The burden test indicated that any autoimmune diagnosis (1.63 [1.14, 2.09], p = 2.665 × 10−3) and multiple sclerosis (3.42 [1.67, 6.02], p = 9.681 × 10−4) are associated with a NOTCH3 cysteine-altering variant in any domain. Here, NOTCH3 is linked to multiple sclerosis.