FEM1C is a substrate recognition component of the Cul2-RING E3 ubiquitin ligase complex that mediates protein degradation through the DesCEND (destruction via C-end degrons) pathway 1. The protein specifically recognizes C-degrons—degradation signals at protein C-termini—with particular specificity for arginine residues at the extreme C-terminus, targeting substrates with -Lys/Arg-Xaa-Arg and -Lys/Arg-Xaa-Xaa-Arg motifs 2. FEM1C utilizes a semi-open binding pocket to capture C-terminal arginines, with the extreme C-terminal residue serving as the major structural determinant for recognition 2. Known substrates include SIL1, OR51B2, truncated MSRB1/SEPX1 selenoproteins produced by failed UGA/Sec decoding, and SLBP (Stem-Loop Binding Protein), which is regulated across the cell cycle 3. FEM1C is evolutionarily conserved from C. elegans to vertebrates 4. Clinically, de novo FEM1C variants have been associated with neurodevelopmental disorders characterized by developmental delay, pyramidal signs, and limb ataxia, likely through impaired substrate binding 5. Additionally, FEM1C expression levels show predictive capacity for liver transplantation tolerance outcomes 6, suggesting potential clinical utility as a biomarker in transplant immunology.