TMEM208 (hSnd2) is an endoplasmic reticulum membrane receptor that functions as a central component of the human SND (SRP-independent) ER protein targeting pathway (PMID:28862756). It preferentially targets precursor proteins bearing C-terminal transmembrane domains to the ER, and proteomic profiling of its substrate spectrum shows that SND clients are predominantly membrane proteins carrying N-terminal, central, or C-terminal targeting signals, distinguishing them from SRP clients (PMID:28862756, PMID:36139500). TMEM208 also mediates ER targeting of GPI-anchored proteins such as CD59, CD55, and CD109, with dependence governed by the hydrophobicity of the C-terminal GPI attachment signal: low-hydrophobicity signals preferentially route through the hSND2-dependent pathway, in cooperation with signal recognition particle receptors (PMID:33838053). It operates within a network of targeting and translocation components, including TMEM109 (hSnd3) as a further pathway member (PMID:28862756, PMID:36139500). Beyond protein targeting, TMEM208 physically interacts with the planar cell polarity receptor Frizzled and is required to maintain proper Frizzled protein levels, linking it to cell polarity in vivo; loss of the gene causes developmental defects and mild ER stress, and human TMEM208 fully rescues the Drosophila null phenotype, establishing functional conservation (PMID:38381787). TMEM208 expression is directly repressed at the transcriptional level by ZBTB14, which binds and represses its promoter (PMID:39692812).