Inborn error of immunity

Summary

Inborn error of immunity (MONDO:0003778) is a disease (an umbrella term covering 41 Mondo subtypes) caused by variants in STXBP3 and TRIM22, with 13 cohort genes and 48 clinical trials. Top therapeutic interventions include human immunoglobulin g, amphotericin b, and autologous cd34+ enriched cell fraction that contains cd34+ cells transduced with retroviral vector that encodes for the human ada cdna sequence.

At a glance

• Prevalence: 1-9 / 100 000 (Norway) [Orphanet-validated]
• Causal genes: STXBP3 (GenCC Strong), TRIM22 (GenCC Strong)
• Umbrella term: 41 Mondo subtypes
• Cohort genes: 13
• ClinVar variants: 41
• Clinical trials: 48

Clinical features

Epidemiology

Prevalence records

14 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	6.8	Norway	Validated
Point prevalence	1-5 / 10 000	11	France	Validated
Point prevalence	1-9 / 100 000	3.6	Spain	Validated
Point prevalence	1-9 / 100 000	2.6	Netherlands	Validated
Point prevalence	1-9 / 100 000	1.84	United Kingdom	Validated
Point prevalence	1-9 / 100 000	1.79	Italy	Validated
Point prevalence	1-9 / 100 000	1.38	Germany	Validated
Point prevalence	1-9 / 100 000	2	Turkey	Validated
Point prevalence	1-9 / 100 000	1.33	Poland	Validated
Point prevalence	1-9 / 100 000	4.9	New Zealand	Validated
Point prevalence	1-9 / 100 000	1.1	Korea, Republic of	Validated
Point prevalence	1-9 / 100 000	4.5	Oman	Validated
Point prevalence	1-9 / 100 000		Europe	Not yet validated
Point prevalence	1-9 / 100 000	5.6	Australia	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	inborn error of immunity
Mondo ID	MONDO:0003778
MeSH	D007153
Orphanet	101997
DOID	DOID:612
SNOMED CT	58606001
UMLS	C0398686
MedGen	585013
GARD	0019813
Is cancer (heuristic)	no

Also known as: antibody deficiency syndrome · antibody deficiency syndromes · deficiency syndrome, antibody · deficiency syndrome, immunologic · deficiency syndrome, immunological · deficiency syndromes, antibody · deficiency syndromes, immunologic · deficiency syndromes, immunological · IEI · immunologic deficiency syndrome · immunological deficiency syndrome · immunological deficiency syndromes · inborn errors of immunity · primary immunodeficiency disease · syndrome, antibody deficiency · syndrome, immunologic deficiency · syndrome, immunological deficiency · syndromes, antibody deficiency · syndromes, immunologic deficiency · syndromes, immunological deficiency

Data availability: 41 ClinVar variants · 10 GenCC gene-disease records · 6 cell lines.

Disease family

An umbrella term covering 41 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity

Related subtypes (46): hypersensitivity reaction disease, immune system cancer, immune system organ benign neoplasm, bone marrow disorder, thymus gland disorder, leukocyte disorder, psoriasis, spondyloarthropathy, aggressive insulitis, benign insulitis, inflammatory bowel disease, autoimmune disease, TNF receptor 1-associated periodic fever syndrome, epidermodysplasia verruciformis, Vici syndrome, proteosome-associated autoinflammatory syndrome, hyperimmunoglobulinemia D with periodic fever, transcobalamin II deficiency, pyogenic arthritis-pyoderma gangrenosum-acne syndrome, granulomatosis with polyangiitis, autosomal recessive osteopetrosis 7, graft versus host disease, congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome, Roifman syndrome, cryopyrin-associated periodic syndrome, anti-HLA hyperimmunization, acquired immunodeficiency, erythroderma desquamativum, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, familial Mediterranean fever, 22q11.2 deletion syndrome, T-cell large granular lymphocyte leukemia, twin to twin transfusion syndrome, immunodeficiency disease, immunoproliferative disorder, cytokine receptor deficiency, immunodeficiency-related disorder, phagocytic cell dysfunction, thrombocytopenic purpura, lymphoid system disorder, immune reconstitution inflammatory syndrome, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, cytokine release syndrome, early-onset autoimmunity-autoinflammation-immunodeficiency syndrome, CADINS disease, autoinflammation, panniculitis, and dermatosis syndrome

