T-B+ severe combined immunodeficiency due to JAK3 deficiency

Summary

T-B+ severe combined immunodeficiency due to JAK3 deficiency (MONDO:0010938) is a disease caused by JAK3 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: JAK3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 1,226
• Phenotypes (HPO): 25

Clinical features

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0003347	Impaired lymphocyte transformation with phytohemagglutinin	Very frequent (80-99%)
HP:0005354	Lack of T cell function	Very frequent (80-99%)
HP:0005403	Decreased total T cell count	Very frequent (80-99%)
HP:0031381	Decreased lymphocyte proliferation in response to mitogen	Very frequent (80-99%)
HP:0001888	Lymphopenia	Frequent (30-79%)
HP:0002028	Chronic diarrhea	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0005390	Recurrent opportunistic infections	Frequent (30-79%)
HP:0009098	Chronic oral candidiasis	Frequent (30-79%)
HP:0040219	Absent natural killer cells	Frequent (30-79%)
HP:0000371	Acute otitis media	Occasional (5-29%)
HP:0001531	Failure to thrive in infancy	Occasional (5-29%)
HP:0002850	Decreased circulating total IgM	Occasional (5-29%)
HP:0004315	Decreased circulating IgG level	Occasional (5-29%)
HP:0004429	Recurrent viral infections	Occasional (5-29%)
HP:0004798	Recurrent infection of the gastrointestinal tract	Occasional (5-29%)
HP:0006532	Recurrent pneumonia	Occasional (5-29%)
HP:0010976	Decreased total B cell count	Occasional (5-29%)
HP:0011837	Partial IgA deficiency	Occasional (5-29%)
HP:0200039	Pustule	Occasional (5-29%)
HP:0000143	Rectovaginal fistula	Very rare (<1-4%)
HP:0000953	Hyperpigmentation of the skin	Very rare (<1-4%)
HP:0000988	Skin rash	Very rare (<1-4%)
HP:0001433	Hepatosplenomegaly	Very rare (<1-4%)
HP:0001999	Abnormal facial shape	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	T-B+ severe combined immunodeficiency due to JAK3 deficiency
Mondo ID	MONDO:0010938
MeSH	C563440
OMIM	600802
Orphanet	35078
SNOMED CT	718107000
UMLS	C1833275
MedGen	331474
GARD	0016632
Is cancer (heuristic)	no

Also known as: SCID, autosomal recessive, T-negative/B-positive type · T-B+ SCID due to JAK3 deficiency · T-B+ severe combined immunodeficiency due to JAK3 deficiency · T-cell negative B-cell positive severe combined immunodeficiency due to JAK3 deficiency

Data availability: 1,226 ClinVar variants · 32 ClinGen variant curations · 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 › familial severe combined immunodeficiency › T-B+ severe combined immunodeficiency due to JAK3 deficiency

Related subtypes (13): severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency, MHC class II deficiency, reticular dysgenesis, T-B+ severe combined immunodeficiency due to gamma chain deficiency, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, severe combined immunodeficiency due to DCLRE1C deficiency, Omenn syndrome, immunodeficiency 104, Cernunnos-XLF deficiency, immunodeficiency 18, immunodeficiency 19, immunodeficiency 49, immunodeficiency 105

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:

