Severe combined immunodeficiency

Summary

Severe combined immunodeficiency (MONDO:0015974) is a disease (an umbrella term covering 11 Mondo subtypes) caused by NUDCD3 (GenCC Strong), with 36 cohort genes and 44 clinical trials. The dominant Reactome pathway is Translocation of ZAP-70 to Immunological synapse (6 cohort genes). Top therapeutic interventions include alemtuzumab, busulfan, and dextrose.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: NUDCD3 (GenCC Strong)
• Umbrella term: 11 Mondo subtypes
• Cohort genes: 36
• ClinVar variants: 211
• Clinical trials: 44

Clinical features

Epidemiology

Prevalence records

8 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	1.65	Europe	Validated
Prevalence at birth	1-9 / 100 000	1.6	France	Validated
Prevalence at birth	1-9 / 100 000	1.7	Greece	Validated
Prevalence at birth	1-9 / 100 000	1.28	Chile	Validated
Prevalence at birth	1-9 / 100 000	3.79	Costa rica	Validated
Prevalence at birth	1-9 / 100 000	1.72	United States	Validated
Prevalence at birth	1-9 / 100 000		Worldwide	Not yet validated
Prevalence at birth	1-9 / 100 000	1.75	Australia	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	severe combined immunodeficiency
Mondo ID	MONDO:0015974
MeSH	D016511
Orphanet	183660
DOID	DOID:627
ICD-11	963193284
NCIT	C3472
SNOMED CT	31323000
UMLS	C0085110
MedGen	88328
GARD	0007628
MedDRA	10069566
NORD	1706
Is cancer (heuristic)	no

Also known as: SCID · severe combined immunodeficiency · severe combined immunodeficiency (disease) · severe combined immunodeficiency disease

Data availability: 211 ClinVar variants · 1 ClinGen variant curation · 2 GenCC gene-disease records · 1 HPO phenotype · 5 cell lines.

Disease family

An umbrella term covering 11 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › combined immunodeficiency › severe combined immunodeficiency

Related subtypes (32): ataxia telangiectasia, combined immunodeficiency due to ZAP70 deficiency, X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia, combined immunodeficiency due to moesin deficiency, Wiskott-Aldrich syndrome, MHC class I deficiency, combined immunodeficiency due to STK4 deficiency, combined immunodeficiency due to MALT1 deficiency, combined immunodeficiency due to OX40 deficiency, combined immunodeficiency due to CD3gamma deficiency, combined immunodeficiency due to CTPS1 deficiency, combined immunodeficiency due to CRAC channel dysfunction, non-SCID combined immunodeficiency, combined immunodeficiency due to RELA haploinsufficiency, combined immunodeficiency due to GINS1 deficiency, combined immunodeficiency syndrome, combined immunodeficiency due to POLE2 deficiency, autosomal recessive combined immunodeficiency due to complete IL6ST deficiency, autosomal recessive combined immunodeficiency due to partial IL6ST deficiency, autosomal dominant combined immunodeficiency due to partial IL6ST deficiency, autosomal recessive combined immunodeficiency due to IL6R deficiency, autosomal dominant combined immunodeficiency due to ERBIN deficiency, combined immunodeficiency due to TBX1 deficiency, RAC2-related combined immunodeficiency-bronchiectasis-cancer-predisposing syndrome, combined immunodeficiency due to dimerization defective IKAROS mutation, late-onset combined immunodeficiency due to ICOSL deficiency, combined immunodeficiency-hypogammaglobulinemia-skeletal anomalies syndrome due to IKBKA deficiency, early-onset combined immunodeficiency with low ig due to dominant negative IKAROS mutation, combined immunodeficiency with low Ig due to BCL10 deficiency, IRF4-related combined immunodeficiency, NFATC1-related combined immunodeficiency, POLD3-related combined immunodeficiency

Subtypes (11): recombinase activating gene 1 deficiency, recombinase activating gene 2 deficiency, janus kinase-3 deficiency, T-cell immunodeficiency, congenital alopecia, and nail dystrophy, T-B- severe combined immunodeficiency, severe combined immunodeficiency due to CARMIL2 deficiency, immunodeficiency 79, familial severe combined immunodeficiency, severe combined immunodeficiency due to CD70 deficiency, T-B+ severe combined immunodeficiency, T+ B+ 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

211 retrieved; paginated sample, class counts are floors:

