ADA2

Summary

ADA2 (adenosine deaminase 2, HGNC:1839) is a protein-coding gene on chromosome 22q11.1, encoding Adenosine deaminase 2 (Q9NZK5). Adenosine deaminase that may contribute to the degradation of extracellular adenosine, a signaling molecule that controls a variety of cellular responses.

This gene encodes a member of a subfamily of the adenosine deaminase protein family. The encoded protein is one of two adenosine deaminases found in humans, which regulate levels of the signaling molecule, adenosine. The encoded protein is secreted from monocytes undergoing differentiation and may regulate cell proliferation and differentiation. This gene may be responsible for some of the phenotypic features associated with cat eye syndrome. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 51816 — RefSeq curated summary.

At a glance

• Gene–disease (curated): obsolete deficiency of adenosine deaminase 2 (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 684 total — 95 pathogenic, 31 likely-pathogenic
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001282225

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1839
Approved symbol	ADA2
Name	adenosine deaminase 2
Location	22q11.1
Locus type	gene with protein product
Status	Approved
Aliases	ADGF
Ensembl gene	ENSG00000093072
Ensembl biotype	protein_coding
OMIM	607575
Entrez	51816

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 22 protein_coding, 6 retained_intron, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000262607, ENST00000330232, ENST00000399837, ENST00000399839, ENST00000449907, ENST00000469063, ENST00000480276, ENST00000543038, ENST00000610390, ENST00000648061, ENST00000648343, ENST00000648668, ENST00000649310, ENST00000649540, ENST00000649746, ENST00000649915, ENST00000650635, ENST00000696189, ENST00000696196, ENST00000696197, ENST00000696198, ENST00000696218, ENST00000696220, ENST00000696221, ENST00000696222, ENST00000696223, ENST00000696224, ENST00000696225, ENST00000696226, ENST00000696227, ENST00000885358, ENST00000885359

RefSeq mRNA: 6 — MANE Select: NM_001282225 NM_001282225, NM_001282226, NM_001282227, NM_001282228, NM_001282229, NM_177405

CCDS: CCDS13742, CCDS13743, CCDS63395, CCDS74809

Canonical transcript exons

ENST00000399837 — 10 exons

Exon	Start	End
ENSE00000650248	17181820	17182022
ENSE00000650252	17188339	17188447
ENSE00000650260	17189942	17190032
ENSE00000650274	17203563	17203773
ENSE00000650281	17207071	17207290
ENSE00001540382	17178790	17181576
ENSE00001540384	17219356	17219435
ENSE00003508775	17191683	17191810
ENSE00003966413	17209356	17209723
ENSE00003966554	17182604	17182761

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 98.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.5150 / max 452.3044, expressed in 1105 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193076	12.0018	469
193075	3.1815	776
193077	0.1223	75
193083	0.0907	36
193073	0.0731	16
193074	0.0211	4
193082	0.0183	6
193078	0.0061	1

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	98.88	gold quality
mononuclear cell	CL:0000842	98.87	gold quality
leukocyte	CL:0000738	98.86	gold quality
granulocyte	CL:0000094	98.21	gold quality
bone marrow cell	CL:0002092	96.94	gold quality
right uterine tube	UBERON:0001302	96.16	gold quality
spleen	UBERON:0002106	96.11	gold quality
blood	UBERON:0000178	95.42	gold quality
lymph node	UBERON:0000029	95.10	gold quality
thymus	UBERON:0002370	94.40	gold quality
sperm	CL:0000019	93.96	silver quality
gall bladder	UBERON:0002110	93.86	gold quality
vermiform appendix	UBERON:0001154	93.65	gold quality
colonic epithelium	UBERON:0000397	92.95	gold quality
rectum	UBERON:0001052	92.86	gold quality
heart right ventricle	UBERON:0002080	92.74	gold quality
palpebral conjunctiva	UBERON:0001812	92.16	gold quality
male germ cell	CL:0000015	92.06	silver quality
caecum	UBERON:0001153	91.77	gold quality
right lung	UBERON:0002167	91.65	gold quality
ileal mucosa	UBERON:0000331	91.59	gold quality
cardiac muscle of right atrium	UBERON:0003379	91.52	gold quality
decidua	UBERON:0002450	91.37	gold quality
epithelium of bronchus	UBERON:0002031	91.09	gold quality
bronchus	UBERON:0002185	90.90	gold quality
apex of heart	UBERON:0002098	90.89	gold quality
trabecular bone tissue	UBERON:0002483	90.71	gold quality
bone marrow	UBERON:0002371	90.65	gold quality
bronchial epithelial cell	CL:0002328	90.46	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.43	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	23.88
E-MTAB-8498	yes	11.65
E-GEOD-93593	yes	7.77
E-MTAB-9801	yes	6.56
E-MTAB-9543	yes	4.58
E-MTAB-8060	no	52.43
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