335 likely benign, 170 uncertain significance, 41 pathogenic, 22 benign, 17 likely pathogenic, 7 pathogenic/likely pathogenic, 7 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1074842	NM_000215.4(JAK3):c.1142+1G>C	JAK3	Pathogenic	criteria provided, single submitter
1174743	NM_000215.4(JAK3):c.3208-1G>A	JAK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323133	NM_000215.4(JAK3):c.1254+2T>A	JAK3	Pathogenic	criteria provided, single submitter
1339536	NM_000215.4(JAK3):c.2324G>A (p.Arg775His)	JAK3	Pathogenic	criteria provided, multiple submitters, no conflicts
1390045	NC_000019.9:g.(?17940897)(17943758_?)del	JAK3	Pathogenic	criteria provided, single submitter
1404557	NM_000215.4(JAK3):c.1383dup (p.Leu462fs)	JAK3	Pathogenic	criteria provided, multiple submitters, no conflicts
1453819	NM_000215.4(JAK3):c.3032G>A (p.Trp1011Ter)	JAK3	Pathogenic	criteria provided, single submitter
1456683	NM_000215.4(JAK3):c.1178dup (p.Ser394fs)	JAK3	Pathogenic	criteria provided, multiple submitters, no conflicts
1459771	NM_000215.4(JAK3):c.2311C>T (p.Arg771Ter)	JAK3	Pathogenic	reviewed by expert panel
1508758	NM_000215.4(JAK3):c.1701+2T>A	JAK3	Pathogenic	criteria provided, single submitter
1705246	NM_000215.4(JAK3):c.3085dup (p.Ser1029fs)	JAK3	Pathogenic	criteria provided, multiple submitters, no conflicts
1878321	NM_000215.4(JAK3):c.2759_2760del (p.Arg920fs)	JAK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191101	NM_000215.4(JAK3):c.913C>T (p.Gln305Ter)	JAK3	Pathogenic	criteria provided, multiple submitters, no conflicts
191102	NM_000215.4(JAK3):c.308G>A (p.Arg103His)	JAK3	Pathogenic	criteria provided, multiple submitters, no conflicts
2131140	NM_000215.4(JAK3):c.1701+1G>A	JAK3	Pathogenic	criteria provided, single submitter
2152312	NM_000215.4(JAK3):c.2350G>A (p.Asp784Asn)	JAK3	Pathogenic	criteria provided, single submitter
2440936	NM_000215.4(JAK3):c.2743C>T (p.Gln915Ter)	JAK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2501779	NM_000215.4(JAK3):c.115dup (p.Gln39fs)	JAK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2577241	NM_000215.4(JAK3):c.2141C>T (p.Thr714Met)	JAK3	Pathogenic	criteria provided, multiple submitters, no conflicts
265205	NM_000215.4(JAK3):c.1765G>A (p.Gly589Ser)	JAK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2692977	NM_000215.4(JAK3):c.2319_2325dup (p.Asp776delinsHisSerTer)	JAK3	Pathogenic	criteria provided, single submitter
2696185	NM_000215.4(JAK3):c.3371_3372insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNTGCCCTGGGCCGCAGCGCAGCCGCGCAAACCACCACCCGCGGCCACCATGGCCGGACAGTATAATTTCCCCTGTCCTTTTC (p.Ser1124_Ter1125insPhePhePhePhePhePheXaaXaaXaaXaaAlaLeuGlyArgSerAlaAlaAlaGlnThrThrThrArgGlyHisHisGlyArgThrValTer)	JAK3	Pathogenic	criteria provided, single submitter
2701655	NM_000215.4(JAK3):c.548del (p.Glu183fs)	JAK3	Pathogenic	criteria provided, single submitter
2704615	NM_000215.4(JAK3):c.2272C>T (p.Gln758Ter)	JAK3	Pathogenic	criteria provided, single submitter
2707279	NM_000215.4(JAK3):c.904_908dup (p.Lys304fs)	JAK3	Pathogenic	criteria provided, single submitter
2736842	NM_000215.4(JAK3):c.3008TCT[1] (p.Phe1004del)	JAK3	Pathogenic	criteria provided, single submitter
2736843	NM_000215.4(JAK3):c.2787T>G (p.Tyr929Ter)	JAK3	Pathogenic	criteria provided, single submitter
2736844	NM_000215.4(JAK3):c.1951C>T (p.Arg651Trp)	JAK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2736845	NM_000215.4(JAK3):c.1786+3G>T	JAK3	Pathogenic	criteria provided, single submitter
2747421	NM_000215.4(JAK3):c.2350+1G>T	JAK3	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
JAK3	Definitive	Autosomal recessive	T-B+ severe combined immunodeficiency due to JAK3 deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
JAK3	Orphanet:35078	T-B+ severe combined immunodeficiency due to JAK3 deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
JAK3	HGNC:6193	ENSG00000105639	P52333	Tyrosine-protein kinase JAK3	gencc,clinvar
RPL18A	HGNC:10311	ENSG00000105640	Q02543	Large ribosomal subunit protein eL20	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
JAK3	Tyrosine-protein kinase JAK3	Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation.
RPL18A	Large ribosomal subunit protein eL20	Component of the large ribosomal subunit.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
JAK3	Kinase	yes	2.7.10.2	FERM_domain, Prot_kinase_dom, SH2
RPL18A	Other/Unknown	no		Ribosomal_eL20_euk, Ribosomal_eL20_dom, Ribosomal_eL20

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
granulocyte	1
spleen	1
skin of abdomen	1
skin of leg	1
zone of skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
JAK3	219	ubiquitous	marker	granulocyte, blood, spleen
RPL18A	158	ubiquitous	marker	skin of leg, zone of skin, skin of abdomen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RPL18A	4,105
JAK3	3,630

