Deficiency of adenosine deaminase 2

Summary

Deficiency of adenosine deaminase 2 (MONDO:0014306) is a disease caused by ADA2 (GenCC Strong), with 1 cohort gene and 1 clinical trial. Top therapeutic interventions include azathioprine.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ADA2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 551
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		48	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	deficiency of adenosine deaminase 2
Mondo ID	MONDO:0014306
OMIM	615688
Orphanet	404553
UMLS	C3887654
MedGen	854497
GARD	0012383
Is cancer (heuristic)	no

Also known as: ADA2 deficiency · adenosine deaminase 2 deficiency · childhood-onset polyarteritis nodosa · DADA2 · deficiency of adenosine deaminase 2 · PAN · polyarteritis nodosa, childhood-onset · vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome

Data availability: 551 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › vascular disorder › vasculitis › deficiency of adenosine deaminase 2

Related subtypes (17): choroiditis, Shwartzman phenomenon, central nervous system vasculitis, phlebitis, lymphangitis, aortitis, hypersensitivity vasculitis, retinal vasculitis, vasculitis, lymphocytic, nodular, Kawasaki disease, immune complex mediated vasculitis, secondary vasculitis, cutaneous vasculitis, livedoid vasculopathy, autoimmune vasculitis, arteritis, necrotizing vasculitis

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

551 retrieved; paginated sample, class counts are floors:

237 uncertain significance, 185 likely benign, 47 pathogenic, 26 conflicting classifications of pathogenicity, 26 likely pathogenic, 15 pathogenic/likely pathogenic, 8 benign/likely benign, 7 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
624589	NM_001282225.2(ADA2):c.[1196G>A;1367A>G]		Pathogenic	no assertion criteria provided
1027878	NM_001282225.2(ADA2):c.1373T>A (p.Val458Asp)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1027880	NM_001282225.2(ADA2):c.882-2A>G	ADA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1076271	NM_001282225.2(ADA2):c.139G>C (p.Gly47Arg)	ADA2	Pathogenic	criteria provided, multiple submitters, no conflicts
120299	NM_001282225.2(ADA2):c.1358A>G (p.Tyr453Cys)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
120300	NM_001282225.2(ADA2):c.326C>A (p.Ala109Asp)	ADA2	Pathogenic	no assertion criteria provided
120301	NM_001282225.2(ADA2):c.140G>C (p.Gly47Ala)	ADA2	Pathogenic	criteria provided, multiple submitters, no conflicts
120302	NM_001282225.2(ADA2):c.336C>G (p.His112Gln)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
120303	NM_001282225.2(ADA2):c.506G>A (p.Arg169Gln)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
120304	NM_001282225.2(ADA2):c.139G>A (p.Gly47Arg)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
120305	NM_001282225.2(ADA2):c.752C>T (p.Pro251Leu)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
120306	NM_001282225.2(ADA2):c.140G>T (p.Gly47Val)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
120307	NM_001282225.2(ADA2):c.791G>C (p.Trp264Ser)	ADA2	Pathogenic	no assertion criteria provided
1285514	NM_001282225.2(ADA2):c.158del (p.Asn53fs)	ADA2	Pathogenic	criteria provided, single submitter
1285515	NM_001282225.2(ADA2):c.2T>A (p.Met1Lys)	ADA2	Pathogenic	criteria provided, single submitter
1353104	NC_000022.10:g.(?17684433)(17690567_?)del	ADA2	Pathogenic	criteria provided, single submitter
1392821	NM_001282225.2(ADA2):c.753G>A (p.Pro251=)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1407177	NM_001282225.2(ADA2):c.2T>C (p.Met1Thr)	ADA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1411116	NM_001282225.2(ADA2):c.940_941del (p.Lys314fs)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1444154	NM_001282225.2(ADA2):c.1362_1370del (p.Asp454_Tyr456del)	ADA2	Pathogenic	criteria provided, single submitter
1489090	NM_001282225.2(ADA2):c.881+1G>A	ADA2	Pathogenic	criteria provided, single submitter
189342	NM_001282225.2(ADA2):c.1078A>G (p.Thr360Ala)	ADA2	Pathogenic	criteria provided, multiple submitters, no conflicts
189343	NM_001282225.2(ADA2):c.1147G>A (p.Gly383Ser)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1911538	NM_001282225.2(ADA2):c.137dup (p.Arg49fs)	ADA2	Pathogenic	criteria provided, single submitter
1954694	NM_001282225.2(ADA2):c.1058_1061del (p.Tyr353fs)	ADA2	Pathogenic	criteria provided, multiple submitters, no conflicts
2005909	NM_001282225.2(ADA2):c.239del (p.Phe80fs)	ADA2	Pathogenic	criteria provided, single submitter
2023773	NM_001282225.2(ADA2):c.1055del (p.Pro352fs)	ADA2	Pathogenic	criteria provided, single submitter
2138412	NM_001282225.2(ADA2):c.984G>C (p.Glu328Asp)	ADA2	Pathogenic	criteria provided, single submitter
2417153	NM_001282225.2(ADA2):c.660C>G (p.Tyr220Ter)	ADA2	Pathogenic	criteria provided, single submitter
2424095	NC_000022.10:g.(?17565982)(20052185_?)del	ADA2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ADA2	Strong	Autosomal recessive	deficiency of adenosine deaminase 2	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADA2	Orphanet:124	Diamond-Blackfan anemia
ADA2	Orphanet:404553	Deficiency of adenosine deaminase 2
ADA2	Orphanet:820	Sneddon syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ADA2	HGNC:1839	ENSG00000093072	Q9NZK5	Adenosine deaminase 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADA2	Adenosine deaminase 2	Adenosine deaminase that may contribute to the degradation of extracellular adenosine, a signaling molecule that controls a variety of cellular responses.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADA2	Enzyme (other)	yes	3.5.4.4	A_deaminase_dom, Ado/ade_deaminase, ADGF

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADA2	254	ubiquitous	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ADA2	1,808

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ADA2	Q9NZK5	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Surfactant metabolism	1	368.4×	0.014	ADA2
Innate Immune System	1	25.5×	0.072	ADA2
Neutrophil degranulation	1	23.1×	0.072	ADA2
Immune System	1	13.0×	0.081	ADA2
Metabolism of proteins	1	12.4×	0.081	ADA2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
inosine biosynthetic process	1	5617.3×	2e-04	ADA2
adenosine catabolic process	1	4213.0×	2e-04	ADA2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ADA2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADA2	3.5.4.4	adenosine deaminase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ADA2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ADA2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00647166	PHASE3	COMPLETED	Association Corticosteroid/Azathioprine in Microscopic Polyangiitis/ Polyarteritis Nodosa or Eosinophilic Granulomatosis With Polyangiitis (Churg Strauss Syndrome)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
AZATHIOPRINE	4	1