SOCE-associated regulatory factor (SARAF) is a regulatory protein of cellular Ca2+ homeostasis, encoded by the TMEM66 gene. SARAF is an ER resident protein, which responds to cytosolic Ca2+ elevation after ER Ca2+ refilling.n SARAF is highly conserved in vertebrates, and in mammals it is ubiquitously expressed with high transcript levels in the immune and neuronal tissues. SARAF structure contains validated signal peptide and a putative single membrane spanning domain, a serine-proline rich domain and arginine rich regions followed by a cluster of basic residues at its C-terminal tail.Store-operated Ca2+ entry (SOCE) is an important Ca2+ influx pathway across plasma membrane in many non-excitable cells. In this pathway, intracellular Ca2+ release through IP3 receptor stimulated by a variety of agonists, results in reduction of Ca2+ concentration in the lumen of endoplasmic or sarcoplasmic reticulum. SARAF negatively regulates store operated calcium entry into cells and protects cells from calcium overfilling.STIM, Ca2+ sensor, and Orai, the channel pore forming subunit proteins have been identified as the essential components enabling the reconstitution of Ca2+ release-activated Ca2+ channels that mediate SOCE. Knock-out of Orai1 or STIM1 in mice and mutations evoke SOCE in lymphocytes and other cells.Several findings show that dysregulation of Ca2+ homeostasis is associated with a plethora of pathological conditions including neurodegenerative diseases, skeletal, muscular and cardiovascular disorders. Inherited defects in SOCE due to mutations in genes of the Ca2+ release-activated Ca2+ (CRAC) channel complex causes patients to suffer from a severe form of immunodeficiency that is due to defects in the function of T cells, NK cells and potentially other immune cells.