NM_181523.2:c.310A>G (p.Thr104Ala) in PIK3R1 is a novel missense variant absent from all population databases including gnomAD v4.1, meeting PM2_Supporting per the VCEP allele frequency threshold (<0.00000132).¹ Computational evidence is benign-leaning: REVEL score is 0.125, BayesDel is -0.618838, and SpliceAI predicts no splice impact (max delta 0.00). PP3 thresholds (REVEL ≥0.644, SpliceAI ≥0.2) are not met.² No functional studies, clinical cases, co-segregation data, or literature reports were identified for this specific variant. PVS1, PS1-PS5, PP1, PP3-PP5, BA1, BS1, BS3-BS4, and BP5 are not met. Multiple criteria (PM1, PM5, PM6, BP1, BP2, BP6, BP7, PP2, PP5, BS2) are designated as not applicable by the PIK3R1 VCEP. BP4 could not be fully assessed due to absence of CADD score.³ Using the Bayesian point-based framework adopted by the Antibody Deficiencies VCEP (Tavtigian 2020, PMID:32720330), the sole met criterion PM2_Supporting contributes +1 point (supporting). The total score of 1 falls in the 0–5 range, corresponding to a classification of Uncertain Significance.⁴