92 targeting ADA2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-6832-5P	99.58	64.82	1132
HSA-MIR-4524A-5P	99.57	71.73	1193
HSA-MIR-4524B-5P	99.57	71.68	1195
HSA-MIR-7844-5P	99.55	68.56	1428
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-4696	99.48	67.48	1040
HSA-MIR-1224-5P	99.48	65.59	803
HSA-MIR-3123	99.47	67.15	2693

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• findings show ADA2 is encoded by the CECR1 gene & belongs to novel family of ADA-related growth factors;ADA2 may be active in sites of inflammation during hypoxia & in areas of tumour growth where adenosine is elevated & extracellular pH is acidic (PMID:15926889)
• The crystal structures of ADA2 and ADA2 bound to a transition state analogue presented here reveal the structural basis of the catalytic/signaling activity of adenosine deaminase growth factor/ADA2 proteins. (PMID:20147294)
• Plasma AD2 may have a role in determining tumour response to treatment. (PMID:22558798)
• Increased ADA2 expression and activity are identified in human and porcine retinas with diabetes. (PMID:23685153)
• Loss-of-function mutations in CECR1 were associated with a spectrum of vascular and inflammatory phenotypes, ranging from early-onset recurrent stroke to systemic vasculopathy or vasculitis. (PMID:24552284)
• Recessive loss-of-function mutations of ADA2, a growth factor that is the major extracellular adenosine deaminase, can cause polyarteritis nodosa vasculopathy with highly varied clinical expression. (PMID:24552285)
• We report on a 5-year-old girl with a severe vasculopathy who carried two novel mutations in CECR1. (PMID:24737293)
• ADA2 (CECR1) may act as a regulator of neutrophil activation, and that a reduction of ADA2 activity results in significant endothelial damage via a neutrophil-driven process. (PMID:25278816)
• Ectopic expression of miR-146b-3p suppressed ADA2 expression, activity, and TNF-alpha release in the AGA-treated human macrophages (PMID:25815338)
• In patients with unexplained young-onset lacunar stroke accompanied by systemic inflammation and a positive family history suspicious of recessively inherited disease, ADA2 deficiency needs to be considered in the differential diagnosis. (PMID:25888558)
• IL-17 receptor A and adenosine deaminase 2 deficiency due to deletion mutations was found in siblings with chronic mucocutaneous candidiasis and chronic systemic inflammation. (PMID:26607704)
• This case series revealed large phenotypic variability in patients with ADA2 deficiency though they were homozygous for the same R169Q mutation in CECR1. (PMID:26867732)
• Deficiency of ADA2 causes IgA-IgG antibody deficiencies in a family. (PMID:26922074)
• The clinical manifestations of adenosine deaminase 2 deficiency ranged in severity from limited cutaneous involvement to severe multisystemic vasculitis; one-third of our cases (5 of 15) were currently asymptomatic, and required close monitoring. We recommend CECR1 screening for unaffected siblings of index cases, cases of familial vasculitis, and cases of PAN that is resistant to standard treatment (PMID:27059682)
• Adenosine deaminase type 2 deficiency with a homozygous premature stop codon masquerading as GATA2 deficiency: successful haploidentical sibling hematopoietic stem cell transplantation. (PMID:27130863)
• We discuss three newly described monogenic autoinflammatory diseases [deficiency of adenosine deaminase 2 (DADA2), a subtype of macrophage activation syndrome (MAS), and stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI)], discuss the possibilities of somatic mosaicism and digenic inheritance, and give an update on new concepts in pathways involved in familial Mediterranean fever (PMID:27362340)
• Deficiency of Adenosine Deaminase 2 (DADA2) is a new autoinflammatory disease secondary to autosomal recessive mutations of CECR1 (Cat Eye Syndrome Chromosome Region 1) gene, mapped to chromosome 22q11.1. (PMID:27609179)
• High CECR1 activity is associated with brain tumor. (PMID:28453746)
• Findings indicate that ADA2 deficiency presents not only with vasculopathy but also with an immunodeficiency of the B cell compartment. Therefore, patients with antibody deficiency should be screened for ADA2 deficiency. (PMID:28493328)