Subtypes (41): B cell deficiency, complement deficiency, phagocyte bactericidal dysfunction, trichohepatoenteric syndrome, hepatic veno-occlusive disease-immunodeficiency syndrome, immunodeficiency with defective T-cell response to interleukin 1, Say-Barber-Miller syndrome, familial isolated congenital asplenia, X-linked immunoneurologic disorder, ectodermal dysplasia and immune deficiency, immunodeficiency 33, immunodeficiency 47, combined immunodeficiency due to moesin deficiency, immunodeficiency, X-linked, with deficiency of 115,000 Dalton surface glycoprotein, properdin deficiency, X-linked, combined immunodeficiency with faciooculoskeletal anomalies, recurrent infections associated with rare immunoglobulin isotypes deficiency, immunodeficiency 28, autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity, immunodeficiency 37, immunodeficiency 39, BENTA disease, primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection, immunodeficiency 49, chronic mucocutaneous candidiasis, hereditary hemophagocytic lymphohistiocytosis, immunoglobulin heavy chain deficiency, immuno-osseous dysplasia, lymphoproliferative syndrome, IL10-related early-onset inflammatory bowel disease, T-cell immunodeficiency with epidermodysplasia verruciformis, Aicardi-Goutieres syndrome, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, inflammatory bowel disease-recurrent sinopulmonary infections syndrome, A20 haploinsufficiency, NK cell deficiency, T cell and NK cell immunodeficiency, dendritic cell deficiency, immunodysregulation with variable immunodeficiency and autoimmunity, immune dysregulation with immunodeficiency due to AIOLOS haploinsufficiency, STAT5 haploinsufficiency

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

41 retrieved; paginated sample, class counts are floors:

15 likely pathogenic, 7 conflicting classifications of pathogenicity, 7 pathogenic, 5 uncertain significance, 4 pathogenic/likely pathogenic, 2 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
13130	NM_000536.4(RAG2):c.686G>A (p.Arg229Gln)	RAG2	Pathogenic	reviewed by expert panel
13131	NM_000536.4(RAG2):c.123C>G (p.Cys41Trp)	RAG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13136	NM_000536.4(RAG2):c.115A>G (p.Arg39Gly)	RAG2	Pathogenic	reviewed by expert panel
13138	NM_000536.4(RAG2):c.1352G>C (p.Gly451Ala)	RAG2	Pathogenic	reviewed by expert panel
36716	NM_000536.4(RAG2):c.104G>C (p.Gly35Ala)	RAG2	Pathogenic	reviewed by expert panel
418453	NM_000536.4(RAG2):c.539C>A (p.Pro180His)	RAG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
496618	NM_000536.4(RAG2):c.104G>T (p.Gly35Val)	RAG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
496624	NM_000536.4(RAG2):c.685C>T (p.Arg229Trp)	RAG2	Pathogenic	reviewed by expert panel
598789	NM_001354930.2(RIPK1):c.1278C>A (p.Tyr426Ter)	RIPK1	Pathogenic	no assertion criteria provided
598790	NM_001354930.2(RIPK1):c.954del (p.Met318fs)	RIPK1	Pathogenic/Likely pathogenic	no assertion criteria provided
598791	NM_001354930.2(RIPK1):c.1802G>A (p.Cys601Tyr)	RIPK1	Pathogenic	no assertion criteria provided
13132	NM_000536.4(RAG2):c.854T>G (p.Met285Arg)	RAG2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
13137	NM_000536.4(RAG2):c.230C>A (p.Thr77Asn)	RAG2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
36717	NM_000536.4(RAG2):c.1247G>T (p.Trp416Leu)	RAG2	Likely pathogenic	reviewed by expert panel
36718	NM_000536.4(RAG2):c.1309G>A (p.Glu437Lys)	RAG2	Likely pathogenic	reviewed by expert panel
427020	NM_000536.4(RAG2):c.193G>T (p.Asp65Tyr)	RAG2	Likely pathogenic	reviewed by expert panel
496619	NM_000536.4(RAG2):c.186C>A (p.Phe62Leu)	RAG2	Likely pathogenic	criteria provided, single submitter
496622	NM_000536.4(RAG2):c.470G>T (p.Gly157Val)	RAG2	Likely pathogenic	criteria provided, single submitter
496623	NM_000536.4(RAG2):c.583T>G (p.Tyr195Asp)	RAG2	Likely pathogenic	criteria provided, single submitter
496626	NM_000536.4(RAG2):c.1320A>C (p.Lys440Asn)	RAG2	Likely pathogenic	criteria provided, single submitter
496627	NM_000536.4(RAG2):c.1329G>T (p.Met443Ile)	RAG2	Likely pathogenic	criteria provided, single submitter
496628	NM_000536.4(RAG2):c.1332C>G (p.Ile444Met)	RAG2	Likely pathogenic	reviewed by expert panel
496629	NM_000536.4(RAG2):c.1338C>G (p.Cys446Trp)	RAG2	Likely pathogenic	reviewed by expert panel
496630	NM_000536.4(RAG2):c.1357T>A (p.Trp453Arg)	RAG2	Likely pathogenic	reviewed by expert panel
496631	NM_000536.4(RAG2):c.1366G>A (p.Ala456Thr)	RAG2	Likely pathogenic	criteria provided, single submitter
496632	NM_000536.4(RAG2):c.1375A>C (p.Met459Leu)	RAG2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
13129	NM_000536.4(RAG2):c.1433G>A (p.Cys478Tyr)	RAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
418443	NM_000536.4(RAG2):c.479C>T (p.Ser160Leu)	RAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
440231	NM_000536.4(RAG2):c.1504A>G (p.Met502Val)	RAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
496620	NM_000536.4(RAG2):c.218G>A (p.Arg73His)	RAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 22 · Orphanet: 12 · 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
STXBP3	Strong	Autosomal recessive	inborn error of immunity
TRIM22	Strong	Autosomal recessive	inborn error of immunity	2
INO80	Moderate	Autosomal recessive	inborn error of immunity
NFAT5	Moderate	Autosomal dominant	inborn error of immunity
NFATC1	Moderate	Autosomal recessive	inborn error of immunity	2
TKFC	Moderate	Autosomal recessive	inborn error of immunity	4
LY96	Limited	Autosomal recessive	inborn error of immunity
RC3H1	Limited	Autosomal dominant	inborn error of immunity	3
TAOK2	Limited	Autosomal recessive	inborn error of immunity	4
TNFSF12	Limited	Autosomal dominant	inborn error of immunity	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STXBP3	Orphanet:714423	Infantile-onset inflammatory bowel disease-hearing loss-recurrent infections syndrome
TNFSF12	Orphanet:696931	Common variable immunodeficiency phenotype due to TWEAK deficiency
TRIM22	Orphanet:597201	TRIM22-related inflammatory bowel disease
TKFC	Orphanet:1369	Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome
INO80	Orphanet:157949	Combined immunodeficiency with granulomatosis
NFAT5	Orphanet:529980	Immune dysregulation-inflammatory bowel disease- recurrent sinopulmonary infections syndrome
RIPK1	Orphanet:529977	Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome
IRF2BP2	Orphanet:520	Acute promyelocytic leukemia
IRF2BP2	Orphanet:696904	Common variable immunodeficiency phenotype due to IRF2BP2 deficiency
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

