RASA1

RASA1, also known as Ras p21 protein activator 1 or p120RasGAP, is a human gene that encodes a member of the Ras GTPase-activating protein (GAP) family. The protein acts as a negative regulator of Ras signaling by accelerating the hydrolysis of Ras-bound GTP to GDP, thereby switching Ras from an active to an inactive state and dampening downstream MAPK pathway activity. Through its SH2/SH3-containing architecture and a GAP-related domain, p120RasGAP participates in recruiting and regulating Ras at membranes and in signaling complexes.

RASA1 is widely expressed in multiple tissues, with notable involvement in vascular development and endothelial cell function. In development, RASA1 participates in angiogenesis and vascular remodeling, and experimental disruption in model organisms results in vascular abnormalities, confirming a role in blood vessel morphogenesis.

Germline pathogenic variants in RASA1 cause capillary malformation-arteriovenous malformation (CM-AVM) syndrome, an autosomal dominant disorder characterized by widespread capillary malformations and a risk of arteriovenous malformations in organs such as the brain, spine, or limbs. The condition shows variable expressivity and incomplete penetrance. Somatic RASA1 mutations have also been reported in sporadic vascular malformations and, less commonly, in tumors, supporting a broader role for RASA1 in vascular biology and oncogenesis.

Diagnosis is based on clinical features and confirmed by sequencing of RASA1. Management focuses on surveillance for AVMs and treatment of vascular lesions when necessary, often using endovascular or surgical approaches tailored to the lesion's location and size. Understanding RASA1 signaling continues to inform approaches to vascular anomalies and Ras pathway–related diseases.