severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive

Summary

severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (MONDO:0011086) is a disease caused by variants in RAG1 and RAG2, with 7 cohort genes. The dominant Reactome pathway is Interleukin-7 signaling (3 cohort genes).

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal genes: RAG1 (GenCC Strong), RAG2 (GenCC Strong)
• Cohort genes: 7
• ClinVar variants: 1,328
• Phenotypes (HPO): 29

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1	Europe	Validated

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0002720	Decreased circulating IgA level	Very frequent (80-99%)
HP:0002850	Decreased circulating total IgM	Very frequent (80-99%)
HP:0004313	Decreased circulating antibody level	Very frequent (80-99%)
HP:0004315	Decreased circulating IgG level	Very frequent (80-99%)
HP:0010975	Abnormal B cell count	Very frequent (80-99%)
HP:0011839	Abnormal T cell count	Very frequent (80-99%)
HP:0004429	Recurrent viral infections	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001888	Lymphopenia	Frequent (30-79%)
HP:0001945	Fever	Frequent (30-79%)
HP:0002718	Recurrent bacterial infections	Frequent (30-79%)
HP:0002743	Recurrent enteroviral infections	Frequent (30-79%)
HP:0002841	Recurrent fungal infections	Frequent (30-79%)
HP:0004385	Protracted diarrhea	Frequent (30-79%)
HP:0031381	Decreased lymphocyte proliferation in response to mitogen	Frequent (30-79%)
HP:0031402	Reduced antigen-specific T cell proliferation	Frequent (30-79%)
HP:0045080	Decreased proportion of CD3-positive T cells	Frequent (30-79%)
HP:0200117	Recurrent upper and lower respiratory tract infections	Frequent (30-79%)
HP:0000980	Pallor	Occasional (5-29%)
HP:0000988	Skin rash	Occasional (5-29%)
HP:0001433	Hepatosplenomegaly	Occasional (5-29%)
HP:0001873	Thrombocytopenia	Occasional (5-29%)
HP:0001880	Eosinophilia	Occasional (5-29%)
HP:0001890	Autoimmune hemolytic anemia	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002840	Lymphadenitis	Occasional (5-29%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Occasional (5-29%)
HP:0002960	Autoimmunity	Occasional (5-29%)
HP:0040089	Abnormal natural killer cell count	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive
Mondo ID	MONDO:0011086
MeSH	C563311
OMIM	601457
Orphanet	331206
DOID	DOID:0090013
UMLS	C1832322
MedGen	321935
GARD	0010339
Is cancer (heuristic)	no

Also known as: SCID due to complete RAG1/2 deficiency · SCID, AR, T-cell negative, B-cell negative, NK cell-positive · severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive · severe combined immunodeficiency, B cell-negative · severe immunodeficiency, autosomal recessive, T-cell negative, B-cell negative, NK cell-positive

Data availability: 1,328 ClinVar variants · 5 GenCC gene-disease records.

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-positive

Related subtypes (15): severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency, short-limb skeletal dysplasia with severe combined immunodeficiency, combined immunodeficiency with skin granulomas, reticular dysgenesis, 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:

