severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency

Summary

severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (MONDO:0007064) is a disease caused by ADA (GenCC Definitive), with 4 cohort genes and 19 clinical trials. Top therapeutic interventions include busulfan, autologous cd34+ enriched cell fraction that contains cd34+ cells transduced with retroviral vector that encodes for the human ada cdna sequence, and elapegademase.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: ADA (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 728
• Phenotypes (HPO): 20
• Clinical trials: 19

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.2	Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.3	Europe	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0000246	Sinusitis	Frequent (30-79%)
HP:0000403	Recurrent otitis media	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001888	Lymphopenia	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002788	Recurrent upper respiratory tract infections	Frequent (30-79%)
HP:0002849	Absence of lymph node germinal center	Frequent (30-79%)
HP:0002960	Autoimmunity	Frequent (30-79%)
HP:0003212	Increased circulating IgE level	Frequent (30-79%)
HP:0005354	Lack of T cell function	Frequent (30-79%)
HP:0005368	Abnormality of humoral immunity	Frequent (30-79%)
HP:0005390	Recurrent opportunistic infections	Frequent (30-79%)
HP:0005403	Decreased total T cell count	Frequent (30-79%)
HP:0006532	Recurrent pneumonia	Frequent (30-79%)
HP:0010444	Pulmonary insufficiency	Frequent (30-79%)
HP:0010976	Decreased total B cell count	Frequent (30-79%)
HP:0011123	Inflammatory abnormality of the skin	Frequent (30-79%)
HP:0012393	Allergy	Frequent (30-79%)
HP:0025379	Anti-thyroid peroxidase antibody positivity	Frequent (30-79%)
HP:0030813	Absent tonsils	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency
Mondo ID	MONDO:0007064
MeSH	C531816
OMIM	102700
Orphanet	277
DOID	DOID:5810
NCIT	C3962
SNOMED CT	44940001
UMLS	C0392607
MedGen	95935
GARD	0005748
MedDRA	10066367
Is cancer (heuristic)	no

Also known as: ADA deficiency · ADA-SCID · adenosine deaminase deficiency · adenosine deaminase deficiency, partial, Autosomal recessive, Somatic mosaicism · adenosine deaminase deficient severe combined immunodeficiency · SCID due to ADA deficiency · SCID due to ADA deficiency, early-onset · SCID due to adenosine deaminase deficiency · severe combined immunodeficiency due to ADA deficiency · severe combined immunodeficiency due to ADA deficiency, Autosomal recessive, Somatic mosaicism · severe combined immunodeficiency due to adenosine deaminase deficiency · severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency

Data availability: 728 ClinVar variants · 60 ClinGen variant curations · 6 GenCC gene-disease records · 43 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › combined immunodeficiency › severe combined immunodeficiency › T-B- severe combined immunodeficiency › severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency

Related subtypes (15): short-limb skeletal dysplasia with severe combined immunodeficiency, combined immunodeficiency with skin granulomas, reticular dysgenesis, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, severe combined immunodeficiency due to DCLRE1C deficiency, Omenn syndrome, DNA ligase IV deficiency, neutrophil immunodeficiency syndrome, combined immunodeficiency due to partial RAG1 deficiency, Cernunnos-XLF deficiency, severe combined immunodeficiency due to LCK deficiency, severe combined immunodeficiency due to DNA-PKcs deficiency, immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia, immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia, reticular dysgenesis-like severe combined immunodeficiency

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

600 retrieved; paginated sample, class counts are floors:

