A variant Adenosine Deaminase 2 protein or a catalytically active portion thereof, comprising a modification(s) in the sequence of amino acids of an unmodified ADA2 polypeptide or a catalytically active portion thereof, wherein: the unmodified ADA2 protein is selected from among an ADA protein that comprises: the sequence of amino acids set forth in SEQ ID NO:5; a sequence of amino acids that exhibits at least 95% sequence identity to the sequence of amino acids set forth in SEQ ID NO:5, or is a catalytically active portion of the sequence of amino acids that exhibits at least 95% sequence identity to the sequence of amino acids set forth in SEQ ID NO:5; or comprises the sequence of amino acids set forth in any of SEQ ID NOS: 5, 326-334, 340, 375 and 380-383 or is a catalytically active portion thereof; the modified ADA2 protein has up to 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid modifications compared to the unmodified ADA2 protein; the amino acid modification(s) are selected from among amino acid replacement(s), deletion(s) and insertion(s); the variant ADA2 protein comprises an amino acid replacement at one or both of positions corresponding to amino acid residue 219 and 262 with reference to amino acid positions set forth in SEQ ID NO:5; the variant ADA2 protein, when in dimer form, exhibits increased adenosine deaminase activity or increased adenosine deaminase activity and reduced heparin binding compared to the dimer form of the unmodified ADA2 protein of SEQ ID NO:5 or dimer form of the catalytically active portion thereof; and the variant ADA2 protein, when in dimer form, exhibits adenosine deaminase activity to convert adenosine to inosine. the unmodified ADA2 protein is selected from among an ADA protein that comprises: the sequence of amino acids set forth in SEQ ID NO:5; a sequence of amino acids that exhibits at least 95% sequence identity to the sequence of amino acids set forth in SEQ ID NO:5, or is a catalytically active portion of the sequence of amino acids that exhibits at least 95% sequence identity to the sequence of amino acids set forth in SEQ ID NO:5; or comprises the sequence of amino acids set forth in any of SEQ ID NOS: 5, 326-334, 340, 375 and 380-383 or is a catalytically active portion thereof; the sequence of amino acids set forth in SEQ ID NO:5; a sequence of amino acids that exhibits at least 95% sequence identity to the sequence of amino acids set forth in SEQ ID NO:5, or is a catalytically active portion of the sequence of amino acids that exhibits at least 95% sequence identity to the sequence of amino acids set forth in SEQ ID NO:5; or comprises the sequence of amino acids set forth in any of SEQ ID NOS: 5, 326-334, 340, 375 and 380-383 or is a catalytically active portion thereof; the modified ADA2 protein has up to 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid modifications compared to the unmodified ADA2 protein; the amino acid modification(s) are selected from among amino acid replacement(s), deletion(s) and insertion(s); the variant ADA2 protein comprises an amino acid replacement at one or both of positions corresponding to amino acid residue 219 and 262 with reference to amino acid positions set forth in SEQ ID NO:5; the variant ADA2 protein, when in dimer form, exhibits increased adenosine deaminase activity or increased adenosine deaminase activity and reduced heparin binding compared to the dimer form of the unmodified ADA2 protein of SEQ ID NO:5 or dimer form of the catalytically active portion thereof; and the variant ADA2 protein, when in dimer form, exhibits adenosine deaminase activity to convert adenosine to inosine.