• CECR1 function in (M2-like) macrophages mediates cross talk between macrophages and pericytes in GBM via paracrine PDGFB-PDGFRbeta signaling, promoting pericyte recruitment and migration, and tumor angiogenesis. (PMID:28534507)
• Data show that 2 patients required a second transplant for engraftment failure were discovered to carry the deleterious ADA2 adenosine deaminase (CECR1) mutations and be ADA2 deficient. (PMID:28974505)
• We imposed no clinical selection or criteria before testing but collected uniform clinical data for each patient. Therefore, this series exactly reflects the context of requests for sequencing the ADA2 gene we receive in our laboratory (PMID:29681619)
• Our work identifies not only a new set of causal mutations but more generally demonstrates the importance of N-glycosylation for normal ADA2 function. To our knowledge, this is the first report of an autoinflammatory disease caused by a defect in glycosylation. (PMID:29936104)
• Case Report: describe phenotype of patient with ADA2 deficiency. (PMID:30148442)
• this study reports two ADA2 deficiency patients in whom recalcitrant warts and mollusca were a predominant phenotype (PMID:30386947)
• ADA2 activity in plasma reliably distinguishes adult Sneddon’s syndrome of unknown cause patients from healthy controls. (PMID:30645994)
• In children with deficiency of ADA2 (DADA2) (5 with polyarteritis nodosa, 3 with unclassifiable vasculitis, and 1 with ANCA-associated vasculitis), 1 patient had no rare variants in the coding region of ADA2 and 8 had biallelic, rare variants (minor allele frequency <0.01) with a known association with DADA2 (p.Gly47Arg and p.Gly47Ala) or a novel association (p.Arg9Trp, p.Leu351Gln, and p.Ala357Thr). (PMID:31008556)
• These results suggest that neutrophils may play a pathogenic role in DADA2. Modulation of adenosine-mediated NET formation may contribute a novel and directed therapeutic approach in the treatment of DADA2 and potentially other inflammatory diseases. (PMID:31015188)
• Description of three families with the same homozygous splice site mutation in ADA2 and observed a novel combination of manifestations resembling Behcet’s disease. (PMID:31856934)
• Role of adenosine deaminase 2 gene variants in pediatric deficiency of adenosine deaminase 2: A structural biological approach. (PMID:31974608)
• Two cases of ADA2 deficiency presenting as childhood polyarteritis nodosa: novel ADA2 variant, atypical CNS manifestations, and literature review. (PMID:32535845)
• Deficiency of Adenosine Deaminase 2 (DADA2): Hidden Variants, Reduced Penetrance, and Unusual Inheritance. (PMID:32638197)
• Dysregulation in B-cell responses and T follicular helper cell function in ADA2 deficiency patients. (PMID:32707604)
• Sequence-Based Screening of Patients With Idiopathic Polyarteritis Nodosa, Granulomatosis With Polyangiitis, and Microscopic Polyangiitis for Deleterious Genetic Variants in ADA2. (PMID:33021335)
• Novel ADA2 Compound Heterozygous Mutations Resulting in Deficiency of Adenosine Deaminase 2 in a Pair of Siblings. (PMID:33517505)
• Detailed analysis of Japanese patients with adenosine deaminase 2 deficiency reveals characteristic elevation of type II interferon signature and STAT1 hyperactivation. (PMID:33529688)
• Adult-onset deficiency of adenosine deaminase 2-a case report and literature review. (PMID:33638065)
• Expanding spectrum of DADA2: a review of phenotypes, genetics, pathogenesis and treatment. (PMID:33791889)
• Targeting Adenosine with Adenosine Deaminase 2 to Inhibit Growth of Solid Tumors. (PMID:33863778)
• Macrophage-Derived Adenosine Deaminase 2 Correlates with M2 Macrophage Phenotype in Triple Negative Breast Cancer. (PMID:33916440)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	ada2b	ENSDARG00000015623
danio_rerio	ada2a	ENSDARG00000051746
drosophila_melanogaster	Adgf-E	FBGN0033952
drosophila_melanogaster	Adgf-B	FBGN0036751
drosophila_melanogaster	Adgf-A	FBGN0036752
drosophila_melanogaster	Adgf-D	FBGN0038172
drosophila_melanogaster	Adgf-C	FBGN0038173
drosophila_melanogaster	Adgf-A2	FBGN0043025

Paralogs (2): MAPDA (ENSG00000168803), ADA (ENSG00000196839)

Protein

Protein identifiers

Adenosine deaminase 2 — Q9NZK5 (reviewed: Q9NZK5)

