DGKE encodes a membrane-bound diacylglycerol kinase that converts diacylglycerol into phosphatidic acid, thereby regulating signaling pathways activated by these competing lipid second messengers. The enzyme displays specificity for diacylglycerols with arachidonoyl acyl chains, particularly those involved in phosphatidylinositol turnover. Clinically, DGKE is most notable for its role in atypical hemolytic uremic syndrome (aHUS). Recessive loss-of-function mutations cause infantile aHUS characterized by thrombocytopenia, hemolytic anemia, acute kidney injury, and podocyte dysfunction with proteinuria 1. Unlike most aHUS cases driven by complement dysregulation, DGKE-deficient aHUS occurs through a distinct mechanism; emerging evidence suggests an interplay between DGKE and complement systems rather than primary complement pathway dysregulation 1. Among patients with no detectable complement defect, some harbor impaired DGKE activity 2. Therapeutic options remain incompletely defined. Complement inhibition with eculizumab (a C5 blocker) typically fails in DGKE-mutant patients, whereas case reports document responses to eculizumab in some DGKE-mutation carriers, and plasma exchange has shown efficacy 2, 3. DGKE also protects against acute kidney injury through KLF15/Klotho signaling 4. At the population level, gnomAD v4.1 classifies DGKE as loss-of-function tolerant (LOEUF=0.99); this population-level constraint is distinct from the clinically significant pathogenic variant burden (59 ClinVar pathogenic/likely pathogenic variants) observed in kidney disease.