63 pathogenic, 59 pathogenic/likely pathogenic, 57 likely pathogenic, 13 uncertain significance, 8 conflicting classifications of pathogenicity, 8 benign, 2 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1074979	NM_000022.4(ADA):c.366_367del (p.Asp123fs)	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
1956	NM_000022.4(ADA):c.302G>A (p.Arg101Gln)	ADA	Pathogenic	criteria provided, multiple submitters, no conflicts
1965	NM_000022.4(ADA):c.320T>C (p.Leu107Pro)	ADA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1970	NM_000022.4(ADA):c.466C>T (p.Arg156Cys)	ADA	Pathogenic	criteria provided, multiple submitters, no conflicts
1971	NM_000022.4(ADA):c.872C>T (p.Ser291Leu)	ADA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1977	NM_000022.4(ADA):c.221G>T (p.Gly74Val)	ADA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1984	NM_000022.4(ADA):c.467G>A (p.Arg156His)	ADA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265025	NM_000022.4(ADA):c.478+1G>A	ADA	Pathogenic	criteria provided, multiple submitters, no conflicts
402341	NM_000022.4(ADA):c.845G>A (p.Arg282Gln)	ADA	Pathogenic	reviewed by expert panel
4848662	NC_000020.10:g.(?43248162)(43280341_?)del	ADA	Pathogenic	criteria provided, single submitter
505549	NM_000022.4(ADA):c.532del (p.Val177_Val178insTer)	ADA	Pathogenic	reviewed by expert panel
550821	NM_000022.4(ADA):c.396dup (p.Val133fs)	ADA	Pathogenic	reviewed by expert panel
552928	NM_000022.4(ADA):c.424C>T (p.Arg142Ter)	ADA	Pathogenic	criteria provided, multiple submitters, no conflicts
555196	NM_000022.4(ADA):c.95+1G>A	ADA	Pathogenic	criteria provided, multiple submitters, no conflicts
555264	NM_000022.4(ADA):c.716G>A (p.Gly239Asp)	ADA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
565486	NM_000022.4(ADA):c.311C>T (p.Pro104Leu)	ADA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68259	NM_000022.4(ADA):c.302G>T (p.Arg101Leu)	ADA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68265	NM_000022.4(ADA):c.529G>A (p.Val177Met)	ADA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
984454	NM_000022.4(ADA):c.975+1G>A	ADA	Pathogenic	reviewed by expert panel
18252	NM_001625.4(AK2):c.1A>G (p.Met1Val)	AK2	Pathogenic	criteria provided, multiple submitters, no conflicts
18255	NM_001625.4(AK2):c.498+1G>A	AK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18260	NM_001625.4(AK2):c.307C>T (p.Arg103Trp)	AK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
419227	NM_198053.3(CD247):c.301C>T (p.Gln101Ter)	CD247	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2691273	NM_000732.6(CD3D):c.107del (p.Asn36fs)	CD3D	Pathogenic	criteria provided, single submitter
2445836	NM_000733.4(CD3E):c.288T>A (p.Tyr96Ter)	CD3E	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
541654	NM_000073.3(CD3G):c.213del (p.Lys71fs)	CD3G	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
580586	NM_000073.3(CD3G):c.213dup (p.Trp72fs)	CD3G	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1698463	NM_001033855.3(DCLRE1C):c.1265C>G (p.Ser422Ter)	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1722324	NM_001033855.3(DCLRE1C):c.161+2T>G	DCLRE1C	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 44 · 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
NUDCD3	Strong	Autosomal recessive	severe combined immunodeficiency
ITPKB	Limited	Autosomal recessive	severe combined immunodeficiency	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STK4	Orphanet:314689	Combined immunodeficiency due to STK4 deficiency
FOXN1	Orphanet:169095	Severe combined immunodeficiency due to FOXN1 deficiency
FOXN1	Orphanet:676039	Combined immunodeficiency due to FOXN1 haploinsufficiency
FOXN1	Orphanet:83471	T-cell immunodeficiency with thymic aplasia
ZAP70	Orphanet:911	Combined immunodeficiency due to ZAP70 deficiency
CD3D	Orphanet:169160	T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta
CD3E	Orphanet:169160	T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta
CD3G	Orphanet:169082	Combined immunodeficiency due to CD3gamma deficiency
CD247	Orphanet:169160	T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta
CD247	Orphanet:85408	Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis
CD247	Orphanet:85410	Oligoarticular juvenile idiopathic arthritis
DCLRE1C	Orphanet:275	Severe combined immunodeficiency due to DCLRE1C deficiency
DCLRE1C	Orphanet:39041	Omenn syndrome
MCFD2	Orphanet:35909	Combined deficiency of factor V and factor VIII
ADA	Orphanet:277	Severe combined immunodeficiency due to adenosine deaminase deficiency
ADA	Orphanet:39041	Omenn syndrome
DOCK8	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DOCK8	Orphanet:217390	Combined immunodeficiency due to DOCK8 deficiency
TTC7A	Orphanet:436252	Combined immunodeficiency-multiple intestinal atresia
CORO1A	Orphanet:228003	Severe combined immunodeficiency due to CORO1A deficiency
NHEJ1	Orphanet:169079	Cernunnos-XLF deficiency
AK2	Orphanet:33355	Reticular dysgenesis
IKBKB	Orphanet:397787	Combined immunodeficiency due to IKBKB deficiency
IKBKB	Orphanet:700205	Combined immunodeficiency due to IKBKB gain-of-function mutation
IL7R	Orphanet:169154	T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency
IL7R	Orphanet:39041	Omenn syndrome
JAK3	Orphanet:35078	T-B+ severe combined immunodeficiency due to JAK3 deficiency
LCK	Orphanet:280142	Combined immunodeficiency due to LCK deficiency
LIG4	Orphanet:235	Dubowitz syndrome
LIG4	Orphanet:39041	Omenn syndrome
LIG4	Orphanet:99812	LIG4 syndrome
MALT1	Orphanet:397964	Combined immunodeficiency due to MALT1 deficiency
MALT1	Orphanet:52417	MALT lymphoma
MTHFD1	Orphanet:658813	Combined immunodeficiency-megaloblastic anemia due to methylenetetrahydrofolate dehydrogenase 1 deficiency
PNP	Orphanet:760	Purine nucleoside phosphorylase deficiency
PGM3	Orphanet:443811	PGM3-CDG
PTPRC	Orphanet:169157	T-B+ severe combined immunodeficiency due to CD45 deficiency
RAG1	Orphanet:157949	Combined immunodeficiency with granulomatosis
RAG1	Orphanet:231154	Combined immunodeficiency due to partial RAG1 deficiency
RAG1	Orphanet:331206	Severe combined immunodeficiency due to complete RAG1/2 deficiency
RAG1	Orphanet:39041	Omenn syndrome
RAG2	Orphanet:157949	Combined immunodeficiency with granulomatosis
RAG2	Orphanet:331206	Severe combined immunodeficiency due to complete RAG1/2 deficiency
RAG2	Orphanet:39041	Omenn syndrome