318 likely benign, 120 uncertain significance, 61 likely pathogenic, 56 pathogenic, 19 pathogenic/likely pathogenic, 16 benign, 7 conflicting classifications of pathogenicity, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1981	NM_000022.2(ADA):c.[290A>G;316C>G]		Pathogenic	no assertion criteria provided
3248279	NC_000020.10:g.(?42223339)(45362473_?)del	ACOT8	Pathogenic	criteria provided, single submitter
1066924	NM_000022.4(ADA):c.1A>G (p.Met1Val)	ADA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068992	NC_000020.10:g.(?43264848)(43264949_?)del	ADA	Pathogenic	criteria provided, single submitter
1068993	NC_000020.10:g.(?43252823)(43255260_?)del	ADA	Pathogenic	criteria provided, single submitter
1069449	NM_000022.4(ADA):c.421G>T (p.Glu141Ter)	ADA	Pathogenic	criteria provided, multiple submitters, no conflicts
1070322	NM_000022.4(ADA):c.33+1G>A	ADA	Pathogenic	criteria provided, multiple submitters, no conflicts
1074979	NM_000022.4(ADA):c.366_367del (p.Asp123fs)	ADA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076251	NM_000022.4(ADA):c.577dup (p.Leu193fs)	ADA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1212273	NM_000022.4(ADA):c.996_997del (p.Ser333fs)	ADA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339532	NM_000022.4(ADA):c.870C>A (p.Tyr290Ter)	ADA	Pathogenic	criteria provided, single submitter
1346719	NM_000022.4(ADA):c.845+2T>C	ADA	Pathogenic	criteria provided, single submitter
1370617	NM_000022.4(ADA):c.34-11_55del	ADA	Pathogenic	criteria provided, single submitter
1396468	NM_000022.4(ADA):c.306C>G (p.Tyr102Ter)	ADA	Pathogenic	criteria provided, single submitter
1437148	NM_000022.4(ADA):c.337G>T (p.Glu113Ter)	ADA	Pathogenic	criteria provided, single submitter
1451616	NM_000022.4(ADA):c.1024G>T (p.Glu342Ter)	ADA	Pathogenic	criteria provided, single submitter
1453235	NM_000022.4(ADA):c.854dup (p.Asn285fs)	ADA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456866	NC_000020.10:g.(?43248475)(43280248_?)del	ADA	Pathogenic	criteria provided, single submitter
1459560	NC_000020.10:g.(?43251625)(43255215_?)del	ADA	Pathogenic	criteria provided, single submitter
1500410	NM_000022.4(ADA):c.976-1_979del	ADA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
193544	NM_000022.4(ADA):c.956_960del (p.Glu319fs)	ADA	Pathogenic	criteria provided, multiple submitters, no conflicts
1955	NM_000022.4(ADA):c.301C>T (p.Arg101Trp)	ADA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1956	NM_000022.4(ADA):c.302G>A (p.Arg101Gln)	ADA	Pathogenic	criteria provided, multiple submitters, no conflicts
1957	NM_000022.4(ADA):c.632G>A (p.Arg211His)	ADA	Pathogenic	reviewed by expert panel
1958	NM_000022.4(ADA):c.911T>G (p.Leu304Arg)	ADA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1959	NM_000022.4(ADA):c.986C>T (p.Ala329Val)	ADA	Pathogenic	reviewed by expert panel
1960	NC_000020.11:g.44649961_44653216del	ADA	Pathogenic	no assertion criteria provided
1965	NM_000022.4(ADA):c.320T>C (p.Leu107Pro)	ADA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1968	NM_000022.4(ADA):c.646G>A (p.Gly216Arg)	ADA	Pathogenic	reviewed by expert panel
1969294	NM_000022.4(ADA):c.1009G>T (p.Glu337Ter)	ADA	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 4 · 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
ADA	Definitive	Autosomal recessive	severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADA	Orphanet:277	Severe combined immunodeficiency due to adenosine deaminase deficiency
ADA	Orphanet:39041	Omenn syndrome
AGXT	Orphanet:93598	Primary hyperoxaluria type 1
JAK3	Orphanet:35078	T-B+ severe combined immunodeficiency due to JAK3 deficiency

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ADA	HGNC:186	ENSG00000196839	P00813	Adenosine deaminase	gencc,clinvar
ACOT8	HGNC:15919	ENSG00000101473	O14734	Acyl-coenzyme A thioesterase 8	clinvar
AGXT	HGNC:341	ENSG00000172482	P21549	Alanine–glyoxylate aminotransferase	clinvar
JAK3	HGNC:6193	ENSG00000105639	P52333	Tyrosine-protein kinase JAK3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADA	Adenosine deaminase	Catalyzes the hydrolytic deamination of adenosine and 2-deoxyadenosine.
ACOT8	Acyl-coenzyme A thioesterase 8	Catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A (CoASH), regulating their respective intracellular levels.
AGXT	Alanine–glyoxylate aminotransferase	Peroxisomal aminotransferase that catalyzes the transamination of glyoxylate to glycine and contributes to the glyoxylate detoxification.
JAK3	Tyrosine-protein kinase JAK3	Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation.