Alternative names: Cat eye syndrome critical region protein 1

All UniProt accessions (13): Q9NZK5, A0A087X0I3, A0A3B3IRN1, A0A3B3IRR5, A0A3B3IT96, A0A8Q3SIG4, A0A8Q3SIK1, A0A8Q3WL33, A0A8Q3WL39, A0A8Q3WM36, A0A8Q3WMB0, B4E3Q4, F5H7J3

UniProt curated annotations — full annotation on UniProt →

Function. Adenosine deaminase that may contribute to the degradation of extracellular adenosine, a signaling molecule that controls a variety of cellular responses. Requires elevated adenosine levels for optimal enzyme activity. Binds to cell surfaces via proteoglycans and may play a role in the regulation of cell proliferation and differentiation, independently of its enzyme activity.

Subunit / interactions. Homodimer. Interacts with adenosine receptors. Binds heparin.

Subcellular location. Secreted.

Tissue specificity. Detected in blood plasma (at protein level). Widely expressed, with most abundant expression in human adult heart, lung, lymphoblasts, and placenta as well as fetal lung, liver, and kidney. In embryo, expressed in the outflow tract and atrium of the developing heart, the VII/VIII cranial nerve ganglion, and the notochord.

Disease relevance. Vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS) [MIM:615688] An autosomal recessive, systemic necrotizing vasculitis that affects medium and small arteries. The ensuing tissue ischemia can affect any organ, including the skin, musculoskeletal system, kidneys, gastrointestinal tract, and the cardiovascular and nervous systems. Organ involvement and disease severity are highly variable. Clinical features include recurrent ischemic stroke affecting the small vessels of the brain and resulting in neurologic dysfunction, recurrent fever, myalgias, livedoid rash, gastrointestinal pain and hepatosplenomegaly. The disease is caused by variants affecting the gene represented in this entry. Sneddon syndrome (SNDNS) [MIM:182410] An autosomal recessive, systemic non-inflammatory thrombotic vasculopathy characterized by the association of livedo racemosa, and in some cases livedo reticularis, with cerebrovascular disease. Livedo racemosa is a persistent net-like violaceous-cyanotic, mottled discoloration of the skin affecting the legs, the arms, the buttocks and the trunk; livedo reticularis is limited to the extremities and is visible only in the cold. Cerebrovascular features include recurrent transient ischemic attacks, infarcts, and rarely spinal strokes or intracranial or subarachnoid hemorrhages. Headache and vertigo may precede the onset of livedo racemosa and cerebrovascular manifestations by several years. Rare neurologic symptoms include seizures, chorea, or myelopathies. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. The PRB domain is involved in receptor binding, and may be responsible for the cytokine-like growth factor activity due to its sharing of several structural properties with chemokines. High-affinity binding to heparin/glycosaminoclycan (GAG) is mediated by a large, highly positively charged surface at the interface of dimer’s subunits involving approximately residues 30-45, 389-396, and 422-428.

Miscellaneous. Candidate gene for the Cat Eye Syndrome (CES), a developmental disorder associated with the duplication of a 2 Mb region of 22q11.2. Duplication usually takes in the form of a surpernumerary bisatellited isodicentric chromosome, resulting in four copies of the region (represents an inv dup(22)(q11)). CES is characterized clinically by the combination of coloboma of the iris and anal atresia with fistula, downslanting palpebral fissures, preauricular tags and/or pits, frequent occurrence of heart and renal malformations, and normal or near-normal mental development.

Similarity. Belongs to the metallo-dependent hydrolases superfamily. Adenosine and AMP deaminases family. ADGF subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NZK5-1	1	yes
Q9NZK5-2	2

RefSeq proteins (6): NP_001269154, NP_001269155, NP_001269156, NP_001269157, NP_001269158, NP_803124 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001365	A_deaminase_dom	Domain
IPR006330	Ado/ade_deaminase	Family
IPR006331	ADGF	Family
IPR013659	A_deaminase_N	Domain
IPR032466	Metal_Hydrolase	Homologous_superfamily

Pfam: PF00962, PF08451

Enzyme classification (BRENDA):

• EC 3.5.4.4 — adenosine deaminase (BRENDA: 55 organisms, 135 substrates, 272 inhibitors, 117 Km, 44 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ADENOSINE	—	69
2’-DEOXYADENOSINE	0.004–0.56	18
5’-METHYLTHIOADENOSINE	0.0044–0.376	14
2’,3’-ISOPROPYLIDENE ADENOSINE	0.29	1
6-CHLOROPURINE RIBOSIDE	0.31	1
6-CHLOROPURINRIBOSIDE	0.277	1
6-METHOXYPURINRIBOSIDE	0.081	1
ADENINE	0.032	1
ADENOSINE-3’-MONOPHOSPHATE	2	1
AMP	0.17	1
CAMP	0.5	1