Cohort genes → proteins

36 cohort genes, 36 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	36

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NUDCD3	HGNC:22208	ENSG00000015676	Q8IVD9	NudC domain-containing protein 3	gencc
ITPKB	HGNC:6179	ENSG00000143772	P27987	Inositol-trisphosphate 3-kinase B	gencc
STK4	HGNC:11408	ENSG00000101109	Q13043	Serine/threonine-protein kinase 4	clinvar
VDAC2	HGNC:12672	ENSG00000165637	P45880	Non-selective voltage-gated ion channel VDAC2	clinvar
FOXN1	HGNC:12765	ENSG00000109101	O15353	Forkhead box protein N1	clinvar
ZAP70	HGNC:12858	ENSG00000115085	P43403	Tyrosine-protein kinase ZAP-70	clinvar
KDM2B	HGNC:13610	ENSG00000089094	Q8NHM5	Lysine-specific demethylase 2B	clinvar
CAMK4	HGNC:1464	ENSG00000152495	Q16566	Calcium/calmodulin-dependent protein kinase type IV	clinvar
CD3D	HGNC:1673	ENSG00000167286	P04234	T-cell surface glycoprotein CD3 delta chain	clinvar
CD3E	HGNC:1674	ENSG00000198851	P07766	T-cell surface glycoprotein CD3 epsilon chain	clinvar
CD3G	HGNC:1675	ENSG00000160654	P09693	T-cell surface glycoprotein CD3 gamma chain	clinvar
CD247	HGNC:1677	ENSG00000198821	P20963	T-cell surface glycoprotein CD3 zeta chain	clinvar
DCLRE1C	HGNC:17642	ENSG00000152457	Q96SD1	Protein artemis	clinvar
MCFD2	HGNC:18451	ENSG00000180398	Q8NI22	Multiple coagulation factor deficiency protein 2	clinvar
ADA	HGNC:186	ENSG00000196839	P00813	Adenosine deaminase	clinvar
DOCK8	HGNC:19191	ENSG00000107099	Q8NF50	Dedicator of cytokinesis protein 8	clinvar
TTC7A	HGNC:19750	ENSG00000068724	Q9ULT0	Tetratricopeptide repeat protein 7A	clinvar
DOP1A	HGNC:21194	ENSG00000083097	Q5JWR5	Protein DOP1A	clinvar
CORO1A	HGNC:2252	ENSG00000102879	P31146	Coronin-1A	clinvar
NHEJ1	HGNC:25737	ENSG00000187736	Q9H9Q4	Non-homologous end-joining factor 1	clinvar
DOCK8-AS1	HGNC:26436	ENSG00000183784	Q5T8R8	Uncharacterized protein DOCK8-AS1	clinvar
AK2	HGNC:362	ENSG00000004455	P54819	Adenylate kinase 2, mitochondrial	clinvar
IKBKB	HGNC:5960	ENSG00000104365	O14920	Inhibitor of nuclear factor kappa-B kinase subunit beta	clinvar
IL7R	HGNC:6024	ENSG00000168685	P16871	Interleukin-7 receptor subunit alpha	clinvar
INPP5D	HGNC:6079	ENSG00000168918	Q92835	Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1	clinvar
JAK3	HGNC:6193	ENSG00000105639	P52333	Tyrosine-protein kinase JAK3	clinvar
LCK	HGNC:6524	ENSG00000182866	P06239	Tyrosine-protein kinase Lck	clinvar
LIG4	HGNC:6601	ENSG00000174405	P49917	DNA ligase 4	clinvar
MALT1	HGNC:6819	ENSG00000172175	Q9UDY8	Mucosa-associated lymphoid tissue lymphoma translocation protein 1	clinvar
MTHFD1	HGNC:7432	ENSG00000100714	P11586	C-1-tetrahydrofolate synthase, cytoplasmic	clinvar
PNP	HGNC:7892	ENSG00000198805	P00491	Purine nucleoside phosphorylase	clinvar
PGM3	HGNC:8907	ENSG00000013375	O95394	Phosphoacetylglucosamine mutase	clinvar
PPY	HGNC:9327	ENSG00000108849	P01298	Pancreatic polypeptide prohormone	clinvar
PTPRC	HGNC:9666	ENSG00000081237	P08575	Receptor-type tyrosine-protein phosphatase C	clinvar
RAG1	HGNC:9831	ENSG00000166349	P15918	V(D)J recombination-activating protein 1	clinvar
RAG2	HGNC:9832	ENSG00000175097	P55895	V(D)J recombination-activating protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ITPKB	Inositol-trisphosphate 3-kinase B	Catalyzes the phosphorylation of 1D-myo-inositol 1,4,5-trisphosphate (InsP3) into 1D-myo-inositol 1,3,4,5-tetrakisphosphate and participates to the regulation of calcium homeostasis.
STK4	Serine/threonine-protein kinase 4	Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation.
VDAC2	Non-selective voltage-gated ion channel VDAC2	Non-selective voltage-gated ion channel that mediates the transport of anions and cations through the mitochondrion outer membrane and plasma membrane.
FOXN1	Forkhead box protein N1	Transcriptional regulator which regulates the development, differentiation, and function of thymic epithelial cells (TECs) both in the prenatal and postnatal thymus.
ZAP70	Tyrosine-protein kinase ZAP-70	Tyrosine kinase that plays an essential role in regulation of the adaptive immune response.
KDM2B	Lysine-specific demethylase 2B	Histone demethylase that demethylates ‘Lys-4’ and ‘Lys-36’ of histone H3, thereby playing a central role in histone code.
CAMK4	Calcium/calmodulin-dependent protein kinase type IV	Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK4 signaling cascade and regulates, mainly by phosphorylation, the activity of several transcription activators, such as CREB1, MEF2D, JUN and RORA…
CD3D	T-cell surface glycoprotein CD3 delta chain	Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response.
CD3E	T-cell surface glycoprotein CD3 epsilon chain	Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response.
CD3G	T-cell surface glycoprotein CD3 gamma chain	Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response.
CD247	T-cell surface glycoprotein CD3 zeta chain	Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response.
DCLRE1C	Protein artemis	Nuclease involved in DNA non-homologous end joining (NHEJ); required for double-strand break repair and V(D)J recombination.
MCFD2	Multiple coagulation factor deficiency protein 2	The MCFD2-LMAN1 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins.
ADA	Adenosine deaminase	Catalyzes the hydrolytic deamination of adenosine and 2-deoxyadenosine.
DOCK8	Dedicator of cytokinesis protein 8	Guanine nucleotide exchange factor (GEF) which specifically activates small GTPase CDC42 by exchanging bound GDP for free GTP.
TTC7A	Tetratricopeptide repeat protein 7A	Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane.
DOP1A	Protein DOP1A	May be involved in protein traffic between late Golgi and early endosomes.
CORO1A	Coronin-1A	May be a crucial component of the cytoskeleton of highly motile cells, functioning both in the invagination of large pieces of plasma membrane, as well as in forming protrusions of the plasma membrane involved in cell locomotion.
NHEJ1	Non-homologous end-joining factor 1	DNA repair protein involved in DNA non-homologous end joining (NHEJ); it is required for double-strand break (DSB) repair and V(D)J recombination and is also involved in telomere maintenance.
AK2	Adenylate kinase 2, mitochondrial	Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP.
IKBKB	Inhibitor of nuclear factor kappa-B kinase subunit beta	Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses.
IL7R	Interleukin-7 receptor subunit alpha	Receptor for interleukin-7.
INPP5D	Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1	Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating the PI3K (phosphoinositide 3-kinas…
JAK3	Tyrosine-protein kinase JAK3	Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation.
LCK	Tyrosine-protein kinase Lck	Non-receptor tyrosine-protein kinase that plays an essential role in the selection and maturation of developing T-cells in the thymus and in the function of mature T-cells.
LIG4	DNA ligase 4	DNA ligase involved in DNA non-homologous end joining (NHEJ); required for double-strand break (DSB) repair and V(D)J recombination.
MALT1	Mucosa-associated lymphoid tissue lymphoma translocation protein 1	Protease that enhances BCL10-induced activation: acts via formation of CBM complexes that channel adaptive and innate immune signaling downstream of CARD domain-containing proteins (CARD9, CARD11 and CARD14) to activate NF-kappa-B and MAP…
MTHFD1	C-1-tetrahydrofolate synthase, cytoplasmic	Trifunctional enzyme that catalyzes the interconversion of three forms of one-carbon-substituted tetrahydrofolate: (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate, 5,10-methenyltetrahydrofolate and (6S)-10-formyltetrahydrofolate.
PNP	Purine nucleoside phosphorylase	Catalyzes the phosphorolytic breakdown of the N-glycosidic bond in the beta-(deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate.
PGM3	Phosphoacetylglucosamine mutase	Catalyzes the conversion of GlcNAc-6-P into GlcNAc-1-P during the synthesis of uridine diphosphate/UDP-GlcNAc, a sugar nucleotide critical to multiple glycosylation pathways including protein N- and O-glycosylation.
PPY	Pancreatic polypeptide prohormone	Hormone secreted by pancreatic cells that acts as a regulator of pancreatic and gastrointestinal functions probably by signaling through the G protein-coupled receptor NPY4R2.
PTPRC	Receptor-type tyrosine-protein phosphatase C	Protein tyrosine-protein phosphatase required for T-cell activation through the antigen receptor.
RAG1	V(D)J recombination-activating protein 1	Catalytic component of the RAG complex, a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination.
RAG2	V(D)J recombination-activating protein 2	Core component of the RAG complex, a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination.

