The lack of immunodeficiency in SHORT syndrome argues that in B cell development, p85α plays an essential role that cannot be complemented by p55α and p50α, and that moreover does not depend critically on the C-terminal SH2 domain, which we show in other cell types is critical for p85 recruitment to IRS1 and phosphotyrosine-containing complexes. Here, PIK3R2 is linked to immunodeficiency disease.