Catalyzed reactions (Rhea), 1 shown:

• adenosine + H2O + H(+) = inosine + NH4(+) (RHEA:24408)

UniProt features (80 total): helix 27, strand 12, sequence variant 11, binding site 9, glycosylation site 4, turn 4, region of interest 2, splice variant 2, mutagenesis site 2, sequence conflict 2, active site 2, signal peptide 1, chain 1, disulfide bond 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3LGD	X-RAY DIFFRACTION	2
3LGG	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZK5-F1	96.03	0.95

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 359 (proton donor); 384 (proton acceptor)

Ligand- & substrate-binding residues (9): 293; 326; 356; 441; 442; 112; 114; 115; 204–211

Disulfide bonds (1): 137–159

Glycosylation sites (4): 127, 174, 185, 378

Mutagenesis-validated functional residues (2):

Position	Phenotype
137	abolishes secretion.
362	reduces dimerization and enzyme activity.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-5683826	Surfactant metabolism
R-HSA-6798695	Neutrophil degranulation
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-392499	Metabolism of proteins

MSigDB gene sets: 562 (showing top): WALLACE_PROSTATE_CANCER_RACE_UP, REACTOME_INNATE_IMMUNE_SYSTEM, MCLACHLAN_DENTAL_CARIES_UP, GOCC_SECRETORY_GRANULE, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOMF_GROWTH_FACTOR_ACTIVITY, WIELAND_UP_BY_HBV_INFECTION, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GNF2_MCL1, GNF2_CD1D, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, MODULE_301

GO Biological Process (3): adenosine catabolic process (GO:0006154), inosine biosynthetic process (GO:0046103), signal transduction (GO:0007165)

GO Molecular Function (10): adenosine deaminase activity (GO:0004000), growth factor activity (GO:0008083), heparin binding (GO:0008201), zinc ion binding (GO:0008270), adenosine receptor binding (GO:0031685), protein homodimerization activity (GO:0042803), proteoglycan binding (GO:0043394), hydrolase activity (GO:0016787), deaminase activity (GO:0019239), metal ion binding (GO:0046872)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), azurophil granule lumen (GO:0035578)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Metabolism of proteins	1
Innate Immune System	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
adenosine metabolic process	1
purine ribonucleoside catabolic process	1
inosine metabolic process	1
purine ribonucleoside biosynthetic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in cyclic amidines	1
deaminase activity	1
receptor ligand activity	1
glycosaminoglycan binding	1
sulfur compound binding	1
transition metal ion binding	1
G protein-coupled receptor binding	1
identical protein binding	1
protein dimerization activity	1
protein binding	1
carbohydrate derivative binding	1
catalytic activity	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds	1
cation binding	1
cellular anatomical structure	1
vacuolar lumen	1
secretory granule lumen	1
azurophil granule	1

Protein interactions and networks

STRING

1798 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADA2	ADA	P00813	923
ADA2	ADK	P55263	505
ADA2	ENTPD1	P49961	491
ADA2	PNP	P00491	467
ADA2	AMPD2	Q01433	463
ADA2	FAM110B	Q8TC76	453
ADA2	BUD31	P41223	451
ADA2	AMPD3	Q01432	447
ADA2	CECR2	Q9BXF3	446
ADA2	GIN1	Q9NXP7	432
ADA2	DHX8	Q14562	427
ADA2	CRY1	Q16526	418
ADA2	ADSL	P30566	415
ADA2	RNASEH2C	Q8TDP1	402
ADA2	ADSS2	P30520	397

IntAct

4 interactions, top by confidence:

A	B	Type	Score
ADA2	TRIO	psi-mi:“MI:0914”(association)	0.350
GCNT4	LRP10	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): CECR1 (Affinity Capture-MS), TRIO (Affinity Capture-MS), DCTPP1 (Affinity Capture-MS), CECR1 (Affinity Capture-MS), CECR1 (Affinity Capture-MS), CECR1 (Affinity Capture-MS)