Protein-family classification

Druggable: 19 · Difficult: 6 · Unknown: 11 · Druggable fraction: 0.53

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
Kinase	7	5.4×	0.002
Antibody/Immunoglobulin	5	4.0×	0.025
Enzyme (other)	6	2.0×	0.175
Phosphatase	1	2.3×	0.614
Scaffold/PPI	2	1.0×	0.758
Transcription factor	4	0.9×	0.758
Other/Unknown	11	0.6×	0.999

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NUDCD3	Other/Unknown	no		CS_dom, HSP20-like_chaperone, NudC_N_dom
ITPKB	Enzyme (other)	yes	2.7.1.127	IPK, IPK_sf
STK4	Kinase	yes	2.7.11.1	Prot_kinase_dom, Kinase-like_dom_sf, SARAH_dom
VDAC2	Other/Unknown	no		Porin_Euk, Porin_dom_sf, Porin_Euk/Tom40
FOXN1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_2, WH-like_DNA-bd_sf
ZAP70	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom
KDM2B	Transcription factor	no		F-box_dom, Znf_PHD, Znf_CXXC
CAMK4	Kinase	yes	2.7.11.17	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
CD3D	Antibody/Immunoglobulin	yes		Phos_immunorcpt_sig_ITAM, Ig-like_fold, CD3_esu/gsu/dsu
CD3E	Antibody/Immunoglobulin	yes		Phos_immunorcpt_sig_ITAM, Ig_sub2, Ig-like_fold
CD3G	Antibody/Immunoglobulin	yes		Phos_immunorcpt_sig_ITAM, Ig_sub2, Ig-like_fold
CD247	Other/Unknown	no		Phos_immunorcpt_sig_ITAM, CD3_zeta/IgE_Fc_rcpt_gamma, T-cell_CD3_zeta
DCLRE1C	Other/Unknown	no		DRMBL, RibonucZ/Hydroxyglut_hydro
MCFD2	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
ADA	Enzyme (other)	yes	3.5.4.4	A_deaminase_dom, Ado/ade_deaminase, A/AMP_deam_AS
DOCK8	Other/Unknown	no		ARM-type_fold, DOCK_C/D_N, DOCK
TTC7A	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, TTC7_N
DOP1A	Other/Unknown	no		DOP1_N, DOP1, DOP1_C
CORO1A	Scaffold/PPI	no		WD40_rpt, DUF1899, Trimer_CC
NHEJ1	Other/Unknown	no		XLF-like_N, XRCC4-like_N_sf, NHEJ_factor
DOCK8-AS1	Other/Unknown	no		DUF5555
AK2	Kinase	yes	2.7.4.3	Adenylat/UMP-CMP_kin, Adenyl_kin_sub, Adenylate_kinase_lid-dom
IKBKB	Kinase	yes	2.7.11.10	Ubiquitin-like_dom, Prot_kinase_dom, Ser/Thr_kinase_AS
IL7R	Antibody/Immunoglobulin	yes		Hempt_rcpt_S_F1_CS, FN3_dom, Ig-like_fold
INPP5D	Scaffold/PPI	no	3.1.3.86	IPPc, SH2, Endo/exonu/phosph_ase_sf
JAK3	Kinase	yes	2.7.10.2	FERM_domain, Prot_kinase_dom, SH2
LCK	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom
LIG4	Enzyme (other)	yes	6.5.1.1	DNA_ligase_ATP-dep, BRCT_dom, DNA_ligase_ATP-dep_N
MALT1	Antibody/Immunoglobulin	yes		Pept_C14_p20, Ig_sub2, Ig_sub
MTHFD1	Enzyme (other)	yes	1.5.1.5	Formate_THF_ligase, THF_DH/CycHdrlase, Formate_THF_ligase_CS
PNP	Enzyme (other)	yes	2.4.2.1	Nucleoside_phosphorylase_d, Purine_phosphorylase, Pur_Nuc_Pase_Ino/Guo-sp
PGM3	Enzyme (other)	yes	5.4.2.3	A-D-PHexomutase_C, A-D-PHexomutase_a/b/a-I, A-D-PHexomutase_a/b/a-I/II/III
PPY	Other/Unknown	no		Pancreatic_hormone-like, Pancreatic_hormone-like_CS
PTPRC	Phosphatase	yes		PTP_cat, Tyr_Pase_dom, Tyr_Pase_cat
RAG1	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_CS
RAG2	Transcription factor	no		RAG2, Znf_FYVE_PHD, Gal_Oxase/kelch_b-propeller

Expression context

Cohort genes with no expression data: 0.