236 uncertain significance, 222 likely benign, 56 pathogenic, 34 pathogenic/likely pathogenic, 26 likely pathogenic, 15 conflicting classifications of pathogenicity, 11 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1959	NM_000022.4(ADA):c.986C>T (p.Ala329Val)	ADA	Pathogenic	reviewed by expert panel
1034220	NM_000448.3(RAG1):c.2487_2488delinsTT (p.Arg829_Lys830delinsSerTer)	RAG1	Pathogenic	reviewed by expert panel
1072413	NM_000448.3(RAG1):c.1211G>A (p.Arg404Gln)	RAG1	Pathogenic	reviewed by expert panel
1072942	NM_000448.3(RAG1):c.2615T>G (p.Leu872Ter)	RAG1	Pathogenic	criteria provided, single submitter
1075542	NM_000448.3(RAG1):c.2867T>C (p.Ile956Thr)	RAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1076023	NM_000448.3(RAG1):c.1798del (p.Glu600fs)	RAG1	Pathogenic	criteria provided, single submitter
1120224	NM_000448.3(RAG1):c.1460T>G (p.Met487Arg)	RAG1	Pathogenic	criteria provided, single submitter
1175181	NM_000448.3(RAG1):c.1528G>T (p.Glu510Ter)	RAG1	Pathogenic	criteria provided, single submitter
13139	NM_000448.3(RAG1):c.2164G>A (p.Glu722Lys)	RAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
13140	NM_000448.3(RAG1):c.2320G>T (p.Glu774Ter)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13143	NM_000448.3(RAG1):c.1682G>A (p.Arg561His)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13144	NM_000448.3(RAG1):c.1186C>T (p.Arg396Cys)	RAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
13146	NM_000448.3(RAG1):c.1187G>A (p.Arg396His)	RAG1	Pathogenic	reviewed by expert panel
13148	NM_000448.3(RAG1):c.1681C>T (p.Arg561Cys)	RAG1	Pathogenic	reviewed by expert panel
13149	NM_000448.3(RAG1):c.2210G>A (p.Arg737His)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13150	NM_000448.3(RAG1):c.1612_1624del (p.Ile538fs)	RAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
13154	NM_000448.3(RAG1):c.2521C>T (p.Arg841Trp)	RAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
13156	NM_000448.3(RAG1):c.940C>T (p.Arg314Trp)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13158	NM_000448.3(RAG1):c.2333G>A (p.Arg778Gln)	RAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
13159	NM_000448.3(RAG1):c.2923C>T (p.Arg975Trp)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13160	NM_000448.3(RAG1):c.983G>A (p.Cys328Tyr)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13161	NM_000448.3(RAG1):c.2326C>T (p.Arg776Trp)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323517	NM_000448.3(RAG1):c.2850del (p.Ile950fs)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1353693	NM_000448.3(RAG1):c.2736_2737del (p.Tyr912_Ser913delinsTer)	RAG1	Pathogenic	criteria provided, single submitter
1458103	NM_000448.3(RAG1):c.2475del (p.Glu827fs)	RAG1	Pathogenic	criteria provided, single submitter
1505484	NM_000448.3(RAG1):c.2882_2891del (p.Ser961fs)	RAG1	Pathogenic	criteria provided, single submitter
1704499	NM_000448.3(RAG1):c.2327G>A (p.Arg776Gln)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191270	NM_000448.3(RAG1):c.555del (p.Lys186fs)	RAG1	Pathogenic	criteria provided, single submitter
1997718	NM_000448.3(RAG1):c.539G>A (p.Trp180Ter)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2022529	NM_000448.3(RAG1):c.2065G>T (p.Glu689Ter)	RAG1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 16 · 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
RAG1	Definitive	Autosomal recessive	immunodeficiency disease	11
RAG2	Strong	Autosomal recessive	severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
SALL4	Orphanet:2307	IVIC syndrome
SALL4	Orphanet:233	Duane retraction syndrome
SALL4	Orphanet:261638	Okihiro syndrome due to 20q13 microdeletion
SALL4	Orphanet:261647	Okihiro syndrome due to a point mutation
SALL4	Orphanet:959	Acro-renal-ocular syndrome
ADA	Orphanet:277	Severe combined immunodeficiency due to adenosine deaminase deficiency
ADA	Orphanet:39041	Omenn syndrome
TXNDC15	Orphanet:564	Meckel syndrome
JAK3	Orphanet:35078	T-B+ severe combined immunodeficiency due to JAK3 deficiency