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RPL18A	Q02543	194
JAK3	P52333	42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 40. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interleukin-9 signaling	1	634.4×	0.023	JAK3
Interleukin-21 signaling	1	571.0×	0.023	JAK3
Interleukin-2 signaling	1	475.8×	0.023	JAK3
Interleukin-15 signaling	1	380.7×	0.023	JAK3
Interleukin-2 family signaling	1	317.2×	0.023	JAK3
Signaling by ALK	1	285.5×	0.023	JAK3
Interleukin-20 family signaling	1	211.5×	0.024	JAK3
Interleukin receptor SHC signaling	1	203.9×	0.024	JAK3
Interleukin-7 signaling	1	158.6×	0.025	JAK3
Interleukin-3, Interleukin-5 and GM-CSF signaling	1	158.6×	0.025	JAK3
MAPK1/MAPK3 signaling	1	65.6×	0.029	JAK3
Peptide chain elongation	1	63.4×	0.029	RPL18A
Viral mRNA Translation	1	63.4×	0.029	RPL18A
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	1	62.8×	0.029	RPL18A
Selenocysteine synthesis	1	60.1×	0.029	RPL18A
Eukaryotic Translation Termination	1	60.1×	0.029	RPL18A
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	1	58.9×	0.029	RPL18A
ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA	1	58.9×	0.029	RPL18A
Potential therapeutics for SARS	1	57.1×	0.029	JAK3
Formation of a pool of free 40S subunits	1	56.0×	0.029	RPL18A
Response of EIF2AK4 (GCN2) to amino acid deficiency	1	55.4×	0.029	RPL18A
Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide	1	53.4×	0.029	RPL18A
MAPK family signaling cascades	1	51.4×	0.029	JAK3
Interleukin-4 and Interleukin-13 signaling	1	51.4×	0.029	JAK3
L13a-mediated translational silencing of Ceruloplasmin expression	1	50.5×	0.029	RPL18A
SRP-dependent cotranslational protein targeting to membrane	1	50.1×	0.029	RPL18A
GTP hydrolysis and joining of the 60S ribosomal subunit	1	50.1×	0.029	RPL18A
Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)	1	48.8×	0.029	RPL18A
Regulation of expression of SLITs and ROBOs	1	34.6×	0.040	RPL18A
Signaling by Interleukins	1	32.1×	0.041	JAK3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 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 dendritic cell cytokine production	1	8426.0×	0.002	JAK3
response to interleukin-15	1	4213.0×	0.002	JAK3
response to interleukin-9	1	4213.0×	0.002	JAK3
response to interleukin-2	1	2808.7×	0.002	JAK3
negative regulation of glycoprotein biosynthetic process	1	2106.5×	0.002	JAK3
negative regulation of T-helper 1 cell differentiation	1	2106.5×	0.002	JAK3
response to interleukin-4	1	2106.5×	0.002	JAK3
tyrosine phosphorylation of STAT protein	1	1404.3×	0.002	JAK3
regulation of T cell apoptotic process	1	1404.3×	0.002	JAK3
interleukin-4-mediated signaling pathway	1	1203.7×	0.002	JAK3
negative regulation of T-helper 17 cell lineage commitment	1	1203.7×	0.002	JAK3
interleukin-2-mediated signaling pathway	1	1053.2×	0.002	JAK3
interleukin-7-mediated signaling pathway	1	1053.2×	0.002	JAK3
interleukin-9-mediated signaling pathway	1	1053.2×	0.002	JAK3
interleukin-15-mediated signaling pathway	1	842.6×	0.002	JAK3
negative regulation of thymocyte apoptotic process	1	842.6×	0.002	JAK3
growth hormone receptor signaling pathway via JAK-STAT	1	766.0×	0.003	JAK3
regulation of receptor signaling pathway via JAK-STAT	1	702.2×	0.003	JAK3
enzyme-linked receptor protein signaling pathway	1	648.1×	0.003	JAK3
negative regulation of interleukin-12 production	1	526.6×	0.003	JAK3
negative regulation of interleukin-10 production	1	366.4×	0.004	JAK3
negative regulation of T cell activation	1	263.3×	0.006	JAK3
T cell homeostasis	1	227.7×	0.006	JAK3
cell surface receptor signaling pathway via JAK-STAT	1	145.3×	0.009	JAK3
B cell differentiation	1	109.4×	0.012	JAK3
cytoplasmic translation	1	92.6×	0.014	RPL18A
cytokine-mediated signaling pathway	1	65.3×	0.019	JAK3
translation	1	51.4×	0.023	RPL18A
adaptive immune response	1	42.1×	0.026	JAK3
regulation of apoptotic process	1	41.7×	0.026	JAK3

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
JAK3	MOMELOTINIB
RPL18A	GENTAMICIN SULFATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
JAK3	91	4
RPL18A	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
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
SUNITINIB	4	JAK3
DASATINIB	4	JAK3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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
RPL18A	90	Binding:90

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
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: 2; 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)
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
SUNITINIB	4	JAK3
DASATINIB	4	JAK3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	JAK3, RPL18A
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.