34 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)	36
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	10
thymus	7
lymph node	6
blood	5
buccal mucosa cell	4
monocyte	4
leukocyte	3
mucosa of transverse colon	3
spleen	3
male germ line stem cell (sensu Vertebrata) in testis	3
cortical plate	2
colonic epithelium	2
rectum	2
islet of Langerhans	2
prefrontal cortex	1
right frontal lobe	1
globus pallidus	1
lateral globus pallidus	1
substantia nigra pars reticulata	1
esophagus mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NUDCD3	287	ubiquitous	marker	cortical plate, prefrontal cortex, right frontal lobe
ITPKB	268	ubiquitous	marker	lateral globus pallidus, substantia nigra pars reticulata, globus pallidus
STK4	267	ubiquitous	marker	colonic epithelium, buccal mucosa cell, blood
VDAC2	161	ubiquitous	marker	esophagus mucosa, gastrocnemius, heart left ventricle
FOXN1	75	tissue_specific	yes	gingival epithelium, gingiva, upper leg skin
ZAP70	182	broad	marker	granulocyte, lymph node, blood
KDM2B	251	ubiquitous	marker	oviduct epithelium, upper arm skin, cortical plate
CAMK4	205	ubiquitous	marker	cerebellar vermis, cerebellar cortex, cerebellar hemisphere
CD3D	221	broad	marker	thymus, granulocyte, lymph node
CD3E	168	broad	marker	granulocyte, vermiform appendix, lymph node
CD3G	166	broad	marker	buccal mucosa cell, lymph node, thymus
CD247	179	broad	marker	granulocyte, thymus, blood
DCLRE1C	284	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, epithelium of nasopharynx
MCFD2	295	ubiquitous	marker	parotid gland, seminal vesicle, adrenal tissue
ADA	202	ubiquitous	marker	jejunal mucosa, duodenum, thymus
DOCK8	236	ubiquitous	marker	bone marrow cell, leukocyte, monocyte
TTC7A	236	ubiquitous	marker	sperm, right testis, left testis
DOP1A	289	ubiquitous	marker	calcaneal tendon, middle temporal gyrus, right hemisphere of cerebellum
CORO1A	252	ubiquitous	marker	granulocyte, monocyte, leukocyte
NHEJ1	189	ubiquitous	marker	rectum, primordial germ cell in gonad, mucosa of transverse colon
DOCK8-AS1	138	tissue_specific	marker	adult mammalian kidney, kidney, cortex of kidney
AK2	270	ubiquitous	marker	rectum, mucosa of transverse colon, metanephros cortex
IKBKB	288	ubiquitous	marker	spleen, granulocyte, lower esophagus mucosa
IL7R	220	ubiquitous	marker	right lung, granulocyte, lymph node
INPP5D	135	ubiquitous	marker	granulocyte, blood, spleen
JAK3	219	ubiquitous	marker	granulocyte, blood, spleen
LCK	207	broad	marker	thymus, granulocyte, lymph node
LIG4	275	ubiquitous	yes	endothelial cell, oocyte, secondary oocyte
MALT1	275	ubiquitous	marker	colonic epithelium, tonsil, male germ line stem cell (sensu Vertebrata) in testis
MTHFD1	289	ubiquitous	marker	right lobe of liver, liver, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 40.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTPRC	6,849
LCK	5,556
IKBKB	5,421
CD3D	4,789
VDAC2	4,289
AK2	4,022
ZAP70	3,648
JAK3	3,630
CORO1A	3,620
RAG1	3,549

Intra-cohort edges

A	B	Sources
ADA	PNP	string_interaction
AK2	DCLRE1C	string_interaction
CD247	CD3D	string_interaction
CD247	CD3E	biogrid_interaction, string_interaction
CD247	CD3G	string_interaction
CD247	JAK3	biogrid_interaction
CD247	LCK	biogrid_interaction, string_interaction
CD247	PTPRC	biogrid_interaction
CD247	ZAP70	biogrid_interaction, intact, string_interaction
CD3D	CD3E	intact, string_interaction
CD3D	CD3G	string_interaction
CD3D	LCK	string_interaction
CD3D	PTPRC	string_interaction
CD3D	ZAP70	biogrid_interaction, string_interaction
CD3E	CD3G	intact, string_interaction
CD3E	IL7R	string_interaction
CD3E	LCK	string_interaction
CD3E	PTPRC	string_interaction
CD3E	ZAP70	biogrid_interaction, intact, string_interaction
CD3G	LCK	string_interaction
CD3G	PTPRC	string_interaction
CD3G	ZAP70	biogrid_interaction, string_interaction
CORO1A	DOCK8	string_interaction
DCLRE1C	LIG4	intact, string_interaction
DCLRE1C	NHEJ1	string_interaction
DCLRE1C	RAG1	string_interaction
DCLRE1C	RAG2	string_interaction
DOCK8	PGM3	string_interaction
FOXN1	RAG1	string_interaction
IKBKB	MALT1	biogrid_interaction, string_interaction
IL7R	JAK3	string_interaction
IL7R	RAG1	string_interaction
LCK	PTPRC	biogrid_interaction, intact, string_interaction
LCK	ZAP70	intact, string_interaction
LIG4	NHEJ1	biogrid_interaction, intact, string_interaction
MTHFD1	STK4	intact
NUDCD3	RAG1	intact
PTPRC	RAG1	string_interaction
PTPRC	RAG2	string_interaction
RAG1	RAG2	biogrid_interaction, string_interaction