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RAG1	HGNC:9831	ENSG00000166349	P15918	V(D)J recombination-activating protein 1	gencc,clinvar
RAG2	HGNC:9832	ENSG00000175097	P55895	V(D)J recombination-activating protein 2	gencc,clinvar
SALL4	HGNC:15924	ENSG00000101115	Q9UJQ4	Sal-like protein 4	clinvar
ADA	HGNC:186	ENSG00000196839	P00813	Adenosine deaminase	clinvar
TXNDC15	HGNC:20652	ENSG00000113621	Q96J42	Thioredoxin domain-containing protein 15	clinvar
IFTAP	HGNC:25142	ENSG00000166352	Q86VG3	Intraflagellar transport-associated protein	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)
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.
SALL4	Sal-like protein 4	Transcription factor with a key role in the maintenance and self-renewal of embryonic and hematopoietic stem cells.
ADA	Adenosine deaminase	Catalyzes the hydrolytic deamination of adenosine and 2-deoxyadenosine.
TXNDC15	Thioredoxin domain-containing protein 15	Acts as a positive regulator of ciliary hedgehog signaling.
IFTAP	Intraflagellar transport-associated protein	Seems to play a role in ciliary BBSome localization, maybe through interaction with IFT-A complex.
JAK3	Tyrosine-protein kinase JAK3	Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation.

Protein-family classification

Druggable: 2 · Difficult: 3 · Unknown: 2 · Druggable fraction: 0.29

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
Transcription factor	3	3.5×	0.171
Kinase	1	4.0×	0.454
Enzyme (other)	1	1.7×	0.609
Other/Unknown	2	0.5×	0.968

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
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
SALL4	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Sal_C2H2-zinc-finger
ADA	Enzyme (other)	yes	3.5.4.4	A_deaminase_dom, Ado/ade_deaminase, A/AMP_deam_AS
TXNDC15	Other/Unknown	no		Thioredoxin_domain, Thioredoxin-like_sf, TXNDC15
IFTAP	Other/Unknown	no		IFTAP
JAK3	Kinase	yes	2.7.10.2	FERM_domain, Prot_kinase_dom, SH2

Expression context

Cohort genes with no expression data: 0.

7 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
thymus	3
male germ line stem cell (sensu Vertebrata) in testis	2
buccal mucosa cell	1
bone marrow	1
left lobe of thyroid gland	1
oocyte	1
secondary oocyte	1
duodenum	1
jejunal mucosa	1
calcaneal tendon	1
colonic epithelium	1
stromal cell of endometrium	1
bronchial epithelial cell	1
left ventricle myocardium	1
myocardium	1
blood	1
granulocyte	1
spleen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAG1	164	broad	marker	thymus, buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis
RAG2	119	tissue_specific	marker	thymus, bone marrow, left lobe of thyroid gland
SALL4	150	broad	marker	secondary oocyte, oocyte, male germ line stem cell (sensu Vertebrata) in testis
ADA	202	ubiquitous	marker	jejunal mucosa, duodenum, thymus
TXNDC15	278	ubiquitous	marker	calcaneal tendon, stromal cell of endometrium, colonic epithelium
IFTAP	247	ubiquitous	marker	left ventricle myocardium, bronchial epithelial cell, myocardium
JAK3	219	ubiquitous	marker	granulocyte, blood, spleen

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
JAK3	3,630
RAG1	3,549
ADA	3,187
RAG2	2,319
SALL4	2,243
TXNDC15	747
IFTAP	479

Intra-cohort edges

A	B	Sources
RAG1	RAG2	biogrid_interaction, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
JAK3	P52333	42
SALL4	Q9UJQ4	13
ADA	P00813	2
RAG2	P55895	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RAG1	P15918	81.68
IFTAP	Q86VG3	66.65
TXNDC15	Q96J42	64.90