Protein-family classification

Druggable: 4 · 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)	3	9.0×	0.004
Kinase	1	6.9×	0.137

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADA	Enzyme (other)	yes	3.5.4.4	A_deaminase_dom, Ado/ade_deaminase, A/AMP_deam_AS
ACOT8	Enzyme (other)	yes	3.1.2.2	Acyl_CoA_thio, HotDog_dom_sf, Acyl-CoA_hotdog
AGXT	Enzyme (other)	yes	2.6.1.44	Aminotrans_V_dom, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase_small
JAK3	Kinase	yes	2.7.10.2	FERM_domain, Prot_kinase_dom, SH2

Expression context

Cohort genes with no expression data: 0.

4 cohort genes 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
duodenum	1
jejunal mucosa	1
thymus	1
mucosa of transverse colon	1
right adrenal gland	1
right adrenal gland cortex	1
endometrium epithelium	1
liver	1
right lobe of liver	1
blood	1
granulocyte	1
spleen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADA	202	ubiquitous	marker	jejunal mucosa, duodenum, thymus
ACOT8	250	ubiquitous	marker	mucosa of transverse colon, right adrenal gland, right adrenal gland cortex
AGXT	125	tissue_specific	marker	right lobe of liver, liver, endometrium epithelium
JAK3	219	ubiquitous	marker	granulocyte, blood, spleen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
JAK3	3,630
ADA	3,187
AGXT	2,648
ACOT8	1,826

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
JAK3	P52333	42
AGXT	P21549	17
ADA	P00813	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACOT8	O14734	88.58

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 49. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Protein localization	2	95.2×	0.005	ACOT8, AGXT
Peroxisomal protein import	2	86.5×	0.005	ACOT8, AGXT
Defective ADA disrupts (deoxy)adenosine deamination	1	2855.0×	0.006	ADA
Nucleotide salvage defects	1	1427.5×	0.007	ADA
Diseases of nucleotide metabolism	1	1427.5×	0.007	ADA
alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	1	475.8×	0.015	ACOT8
Interleukin-9 signaling	1	317.2×	0.015	JAK3
Beta-oxidation of pristanoyl-CoA	1	285.5×	0.015	ACOT8
Nucleotide salvage	1	285.5×	0.015	ADA
Interleukin-21 signaling	1	285.5×	0.015	JAK3
Ribavirin ADME	1	259.6×	0.015	ADA
Interleukin-2 signaling	1	237.9×	0.015	JAK3
Beta-oxidation of very long chain fatty acids	1	219.6×	0.015	ACOT8
Purine salvage	1	219.6×	0.015	ADA
Metabolism	3	8.7×	0.015	ADA, ACOT8, AGXT
Glyoxylate metabolism and glycine degradation	1	190.3×	0.015	AGXT
Interleukin-15 signaling	1	190.3×	0.015	JAK3
alpha-linolenic acid (ALA) metabolism	1	178.4×	0.015	ACOT8
Peroxisomal lipid metabolism	1	167.9×	0.015	ACOT8
Interleukin-2 family signaling	1	158.6×	0.015	JAK3
Signaling by ALK	1	142.8×	0.016	JAK3
Bile acid and bile salt metabolism	1	124.1×	0.018	ACOT8
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	1	114.2×	0.018	ACOT8
Interleukin-20 family signaling	1	105.7×	0.018	JAK3
Synthesis of bile acids and bile salts	1	102.0×	0.018	ACOT8
Interleukin receptor SHC signaling	1	102.0×	0.018	JAK3
Interleukin-7 signaling	1	79.3×	0.022	JAK3
Interleukin-3, Interleukin-5 and GM-CSF signaling	1	79.3×	0.022	JAK3
Metabolism of nucleotides	1	75.1×	0.022	ADA
Drug ADME	1	57.1×	0.028	ADA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of glycoprotein biosynthetic process	2	2106.5×	3e-05	ACOT8, JAK3
negative regulation of thymocyte apoptotic process	2	842.6×	1e-04	ADA, JAK3
negative regulation of dendritic cell cytokine production	1	4213.0×	0.003	JAK3
mature B cell apoptotic process	1	4213.0×	0.003	ADA
purine nucleotide salvage	1	4213.0×	0.003	ADA
xanthine biosynthetic process	1	4213.0×	0.003	ADA
negative regulation of adenosine receptor signaling pathway	1	4213.0×	0.003	ADA
negative regulation of penile erection	1	4213.0×	0.003	ADA
positive regulation of germinal center formation	1	2106.5×	0.003	ADA
penile erection	1	2106.5×	0.003	ADA
purine-containing compound salvage	1	2106.5×	0.003	ADA
hypoxanthine salvage	1	2106.5×	0.003	ADA
dicarboxylic acid catabolic process	1	2106.5×	0.003	ACOT8
dATP catabolic process	1	2106.5×	0.003	ADA
negative regulation of mucus secretion	1	2106.5×	0.003	ADA
response to interleukin-15	1	2106.5×	0.003	JAK3
response to interleukin-9	1	2106.5×	0.003	JAK3
deoxyadenosine catabolic process	1	1404.3×	0.003	ADA
obsolete glycine biosynthetic process, by transamination of glyoxylate	1	1404.3×	0.003	AGXT
regulation of cell-cell adhesion mediated by integrin	1	1404.3×	0.003	ADA
inosine biosynthetic process	1	1404.3×	0.003	ADA
oxalic acid secretion	1	1404.3×	0.003	AGXT
response to interleukin-2	1	1404.3×	0.003	JAK3
negative regulation of mature B cell apoptotic process	1	1053.2×	0.003	ADA
adenosine catabolic process	1	1053.2×	0.003	ADA
glyoxylate catabolic process	1	1053.2×	0.003	AGXT
L-cysteine catabolic process	1	1053.2×	0.003	AGXT
L-alanine catabolic process	1	1053.2×	0.003	AGXT
negative regulation of T-helper 1 cell differentiation	1	1053.2×	0.003	JAK3
dAMP catabolic process	1	1053.2×	0.003	ADA

