NACA2 (nascent polypeptide associated complex subunit alpha 2) is a cytoplasmic protein that prevents inappropriate targeting of non-secretory polypeptides to the endoplasmic reticulum. It functions by binding to nascent polypeptide chains as they emerge from the ribosome and blocking their interaction with the signal recognition particle (SRP), which normally directs secretory peptides to the ER for translocation. This mechanism protects the cell from mistargeting cytoplasmic proteins to the ER membrane. At the molecular level, NACA2 reduces the inherent affinity of ribosomes for protein translocation sites (M sites) in the ER membrane, providing an additional safeguard against inappropriate ER targeting. The protein exhibits unfolded protein binding capacity, suggesting involvement in protein quality control during translation. Clinically, NACA2 has been associated with skin inflammatory response phenotypes. Population genetics studies identified NACA2 as a gene influenced by extreme allele frequency differences across world populations, linking genetic variants to skin inflammatory responses 1. Additionally, a rare microduplication on chromosome 17.1q23.2 including NACA2 was identified in a clubfoot pedigree, though NACA2 itself was not implicated as a primary clubfoot causative gene 2. The protein's role in regulating protein targeting and handling may have broader implications for cellular homeostasis and disease states involving protein misfolding or trafficking defects.