ESM2 similar proteins: A2RSQ1, A3QVN2, A3QVN3, A3QVN4, A3QVN5, A3QVN6, A3QVN9, A3QVP0, C0HLL4, C0HLL5, E0XKJ9, E3W9M2, G5ECE8, I0CME7, I0CME8, J3S820, O22585, P23613, P38566, P38567, P38568, P48794, P49370, P49371, P49713, P58781, P85841, P86100, P86687, P86875, Q05A56, Q08169, Q10916, Q2M3T9, Q2QSR8, Q2VQV9, Q5D7H4, Q5RC46, Q60V90, Q62803

Diamond homologs: A0LRH8, A0PNJ1, A0QKJ4, A1KP00, A1UCA4, A3PVY4, A4VQI5, A4XYN8, A5G460, A5KE01, A5U7Y8, A6UET5, A6VWL7, B1MFZ9, B1WR40, B1ZYW1, B2HDU8, B2T672, B2U7U6, B2VK11, B3E600, B3PXN1, B3R3T1, B5ZXI3, B8H3Z4, B8ZUW8, B9J6V8, B9JYP8, C1DGB0, C3MBH4, C5BDE0, O86737, P15287, P53984, P58780, P58781, P63907, P63908, Q0KCW5, Q11C48

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

684 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	95
Likely pathogenic	31
Uncertain significance	270
Likely benign	191
Benign	37

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1027880	NM_001282225.2(ADA2):c.882-2A>G	Pathogenic
1033820	NM_001282225.2(ADA2):c.1040del (p.Asp347fs)	Pathogenic
1076271	NM_001282225.2(ADA2):c.139G>C (p.Gly47Arg)	Pathogenic
1171011	NM_001282225.2(ADA2):c.631TTC[1] (p.Phe212del)	Pathogenic
120300	NM_001282225.2(ADA2):c.326C>A (p.Ala109Asp)	Pathogenic
120301	NM_001282225.2(ADA2):c.140G>C (p.Gly47Ala)	Pathogenic
120307	NM_001282225.2(ADA2):c.791G>C (p.Trp264Ser)	Pathogenic
1285514	NM_001282225.2(ADA2):c.158del (p.Asn53fs)	Pathogenic
1285515	NM_001282225.2(ADA2):c.2T>A (p.Met1Lys)	Pathogenic
1321995	GRCh37/hg19 22q11.1-11.21(chr22:16850000-18885000)x3	Pathogenic
1353104	NC_000022.10:g.(?17684433)(17690567_?)del	Pathogenic
1407177	NM_001282225.2(ADA2):c.2T>C (p.Met1Thr)	Pathogenic
144200	GRCh38/hg38 22q11.1-11.21(chr22:16916608-20343532)x3	Pathogenic
144303	GRCh38/hg38 22q11.1-11.21(chr22:16916608-20354644)x3	Pathogenic
1444154	NM_001282225.2(ADA2):c.1362_1370del (p.Asp454_Tyr456del)	Pathogenic
144589	GRCh38/hg38 22q11.1-11.21(chr22:16916743-19597367)x3	Pathogenic
1489090	NM_001282225.2(ADA2):c.881+1G>A	Pathogenic
149401	GRCh38/hg38 22q11.1-11.21(chr22:16916743-18178991)x3	Pathogenic
149666	GRCh38/hg38 22q11.1-11.21(chr22:16916743-18718546)x3	Pathogenic
150808	GRCh38/hg38 22q11.1-11.21(chr22:16916743-18145439)x3	Pathogenic
152141	GRCh38/hg38 22p11.2-q11.1(chr22:16367190-18178957)x4	Pathogenic
154375	GRCh38/hg38 22q11.1-11.21(chr22:16916608-18997006)x4	Pathogenic
154503	GRCh38/hg38 22q11.1-11.21(chr22:16916608-18179006)x4	Pathogenic
1703650	GRCh37/hg19 22q11.1-11.21(chr22:16888899-21915509)	Pathogenic
1879547	NM_001282225.2(ADA2):c.1223G>A (p.Cys408Tyr)	Pathogenic
1879564	GRCh37/hg19 22q11.1(chr22:17669229-17669337)x1	Pathogenic
189342	NM_001282225.2(ADA2):c.1078A>G (p.Thr360Ala)	Pathogenic
1911538	NM_001282225.2(ADA2):c.137dup (p.Arg49fs)	Pathogenic
1954694	NM_001282225.2(ADA2):c.1058_1061del (p.Tyr353fs)	Pathogenic
2005909	NM_001282225.2(ADA2):c.239del (p.Phe80fs)	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000045253 (22:17207740 A>G), RS1000086491 (22:17181224 A>T), RS1000533523 (22:17211948 T>A), RS1000582864 (22:17206032 T>C), RS1000696176 (22:17217646 C>G), RS1000748550 (22:17217976 T>TA), RS1000865554 (22:17190477 A>G), RS1000889577 (22:17200627 G>A,C), RS1000891090 (22:17194916 C>T), RS1000939661 (22:17194583 C>T), RS1000966230 (22:17211846 T>C), RS1001050420 (22:17206443 A>G), RS1001141877 (22:17179714 G>A), RS1001231652 (22:17184044 C>G), RS1001308180 (22:17221841 CTGT>C)