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 2

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ADA	PENTOSTATIN
JAK3	MOMELOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
JAK3	91	4
ADA	3	4
ACOT8	0	0
AGXT	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PENTOSTATIN	4	ADA
AFAMELANOTIDE	4	ADA
MOMELOTINIB	4	JAK3
FEDRATINIB	4	JAK3
AXITINIB	4	JAK3
SORAFENIB	4	JAK3
RUXOLITINIB	4	JAK3
RUXOLITINIB PHOSPHATE	4	JAK3
NERATINIB	4	JAK3
IBRUTINIB	4	JAK3
PALBOCICLIB	4	JAK3
ENTRECTINIB	4	JAK3
PACRITINIB	4	JAK3
TOFACITINIB CITRATE	4	JAK3
BARICITINIB	4	JAK3
DACOMITINIB ANHYDROUS	4	JAK3
TOFACITINIB	4	JAK3
CERITINIB	4	JAK3
BOSUTINIB	4	JAK3
PEFICITINIB	4	JAK3
FILGOTINIB	4	JAK3
OSIMERTINIB	4	JAK3
UPADACITINIB	4	JAK3
ABROCITINIB	4	JAK3
ACALABRUTINIB	4	JAK3
ZANUBRUTINIB	4	JAK3
RITLECITINIB	4	JAK3
DEUCRAVACITINIB	4	JAK3
PAZOPANIB	4	JAK3
NINTEDANIB	4	JAK3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
JAK3	1,461	Binding:1400, Functional:37, ADMET:22, Toxicity:2
ADA	40	Binding:35, ADMET:5
AGXT	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADA	3.5.4.4	adenosine deaminase
ACOT8	3.1.2.2, 3.1.2.20	palmitoyl-CoA hydrolase, acyl-CoA hydrolase
AGXT	2.6.1.44, 2.6.1.51	alanine-glyoxylate transaminase, serine-pyruvate transaminase
JAK3	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
JAK3	1,461

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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.

