TM2D3 (TM2 domain containing 3) is a transmembrane protein localized to the endoplasmic reticulum that functions as a positive regulator of Notch signaling 12. The protein is conserved across metazoans and appears to regulate Notch signaling at the γ-secretase cleavage step, with overexpression of its conserved region acting as a potent inhibitor of this pathway 3. TM2D3 also influences phagocytosis, particularly the uptake of amyloid-β aggregates 4. The gene is highly expressed in the central nervous system and plays critical roles in cellular stress response and mitochondrial function 2. Bi-allelic variants in TM2D3 cause severe syndromic neurodevelopmental disorders characterized by microcephaly, developmental delay, and dysmorphic features, associated with ER stress sensitivity and secondary mitochondrial alterations 2. A rare functional variant (P155L) is associated with increased risk and earlier onset of late-onset Alzheimer's disease in Icelandic populations 1. The variant abolishes the protein's ability to rescue Notch signaling defects in Drosophila models, establishing it as functionally damaging 1. TM2D3 is also subject to clonal selection in hematopoiesis, suggesting broader roles in cellular proliferation and cancer predisposition 5.