PP2, PP5, BS2, BP1, BP2, BP3, BP6, and BP7 are not applicable under the Antibody Deficiencies VCEP specifications. PM4 is not met because the deletion removes only one amino acid (threshold: >=2 amino acids). PP3 and BP4 do not apply to in-frame deletions under current VCEP rules. BA1 and BS1 are not met as the variant is absent from population databases.³ PS2, PS4, PP1, PP4, BS4, and BP5 cannot be assessed due to absence of proband phenotype data, family segregation studies, and alternative molecular diagnoses in the available literature and case materials. Applying the PIK3R1 VCEP Bayesian point-based classification framework (Tavtigian 2020 adaptation): the only met criterion is PM2_Supporting (+1 point). Total = 1 point, which falls in the VUS range (0-5 points). The evidence is insufficient to classify this variant as pathogenic or benign at this time.⁴