Structural data

PDB: 28 · AlphaFold-only: 8 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
INPP5D	Q92835	99
LCK	P06239	57
CD3E	P07766	44
JAK3	P52333	42
PNP	P00491	41
CD3G	P09693	38
CD247	P20963	38
CD3D	P04234	31
LIG4	P49917	31
NHEJ1	Q9H9Q4	26
MALT1	Q9UDY8	26
MCFD2	Q8NI22	17
STK4	Q13043	16
ZAP70	P43403	15
DCLRE1C	Q96SD1	14
MTHFD1	P11586	12
IL7R	P16871	8
PTPRC	P08575	6
IKBKB	O14920	5
KDM2B	Q8NHM5	4
VDAC2	P45880	3
AK2	P54819	3
PPY	P01298	3
FOXN1	O15353	2
ADA	P00813	2
NUDCD3	Q8IVD9	1
CAMK4	Q16566	1
RAG2	P55895	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PGM3	O95394	95.54
CORO1A	P31146	93.25
TTC7A	Q9ULT0	84.59
RAG1	P15918	81.68
DOCK8	Q8NF50	75.17
DOP1A	Q5JWR5	67.63
ITPKB	P27987	56.58
DOCK8-AS1	Q5T8R8	47.31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 200. Enrichment computed across 36 evidence-associated genes (31 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 31 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Translocation of ZAP-70 to Immunological synapse	6	122.8×	9e-10	ZAP70, CD3D, CD3E, CD3G, CD247, LCK
Phosphorylation of CD3 and TCR zeta chains	6	105.2×	1e-09	CD3D, CD3E, CD3G, CD247, LCK, PTPRC
TCR signaling	6	96.1×	2e-09	CD3D, CD3E, CD3G, INPP5D, LCK, MALT1
Downstream TCR signaling	8	33.1×	3e-09	CD3D, CD3E, CD3G, CD247, IKBKB, INPP5D, LCK, MALT1
Generation of second messenger molecules	6	67.0×	1e-08	ZAP70, CD3D, CD3E, CD3G, CD247, LCK
Co-inhibition by PD-1	5	83.7×	9e-08	CD3D, CD3E, CD3G, CD247, LCK
Regulation of T cell activation by CD28 family	4	54.6×	2e-05	CD3D, CD3E, CD3G, LCK
Interleukin-7 signaling	4	40.9×	6e-05	IL7R, JAK3, RAG1, RAG2
Interleukin-2 family signaling	3	61.4×	3e-04	INPP5D, JAK3, LCK
Nef and signal transduction	2	81.9×	0.005	CD247, LCK
Ribavirin ADME	2	67.0×	0.006	ADA, PNP
Interleukin-2 signaling	2	61.4×	0.006	JAK3, LCK
FCGR activation	2	56.7×	0.006	CD3G, CD247
PECAM1 interactions	2	56.7×	0.006	INPP5D, LCK
Purine salvage	2	56.7×	0.006	ADA, PNP
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	4	11.2×	0.006	CD3D, CD3E, CD3G, CD247
Adaptive Immune System	6	5.8×	0.006	CD3D, CD3E, CD3G, INPP5D, LCK, MALT1
Nonhomologous End-Joining (NHEJ)	3	16.2×	0.009	DCLRE1C, NHEJ1, LIG4
Inositol phosphate metabolism	2	30.7×	0.020	INPP5D, ITPKB
Role of phospholipids in phagocytosis	2	29.5×	0.021	CD3G, CD247
Defective ADA disrupts (deoxy)adenosine deamination	1	368.4×	0.023	ADA
Defective PNP disrupts phosphorolysis of (deoxy)guanosine and (deoxy)inosine	1	368.4×	0.023	PNP
Synthesis of IP3 and IP4 in the cytosol	2	27.3×	0.023	INPP5D, ITPKB
Interleukin receptor SHC signaling	2	26.3×	0.023	INPP5D, JAK3
Cargo recognition for clathrin-mediated endocytosis	3	10.1×	0.025	CD3D, CD3G, IL7R
Interleukin-3, Interleukin-5 and GM-CSF signaling	2	20.5×	0.033	INPP5D, JAK3
RHOH GTPase cycle	2	19.9×	0.033	ZAP70, LCK
Metabolism of nucleotides	2	19.4×	0.034	ADA, AK2
FCGR3A-mediated IL10 synthesis	2	18.9×	0.034	CD3G, CD247
Nucleotide salvage defects	1	184.2×	0.035	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 35 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
T cell receptor signaling pathway	11	47.7×	1e-13	ZAP70, CD3D, CD3E, CD3G, CD247, ADA, IKBKB, INPP5D (+3 more)
positive thymic T cell selection	6	240.7×	1e-11	ZAP70, CD3D, CD3E, CD3G, ITPKB, PTPRC
alpha-beta T cell activation	4	385.2×	1e-08	CD3D, CD3E, CD3G, CD247
adaptive immune response	9	21.7×	2e-08	ZAP70, CAMK4, CD3D, CD3E, CD3G, CD247, DCLRE1C, JAK3 (+1 more)
V(D)J recombination	4	240.7×	1e-07	DCLRE1C, LIG4, RAG1, RAG2
positive regulation of alpha-beta T cell differentiation	4	192.6×	2e-07	ZAP70, ADA, ITPKB, PNP
T cell activation	6	44.4×	3e-07	ZAP70, CD3E, CD3G, ADA, LCK, PTPRC
T cell homeostasis	5	65.1×	6e-07	FOXN1, CORO1A, IL7R, JAK3, RAG1
B cell differentiation	6	37.5×	6e-07	DCLRE1C, NHEJ1, JAK3, PTPRC, RAG1, RAG2
T cell differentiation in thymus	5	58.7×	9e-07	ADA, IL7R, LIG4, RAG1, RAG2
DN2 thymocyte differentiation	3	361.1×	1e-06	LIG4, PTPRC, RAG2
gamma-delta T cell activation	3	180.6×	2e-05	CD3E, CD3G, CD247
negative regulation of thymocyte apoptotic process	3	144.4×	3e-05	ADA, JAK3, RAG1
positive regulation of interleukin-2 production	4	53.5×	3e-05	CD3E, MALT1, PNP, PTPRC
cell surface receptor signaling pathway	7	12.8×	3e-05	CD3D, CD3E, CD3G, CD247, IL7R, ITPKB, PTPRC
positive regulation of calcium-mediated signaling	4	48.1×	4e-05	ZAP70, CD3E, ADA, PTPRC
negative thymic T cell selection	3	120.4×	5e-05	ZAP70, CD3E, PTPRC
T cell differentiation	4	43.8×	5e-05	ZAP70, NHEJ1, LCK, PTPRC
purine-containing compound salvage	2	481.5×	1e-04	ADA, PNP
hemopoiesis	4	30.6×	2e-04	TTC7A, IL7R, LCK, PGM3
positive regulation of T cell proliferation	4	29.6×	2e-04	CD3E, CORO1A, PNP, PTPRC
pre-B cell allelic exclusion	2	321.0×	2e-04	RAG1, RAG2
deoxyadenosine catabolic process	2	321.0×	2e-04	ADA, PNP
dAMP catabolic process	2	240.7×	5e-04	ADA, PNP
regulation of T cell receptor signaling pathway	2	240.7×	5e-04	MALT1, PTPRC
T cell lineage commitment	2	192.6×	7e-04	FOXN1, RAG2
B cell proliferation	3	41.3×	9e-04	ADA, IL7R, PTPRC
immunoglobulin V(D)J recombination	2	160.5×	1e-03	NHEJ1, LIG4
positive regulation of alpha-beta T cell proliferation	2	160.5×	1e-03	ZAP70, PTPRC
double-strand break repair via nonhomologous end joining	3	36.1×	0.001	DCLRE1C, NHEJ1, LIG4

Therapeutics

Drugs indicated for this disease

2 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
AUTOLOGOUS CD34+ ENRICHED CELL FRACTION THAT CONTAINS CD34+ CELLS TRANSDUCED WITH RETROVIRAL VECTOR THAT ENCODES FOR THE HUMAN ADA CDNA SEQUENCE	Approved (phase 4)
Elapegademase	Approved (phase 4)
Pegademase Bovine	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Alemtuzumab, Busulfan, Fludarabine Phosphate, Melphalan, Methotrexate, Mycophenolate Mofetil, Sirolimus, Tacrolimus Anhydrous.

