HYCC2 and colorectal carcinoma: Here we devised a bioinformatic method to identify SL interactions among gene paralogs in CRC cell lines and discovered that the expression level of FAM126A correlated with the essentiality of FAM126B. Using a combination of in vitro and in vivo approaches, we validated the SL interaction between FAM126A and FAM126B and demonstrated that loss of both FAM126A and FAM126B impaired plasma membrane phosphoinositide 4-phosphate synthesis to cause cell death.