Compound	Max phase	Cohort target (bioactivity)
PENTOSTATIN	4	ADA
AFAMELANOTIDE	4	ADA
MOMELOTINIB	4	JAK3
FEDRATINIB	4	JAK3
AXITINIB	4	JAK3
SORAFENIB	4	JAK3
RUXOLITINIB	4	JAK3
RUXOLITINIB PHOSPHATE	4	JAK3
NERATINIB	4	JAK3
IBRUTINIB	4	JAK3
PALBOCICLIB	4	JAK3
ENTRECTINIB	4	JAK3
PACRITINIB	4	JAK3
TOFACITINIB CITRATE	4	JAK3
BARICITINIB	4	JAK3
DACOMITINIB ANHYDROUS	4	JAK3
TOFACITINIB	4	JAK3
CERITINIB	4	JAK3
BOSUTINIB	4	JAK3
PEFICITINIB	4	JAK3
FILGOTINIB	4	JAK3
OSIMERTINIB	4	JAK3
UPADACITINIB	4	JAK3
ABROCITINIB	4	JAK3
ACALABRUTINIB	4	JAK3
ZANUBRUTINIB	4	JAK3
RITLECITINIB	4	JAK3
DEUCRAVACITINIB	4	JAK3
PAZOPANIB	4	JAK3
NINTEDANIB	4	JAK3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	ADA, JAK3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	AGXT
D	Druggable family + AlphaFold only, no drug	1	ACOT8
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ACOT8	0	—
AGXT	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 19.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	10
PHASE1/PHASE2	5
PHASE1	2
PHASE3	1
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01420627	PHASE3	COMPLETED	EZN-2279 in Patients With ADA-SCID
NCT04140539	PHASE2/PHASE3	WITHDRAWN	A Clinical Study to Enable Process Validation of Commercial Grade OTL-101
NCT01279720	PHASE1/PHASE2	COMPLETED	Gene Therapy ADA Deficiency
NCT01380990	PHASE1/PHASE2	COMPLETED	Lentiviral (LV) Gene Therapy for Adenosine Deaminase (ADA) Deficiency
NCT01852071	PHASE1/PHASE2	COMPLETED	Autologous CD34+ Hematopoietic Stem Cells Transduced ex Vivo With Elongation Factor 1 Alpha Shortened (EFS) Lentiviral Vector Encoding for the Human ADA Gene
NCT02999984	PHASE1/PHASE2	COMPLETED	Efficacy and Safety of the Cryopreserved Formulation of OTL-101 in Subjects With ADA-SCID
NCT03765632	PHASE1/PHASE2	COMPLETED	Efficacy and Safety of the Cryopreserved Formulation of OTL-101 in Subjects With ADA-SCID
NCT00008450	PHASE1	COMPLETED	Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Severe Combined Immunodeficiency Undergoing Donor Bone Marrow Transplant
NCT02022696	PHASE1	COMPLETED	Treatment of SCID Due to ADA Deficiency With Autologous Transplantation of Cord Blood or Hematopoietic CD 34+ Cells After Addition of a Normal Human ADA cDNA by the EFS-ADA Lentiviral Vector
NCT01186913	Not specified	ENROLLING_BY_INVITATION	Natural History Study of SCID Disorders
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04049084	Not specified	ENROLLING_BY_INVITATION	An Observational LTFU Study for Patients Previously Treated With Autologous ex Vivo Gene Therapy for ADA-SCID
NCT01182857	Not specified	WITHDRAWN	Quality of Life and Neuropsychiatric Sequelae in Patients Treated With Gene Therapy for ADA-SCID and in Their Parents
NCT01346150	Not specified	UNKNOWN	Patients Treated for SCID (1968-Present)
NCT03232203	Not specified	COMPLETED	Evaluating the Effectiveness of STRIMVELIS Risk Minimization Measures (RMMs)
NCT04959890	Not specified	UNKNOWN	Methodology Study of Retroviral Insertion Site Analysis in Strimvelis Gene Therapy
NCT05300334	Not specified	UNKNOWN	Investigation of ADA Enzyme Deficiency
NCT05300347	Not specified	UNKNOWN	Observational Study Evaluating the Prevalence of Enzyme Deficiency in Pulmonology Clinics (ADA)
NCT05300373	Not specified	UNKNOWN	Evaluation of Adenosine Deaminase (ADA) Enzyme Deficiency in Patients With Lymphopenia and/or Elevated Immunoglobulin E

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BUSULFAN	4	4
AUTOLOGOUS CD34+ ENRICHED CELL FRACTION THAT CONTAINS CD34+ CELLS TRANSDUCED WITH RETROVIRAL VECTOR THAT ENCODES FOR THE HUMAN ADA CDNA SEQUENCE	4	2
ELAPEGADEMASE	4	1
PEGADEMASE BOVINE	4	1
SIMOLADAGENE AUTOTEMCEL	2	1