Disease associations

OMIM: gene MIM:607575 | disease phenotypes: MIM:615688, MIM:182410, MIM:608363, MIM:613953, MIM:109650

GenCC curated gene-disease

Disease	Classification	Inheritance
deficiency of adenosine deaminase 2	Strong	Autosomal recessive
polyarteritis nodosa	Moderate	Autosomal recessive
Sneddon syndrome	Moderate	Autosomal recessive
Diamond-Blackfan anemia	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
obsolete deficiency of adenosine deaminase 2	Definitive	AR

Mondo (9): deficiency of adenosine deaminase 2 (MONDO:0014306), Sneddon syndrome (MONDO:0008436), autoinflammatory syndrome (MONDO:0019751), chromosome 22q11.2 microduplication syndrome (MONDO:0012020), immunodeficiency 51 (MONDO:0013500), Behcet disease (MONDO:0007191), neurodevelopmental disorder (MONDO:0700092), polyarteritis nodosa (MONDO:0019170), Diamond-Blackfan anemia (MONDO:0015253)

Orphanet (7): Deficiency of adenosine deaminase 2 (Orphanet:404553), Sneddon syndrome (Orphanet:820), Autoinflammatory syndrome (Orphanet:93665), 22q11.2 duplication syndrome (Orphanet:1727), Chronic mucocutaneous candidiasis (Orphanet:1334), Behçet disease (Orphanet:117), Polyarteritis nodosa (Orphanet:767)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002701_8	Verbal declarative memory	1.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004874	memory performance
EFO:0006805	word list delayed recall measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D029503	Anemia, Diamond-Blackfan	C15.378.050.085.080.090; C15.378.050.750.500; C15.378.190.223.500.500.090; C16.320.077.090
D001528	Behcet Syndrome	C07.465.075; C11.941.879.780.880.200; C14.907.940.100; C16.320.382.250; C17.800.827.368.250; C17.800.862.150
D065886	Neurodevelopmental Disorders	F03.625
D010488	Polyarteritis Nodosa	C14.907.940.090.720; C14.907.940.897.500; C17.800.862.625
D018860	Sneddon Syndrome	C10.228.140.300.750; C14.907.253.774; C17.800.862.775
C567224	Chromosome 22q11.2 Microduplication Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases expression	9
trichostatin A	decreases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Aflatoxin B1	decreases methylation, increases methylation, affects methylation	2
GSK-J4	decreases expression	1
methylmercuric chloride	decreases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
sodium arsenite	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
entinostat	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Vorinostat	decreases expression	1
Amiodarone	increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Doxorubicin	decreases expression	1
Methapyrilene	increases methylation	1
Naled	affects expression	1
Nickel	increases expression	1
Smoke	decreases expression	1
Thimerosal	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Triclosan	decreases expression	1
Isotretinoin	increases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Antirheumatic Agents	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E1CN	Ubigene THP-1 ADA2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

