PIK3CA-related overgrowth spectrum (PROS) comprises mosaic gain-of-function variants in PIK3CA that lead to segmental overgrowth and complex vascular malformations. Renal involvement has been inconsistently described and mainly includes glomerulomegaly and focal segmental glomerulosclerosis. We report a 39-year-old woman with a phenotypic diagnosis of CLOVES syndrome molecularly supported by a somatic mosaic PIK3CA variant, NM_006218.4:c.1634 A > C, p.Glu545Ala, detected in affected hypertrophic tissue. She presented with acute kidney injury and subnephrotic-range proteinuria secondary to left renal vein thrombosis. Imaging revealed intrarenal venous congestion in the setting of extensive abdominal venous malformations. Anticoagulation resulted in complete radiologic and functional recovery. Renal vein thrombosis should be considered as a potentially reversible vascular cause of acute kidney injury and proteinuria in patients with CLOVES syndrome/PROS, particularly in the presence of extensive venous malformations.