Drug target analysis

Approved (phase 4): 10 · Phase ≥3: 10 · Phased (≥1): 13 · Undrugged: 23

Druggability breadth: 21 of 36 evidence-associated genes (58%) 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
STK4	AXITINIB
ZAP70	FEDRATINIB
KDM2B	DEFERIPRONE
CAMK4	RUXOLITINIB
ADA	PENTOSTATIN
IKBKB	FEDRATINIB
JAK3	MOMELOTINIB
LCK	LEVODOPA
MALT1	MEPAZINE
PNP	CLADRIBINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LCK	126	4
JAK3	91	4
STK4	38	4
IKBKB	16	4
ZAP70	14	4
CAMK4	14	4
PNP	9	4
MALT1	5	4
ADA	3	4
KDM2B	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AXITINIB	4	JAK3, LCK, STK4
NERATINIB	4	JAK3, LCK, STK4
BOSUTINIB	4	JAK3, LCK, STK4, ZAP70
NINTEDANIB	4	CAMK4, JAK3, LCK, STK4, ZAP70
SUNITINIB	4	CAMK4, JAK3, LCK, STK4
DASATINIB	4	JAK3, LCK, STK4
CRIZOTINIB	4	IKBKB, JAK3, LCK, STK4, ZAP70
MIDOSTAURIN	4	IKBKB, JAK3, LCK, STK4, ZAP70
FEDRATINIB	4	IKBKB, JAK3, LCK, ZAP70
CERITINIB	4	CAMK4, JAK3, LCK, ZAP70
QUIZARTINIB	4	LCK, ZAP70
DEFERIPRONE	4	KDM2B
RUXOLITINIB	4	CAMK4, IKBKB, JAK3
DABRAFENIB	4	CAMK4, LCK
GILTERITINIB	4	CAMK4
PENTOSTATIN	4	ADA
AFAMELANOTIDE	4	ADA
DIOSMIN	4	IKBKB
DEXAMETHASONE	4	IKBKB
MOMELOTINIB	4	JAK3
SORAFENIB	4	JAK3, LCK
RUXOLITINIB PHOSPHATE	4	JAK3
IBRUTINIB	4	JAK3, LCK
PALBOCICLIB	4	JAK3
ENTRECTINIB	4	JAK3, LCK
PACRITINIB	4	JAK3, LCK
TOFACITINIB CITRATE	4	JAK3, LCK
BARICITINIB	4	JAK3
DACOMITINIB ANHYDROUS	4	JAK3, LCK
TOFACITINIB	4	JAK3, LCK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 14.

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
LCK	1,393	Binding:1379, Functional:8, ADMET:5, Toxicity:1
IKBKB	855	Binding:839, Functional:11, ADMET:5
ZAP70	451	Binding:448, Functional:2, ADMET:1
STK4	362	Binding:362
CAMK4	342	Binding:342
PNP	156	Binding:139, Functional:16, ADMET:1
MALT1	130	Binding:128, Functional:2
PTPRC	111	Binding:110, ADMET:1
ADA	40	Binding:35, ADMET:5
MTHFD1	30	Binding:30
KDM2B	28	Binding:28
INPP5D	16	Binding:16
CORO1A	12	Binding:12
AK2	6	Binding:6
VDAC2	5	Binding:5
ITPKB	2	Binding:2
LIG4	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ITPKB	2.7.1.127	inositol-trisphosphate 3-kinase
STK4	2.7.11.1	non-specific serine/threonine protein kinase
ZAP70	2.7.10.2	non-specific protein-tyrosine kinase
CAMK4	2.7.11.17	Ca2+/calmodulin-dependent protein kinase
ADA	3.5.4.4	adenosine deaminase
AK2	2.7.4.3	adenylate kinase
IKBKB	2.7.11.10	IkappaB kinase
INPP5D	3.1.3.86	phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase
JAK3	2.7.10.2	non-specific protein-tyrosine kinase
LCK	2.7.10.2	non-specific protein-tyrosine kinase
LIG4	6.5.1.1	DNA ligase (ATP)
MTHFD1	1.5.1.5, 3.5.4.9, 6.3.3.2, 6.3.4.3	methylenetetrahydrofolate dehydrogenase (NADP+), methenyltetrahydrofolate cyclohydrolase, 5-formyltetrahydrofolate cyclo-ligase, formate-tetrahydrofolate ligase
PNP	2.4.2.1	purine-nucleoside phosphorylase
PGM3	5.4.2.3	phosphoacetylglucosamine mutase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
STK4	362
ZAP70	451
CAMK4	342
IKBKB	855
JAK3	1,461
LCK	1,393
MALT1	130
PNP	156
PTPRC	111

