PIK3R1 encodes p85α, the regulatory subunit of phosphoinositide 3-kinase (PI3K), an enzyme complex that produces signaling molecules controlling cell growth, proliferation, and survival. The protein normally stabilizes and inhibits the PI3K catalytic subunit and helps the complex respond to signals from cell-surface receptors, including insulin, so alterations in this gene are associated with insulin resistance. PIK3R1 acts as a tumor suppressor: mutations that disrupt its inhibitory function can lead to abnormally active PI3K/AKT signaling and are found in several cancers, most often glioblastoma, as well as endometrial, breast, and colorectal cancers.

PIK3R1 encodes p85α, which restrains PI3K signaling, and damaging germline changes are linked to immunodeficiency with insulin resistance, while somatic mutations in this gene drive several cancers. This p.(Gly376Arg) change sits in a region where cancer-associated PIK3R1 mutations cluster, yet it is classified VUS: with only PM2 met, current evidence is insufficient to determine whether this germline change disrupts p85α function.