350 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00307671	PHASE4	COMPLETED	Treatment of Necrotizing Vasculitides for Patients Older Than 65 Years
NCT00400075	PHASE4	UNKNOWN	CHUSPAN PAN BP Treatment of Polyarteritis Nodosa and Microscopic Polyangiitis Without Poor-Prognosis Factors
NCT00673608	PHASE4	COMPLETED	Magnetic Resonance Imaging (MRI) Assessments of the Heart and Liver Iron Load in Patients With Transfusion Induced Iron Overload
NCT05879419	PHASE4	ACTIVE_NOT_RECRUITING	Recombinant Herpes Zoster Vaccine in Patients With Autoimmune Rheumatic Diseases
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00647166	PHASE3	COMPLETED	Association Corticosteroid/Azathioprine in Microscopic Polyangiitis/ Polyarteritis Nodosa or Eosinophilic Granulomatosis With Polyangiitis (Churg Strauss Syndrome)
NCT00235391	PHASE3	COMPLETED	Expanded Access of Deferasirox to Patients With Congenital Disorders of Red Blood Cells and Chronic Iron Overload
NCT00995709	PHASE3	COMPLETED	Phase III Study in Refractory Behcet’s Disease
NCT01532570	PHASE3	COMPLETED	Clinical Study of TA-650 in Patients With Behcet’s Disease (BD) With Special Lesions
NCT02307513	PHASE3	COMPLETED	A Phase 3 Randomized, Double-blind Study to Evaluate the Efficacy and Safety of Apremilast (CC-10004) in Subjects With Active Behçet’s Disease
NCT02505568	PHASE3	COMPLETED	A Study to Evaluate Efficacy and Safety of Infliximab in Participant With Moderate-to-Severe Refractory Intestinal Behcet’s Disease
NCT03209219	PHASE3	COMPLETED	Interferon α2a Versus Cyclosporine for Refractory Behçet’s Disease Uveitis
NCT04528082	PHASE3	RECRUITING	Apremilast Pediatric Study in Children With Active Oral Ulcers Associated With Behçet’s Disease
NCT05767047	PHASE3	RECRUITING	A Study of Apremilast in Children With Oral Ulcers Associated With Behçet’s Disease or Juvenile Psoriatic Arthritis
NCT06145893	PHASE3	RECRUITING	A Study of Efficacy and Safety of Hemay005 Tablets in Patients With Behçet’s Disease
NCT06780462	PHASE3	RECRUITING	Randomized Controlled Multicenter Study Comparing Steroid Therapy Plus Anticoagulants to Steroid Therapy Alone in Deep Venous Thrombosis of Behçet’s Syndrome
NCT06925698	PHASE3	NOT_YET_RECRUITING	Immunosuppressive Therapy Alone Versus Plus Oral Anticoagulation in the Treatment of VT Associated With Behcet’s Disease
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00001457	PHASE2	COMPLETED	Lamivudine for Chronic Hepatitis B
NCT00751517	PHASE2	UNKNOWN	Cyclophosphamide Versus Methotrexate for Remission Maintenance in Systemic Necrotizing Vasculitides
NCT03482479	PHASE2	COMPLETED	Low Dose Naltrexone to Improve Physical Health in Patients With Vasculitis
NCT05168475	PHASE2	TERMINATED	Biologics in Refractory Vasculitis: A Trial of Biologic Therapy for Refractory Primary Non-ANCA Associated Vasculitis
NCT00001962	PHASE2	TERMINATED	A Study to Determine Whether Therapy With Daclizumab Will Benefit Patients With Bone Marrow Failure
NCT00011505	PHASE2	COMPLETED	Mobilization of Stem Cells With G-CSF for Collection From Patients With Diamond-Blackfan Anemia
NCT00301834	PHASE2	COMPLETED	Alemtuzumab, Fludarabine, and Busulfan Followed By Donor Stem Cell Transplant in Treating Young Patients With Hematologic Disorders
NCT00957931	PHASE2	COMPLETED	Allo-HCT MUD for Non-malignant Red Blood Cell (RBC) Disorders: Sickle Cell, Thal, and DBA: Reduced Intensity Conditioning, Co-tx MSCs
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT02386267	PHASE2	UNKNOWN	L-leucine in Diamond Blackfan Anemia Patients
NCT02512679	PHASE2	TERMINATED	Related Hematopoietic Stem Cell Transplantation (HSCT) for Genetic Diseases of Blood Cells
NCT03333486	PHASE2	TERMINATED	Fludarabine Phosphate, Cyclophosphamide, Total Body Irradiation, and Donor Stem Cell Transplant in Treating Patients With Blood Cancer
NCT04099966	PHASE2	RECRUITING	AlloSCT for Malignant and Non-malignant Hematologic Diseases Utilizing Alpha/Beta T Cell and CD19+ B Cell Depletion
NCT04965597	PHASE2	COMPLETED	Treosulfan-Based Conditioning Regimen Before a Blood or Bone Marrow Transplant for the Treatment of Bone Marrow Failure Diseases (BMT CTN 1904)
NCT00442182	PHASE2	UNKNOWN	The Efficacy and Safety of ITF2357 in AIS
NCT00001865	PHASE2	COMPLETED	HAT in Eye Complications of Behcet’s Disease
NCT00483184	PHASE2	COMPLETED	Low Dose Interferon Alpha Treatment for Oral Ulcers of Behcet’s Disease
NCT00664599	PHASE2	COMPLETED	Rituximab for the Treatment of Severe Ocular Manifestations of Behcet’s Disease