Pharmacogenomics

Cohort genes with a PharmGKB record: 35; 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)
AXITINIB	4	JAK3, LCK, STK4
NERATINIB	4	JAK3, LCK, STK4
BOSUTINIB	4	JAK3, LCK, STK4, ZAP70
NINTEDANIB	4	CAMK4, JAK3, LCK, STK4, ZAP70
SUNITINIB	4	CAMK4, JAK3, LCK, STK4
DASATINIB	4	JAK3, LCK, STK4
CRIZOTINIB	4	IKBKB, JAK3, LCK, STK4, ZAP70
MIDOSTAURIN	4	IKBKB, JAK3, LCK, STK4, ZAP70
FEDRATINIB	4	IKBKB, JAK3, LCK, ZAP70
CERITINIB	4	CAMK4, JAK3, LCK, ZAP70
QUIZARTINIB	4	LCK, ZAP70
DEFERIPRONE	4	KDM2B
RUXOLITINIB	4	CAMK4, IKBKB, JAK3
DABRAFENIB	4	CAMK4, LCK
GILTERITINIB	4	CAMK4
PENTOSTATIN	4	ADA
AFAMELANOTIDE	4	ADA
DIOSMIN	4	IKBKB
DEXAMETHASONE	4	IKBKB
MOMELOTINIB	4	JAK3
SORAFENIB	4	JAK3, LCK
RUXOLITINIB PHOSPHATE	4	JAK3
IBRUTINIB	4	JAK3, LCK
PALBOCICLIB	4	JAK3
ENTRECTINIB	4	JAK3, LCK
PACRITINIB	4	JAK3, LCK
TOFACITINIB CITRATE	4	JAK3, LCK
BARICITINIB	4	JAK3
DACOMITINIB ANHYDROUS	4	JAK3, LCK
TOFACITINIB	4	JAK3, LCK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	10	STK4, ZAP70, KDM2B, CAMK4, ADA, IKBKB, JAK3, LCK, MALT1, PNP
B	Phased (≥1) drug, not yet approved	3	AK2, INPP5D, MTHFD1
C	Druggable family + PDB, no drug	6	CD3D, CD3E, CD3G, IL7R, LIG4, PTPRC
D	Druggable family + AlphaFold only, no drug	2	ITPKB, PGM3
E	Difficult family or no structure, no drug	15	NUDCD3, VDAC2, FOXN1, CD247, DCLRE1C, MCFD2, DOCK8, TTC7A, DOP1A, CORO1A (+5 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PTPRC	111	LCK
CD3D	0	LCK
CD3E	0	LCK
CD247	0	ZAP70
NUDCD3	0	—
ITPKB	2	—
VDAC2	5	—
FOXN1	0	—
CD3G	0	—
DCLRE1C	0	—
MCFD2	0	—
DOCK8	0	—
TTC7A	0	—
DOP1A	0	—
CORO1A	12	—
NHEJ1	0	—
DOCK8-AS1	0	—
IL7R	0	—
LIG4	2	—
PGM3	0	—
PPY	0	—
RAG1	0	—
RAG2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 44.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	20
PHASE1/PHASE2	9
PHASE2	7
PHASE1	4
PHASE3	3
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT01019876	PHASE2/PHASE3	COMPLETED	Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Non-Malignant Diseases
NCT01420627	PHASE3	COMPLETED	EZN-2279 in Patients With ADA-SCID
NCT06940570	PHASE3	SUSPENDED	Methadone as an Alternative Treatment for Children Underdoing HSCT
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT01852370	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases
NCT03538899	PHASE1/PHASE2	RECRUITING	Autologous Gene Therapy for Artemis-Deficient SCID
NCT03597594	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Haplocompatible Transplant Using TCRα/β Depletion Followed by CD45RA-Depleted Donor Lymphocyte Infusions for Severe Combined Immunodeficiency (SCID)
NCT03619551	PHASE2	ACTIVE_NOT_RECRUITING	Conditioning SCID Infants Diagnosed Early
NCT00000603	PHASE2	COMPLETED	Cord Blood Stem Cell Transplantation Study (COBLT)
NCT00228852	PHASE1/PHASE2	COMPLETED	IMM 0212: Busulfan With Fludarabine and Antithymocyte Globulin as Preparative Therapy for Hematopoietic Stem Cell Transplant for the Treatment of Severe Congenital T-Cell Immunodeficiency
NCT00579137	PHASE1/PHASE2	TERMINATED	Allogeneic SCT Of Pts With SCID And Other Primary Immunodeficiency Disorders
NCT00794508	PHASE2	COMPLETED	MND-ADA Transduction of CD34+ Cells From Children With ADA-SCID
NCT01129544	PHASE1/PHASE2	COMPLETED	Gene Transfer for Severe Combined Immunodeficiency, X-linked (SCID-X1) Using a Self-inactivating (SIN) Gammaretroviral Vector
NCT01182675	PHASE2	TERMINATED	Hematopoietic Stem Cell Transplantation (HSCT) for Children With SCID Utilizing Alemtuzumab, Plerixafor & Filgrastim
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
NCT02127892	PHASE1/PHASE2	TERMINATED	SCID Bu/Flu/ATG Study With T Cell Depletion
NCT02177760	PHASE2	WITHDRAWN	Sirolimus Prophylaxis for aGVHD in TME SCID
NCT02963064	PHASE1/PHASE2	TERMINATED	JSP191 Antibody Targeting Conditioning in SCID Patients
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT00008450	PHASE1	COMPLETED	Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Severe Combined Immunodeficiency Undergoing Donor Bone Marrow Transplant
NCT00028236	PHASE1	COMPLETED	Stem Cell Gene Therapy to Treat X-Linked Severe Combined Immunodeficiency (XSCID)
NCT00152100	PHASE1	COMPLETED	Transplantation of Hematopoietic Cells in Children With Severe Combined Immunodeficiency Syndrome
NCT02860559	PHASE1	UNKNOWN	Safety and Early Efficacy Study of TBX-1400 in Patients With Severe Combined Immunodeficiency
NCT00055172	Not specified	RECRUITING	Genetic Basis of Immunodeficiency
NCT01186913	Not specified	ENROLLING_BY_INVITATION	Natural History Study of SCID Disorders
NCT01652092	Not specified	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies
NCT04049084	Not specified	ENROLLING_BY_INVITATION	An Observational LTFU Study for Patients Previously Treated With Autologous ex Vivo Gene Therapy for ADA-SCID
NCT05651113	Not specified	RECRUITING	The Experience of Screening for SCID
NCT06659588	Not specified	RECRUITING	Study of Populations at Risk of Developing Chronic Hepatitis Linked to Chronic Enteric Virus Infection in Patients With Primary Immunodeficiency and Secondary Humoral Deficiency
NCT06731036	Not specified	AVAILABLE	Expanded Access to CD34+ Selection Utilizing Miltenyi CliniMACS Prodigy® for Patients Receiving Peripheral Blood Stem Cell Transplantations and Stem Cell Boosts
NCT00001255	Not specified	COMPLETED	Gene Transfer Therapy for Severe Combined Immunodeficieny Disease (SCID) Due to Adenosine Deaminase (ADA) Deficiency: A Natural History Study
NCT00006054	Not specified	TERMINATED	Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies
NCT00006335	Not specified	COMPLETED	Influences on Female Adolescents’ Decisions Regarding Testing for Carrier Status of XSCID
NCT00695279	Not specified	COMPLETED	Long Term Follow Up Of Patients Who Have Received Gene Therapy Or Gene Marked Products
NCT00845416	Not specified	COMPLETED	Newborn Screening for Severe Combined Immunodeficiency (SCID) in a High-Risk Population
NCT01346150	Not specified	UNKNOWN	Patients Treated for SCID (1968-Present)
NCT01953016	Not specified	COMPLETED	Participation in a Research Registry for Immune Disorders
NCT02231983	Not specified	UNKNOWN	Clinical Characteristics and Genetic Profiles of Severe Combined Immunodeficiency in China
NCT02590328	Not specified	COMPLETED	Neonatal Screening of Severe Combined Immunodeficiencies

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ALEMTUZUMAB	4	1
BUSULFAN	4	1
DEXTROSE	4	1
ELAPEGADEMASE	4	1
FLUDARABINE PHOSPHATE	4	1
PEGADEMASE BOVINE	4	1
FLUDARABINE	3	1
ANTILYMPHOCYTE IMMUNOGLOBULIN (HORSE)	2	1
CHEMBL423707	0	1
CHEMBL290077	0	1