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 42. Enrichment computed across 7 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interleukin-7 signaling	3	190.3×	1e-05	RAG1, RAG2, JAK3
Defective ADA disrupts (deoxy)adenosine deamination	1	2284.0×	0.007	ADA
Nucleotide salvage defects	1	1142.0×	0.007	ADA
Diseases of nucleotide metabolism	1	1142.0×	0.007	ADA
MAPK6/MAPK4 signaling	2	54.4×	0.007	RAG1, RAG2
Interleukin-9 signaling	1	253.8×	0.020	JAK3
Nucleotide salvage	1	228.4×	0.020	ADA
Interleukin-21 signaling	1	228.4×	0.020	JAK3
Ribavirin ADME	1	207.6×	0.020	ADA
Interleukin-2 signaling	1	190.3×	0.020	JAK3
POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation	1	175.7×	0.020	SALL4
Purine salvage	1	175.7×	0.020	ADA
Interleukin-15 signaling	1	152.3×	0.021	JAK3
Interleukin-2 family signaling	1	126.9×	0.024	JAK3
Signaling by ALK	1	114.2×	0.024	JAK3
Transcriptional regulation of pluripotent stem cells	1	108.8×	0.024	SALL4
Interleukin-20 family signaling	1	84.6×	0.028	JAK3
Interleukin receptor SHC signaling	1	81.6×	0.028	JAK3
Interleukin-3, Interleukin-5 and GM-CSF signaling	1	63.4×	0.035	JAK3
Metabolism of nucleotides	1	60.1×	0.035	ADA
PTEN Regulation	1	45.7×	0.041	SALL4
Drug ADME	1	45.7×	0.041	ADA
Regulation of PTEN gene transcription	1	35.7×	0.051	SALL4
MAPK1/MAPK3 signaling	1	26.2×	0.066	JAK3
Potential therapeutics for SARS	1	22.8×	0.072	JAK3
MAPK family signaling cascades	1	20.6×	0.074	JAK3
Interleukin-4 and Interleukin-13 signaling	1	20.6×	0.074	JAK3
Disease	2	5.2×	0.075	ADA, JAK3
Intracellular signaling by second messengers	1	18.3×	0.078	SALL4
Diseases of metabolism	1	16.1×	0.085	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 7 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 thymocyte apoptotic process	3	722.2×	6e-07	RAG1, ADA, JAK3
pre-B cell allelic exclusion	2	1605.0×	2e-05	RAG1, RAG2
T cell differentiation in thymus	3	176.2×	2e-05	RAG1, RAG2, ADA
B cell differentiation	3	93.8×	9e-05	RAG1, RAG2, JAK3
V(D)J recombination	2	601.9×	1e-04	RAG1, RAG2
T cell homeostasis	2	130.1×	0.002	RAG1, JAK3
negative regulation of dendritic cell cytokine production	1	2407.4×	0.004	JAK3
mature B cell apoptotic process	1	2407.4×	0.004	ADA
purine nucleotide salvage	1	2407.4×	0.004	ADA
xanthine biosynthetic process	1	2407.4×	0.004	ADA
negative regulation of adenosine receptor signaling pathway	1	2407.4×	0.004	ADA
negative regulation of penile erection	1	2407.4×	0.004	ADA
B cell homeostatic proliferation	1	1203.7×	0.005	RAG2
positive regulation of germinal center formation	1	1203.7×	0.005	ADA
penile erection	1	1203.7×	0.005	ADA
purine-containing compound salvage	1	1203.7×	0.005	ADA
hypoxanthine salvage	1	1203.7×	0.005	ADA
dATP catabolic process	1	1203.7×	0.005	ADA
negative regulation of mucus secretion	1	1203.7×	0.005	ADA
response to interleukin-15	1	1203.7×	0.005	JAK3
response to interleukin-9	1	1203.7×	0.005	JAK3
deoxyadenosine catabolic process	1	802.5×	0.006	ADA
regulation of cell-cell adhesion mediated by integrin	1	802.5×	0.006	ADA
inosine biosynthetic process	1	802.5×	0.006	ADA
response to interleukin-2	1	802.5×	0.006	JAK3
mature B cell differentiation involved in immune response	1	601.9×	0.006	RAG2
negative regulation of mature B cell apoptotic process	1	601.9×	0.006	ADA
adenosine catabolic process	1	601.9×	0.006	ADA
negative regulation of glycoprotein biosynthetic process	1	601.9×	0.006	JAK3
negative regulation of T-helper 1 cell differentiation	1	601.9×	0.006	JAK3

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 5

Druggability breadth: 3 of 7 evidence-associated genes (43%) 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
RAG1	0	0
RAG2	0	0
SALL4	0	0
TXNDC15	0	0
IFTAP	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): 2.

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
SALL4	12	Binding:12

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADA	3.5.4.4	adenosine deaminase
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: 7; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	RAG1, RAG2, SALL4, TXNDC15, IFTAP

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RAG1	0	—
RAG2	0	—
SALL4	12	—
TXNDC15	0	—
IFTAP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.