13 cohort genes, 13 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	13

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
STXBP3	HGNC:11446	ENSG00000116266	O00186	Syntaxin-binding protein 3	gencc
TNFSF12	HGNC:11927	ENSG00000239697	O43508	Tumor necrosis factor ligand superfamily member 12	gencc
TRIM22	HGNC:16379	ENSG00000132274	Q8IYM9	E3 ubiquitin-protein ligase TRIM22	gencc
TAOK2	HGNC:16835	ENSG00000149930	Q9UL54	Serine/threonine-protein kinase TAO2	gencc
LY96	HGNC:17156	ENSG00000154589	Q9Y6Y9	Lymphocyte antigen 96	gencc
TKFC	HGNC:24552	ENSG00000149476	Q3LXA3	Triokinase/FMN cyclase	gencc
INO80	HGNC:26956	ENSG00000128908	Q9ULG1	Chromatin-remodeling ATPase INO80	gencc
RC3H1	HGNC:29434	ENSG00000135870	Q5TC82	Roquin-1	gencc
NFAT5	HGNC:7774	ENSG00000102908	O94916	Nuclear factor of activated T-cells 5	gencc
NFATC1	HGNC:7775	ENSG00000131196	O95644	Nuclear factor of activated T-cells, cytoplasmic 1	gencc
RIPK1	HGNC:10019	ENSG00000137275	Q13546	Receptor-interacting serine/threonine-protein kinase 1	clinvar
IRF2BP2	HGNC:21729	ENSG00000168264	Q7Z5L9	Interferon regulatory factor 2-binding protein 2	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)
STXBP3	Syntaxin-binding protein 3	Together with STX4 and VAMP2, may play a role in insulin-dependent movement of GLUT4 and in docking/fusion of intracellular GLUT4-containing vesicles with the cell surface in adipocytes.
TNFSF12	Tumor necrosis factor ligand superfamily member 12	Binds to FN14 and possibly also to TNRFSF12/APO3.
TRIM22	E3 ubiquitin-protein ligase TRIM22	Interferon-induced E3 ubiquitin ligase that plays important roles in innate and adaptive immunity.
TAOK2	Serine/threonine-protein kinase TAO2	Serine/threonine-protein kinase involved in different processes such as membrane blebbing and apoptotic bodies formation DNA damage response and MAPK14/p38 MAPK stress-activated MAPK cascade.
LY96	Lymphocyte antigen 96	Binds bacterial lipopolysaccharide (LPS).
TKFC	Triokinase/FMN cyclase	Catalyzes both the phosphorylation of dihydroxyacetone and of glyceraldehyde, and the splitting of ribonucleoside diphosphate-X compounds among which FAD is the best substrate.
INO80	Chromatin-remodeling ATPase INO80	ATPase component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and DNA repair.
RC3H1	Roquin-1	Post-transcriptional repressor of mRNAs containing a conserved stem loop motif, called constitutive decay element (CDE), which is often located in the 3’-UTR, as in HMGXB3, ICOS, IER3, NFKBID, NFKBIZ, PPP1R10, TNF, TNFRSF4 and in many more…
NFAT5	Nuclear factor of activated T-cells 5	Transcription factor involved, among others, in the transcriptional regulation of osmoprotective and inflammatory genes.
NFATC1	Nuclear factor of activated T-cells, cytoplasmic 1	Plays a role in the inducible expression of cytokine genes in T-cells, especially in the induction of the IL-2 or IL-4 gene transcription.
RIPK1	Receptor-interacting serine/threonine-protein kinase 1	Serine-threonine kinase which is a key regulator of TNF-mediated apoptosis, necroptosis and inflammatory pathways.
IRF2BP2	Interferon regulatory factor 2-binding protein 2	Acts as a transcriptional corepressor in a IRF2-dependent manner; this repression is not mediated by histone deacetylase activities.
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: 3 · Difficult: 6 · Unknown: 4 · Druggable fraction: 0.23

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	6	3.8×	0.008
Kinase	3	6.4×	0.015
Other/Unknown	4	0.6×	0.982

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STXBP3	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
TNFSF12	Other/Unknown	no		TNF_dom, Tumour_necrosis_fac-like_dom, TNF_Ligand_Superfamily
TRIM22	Transcription factor	no	2.3.2.27	Znf_B-box, Znf_RING, B30.2/SPRY
TAOK2	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
LY96	Other/Unknown	no		ML_dom, Ig_E-set, LY96
TKFC	Kinase	yes	2.7.1.28	DhaK_dom, DhaL_dom, DhaK_ATP
INO80	Other/Unknown	no		SNF2_N, Helicase_C-like, Helicase_ATP-bd
RC3H1	Transcription factor	no		Znf_CCCH, Znf_RING, Znf_RING/FYVE/PHD
NFAT5	Transcription factor	no		IPT_dom, NFAT, p53-like_TF_DNA-bd_sf
NFATC1	Transcription factor	no		IPT_dom, NFAT, p53-like_TF_DNA-bd_sf
RIPK1	Kinase	yes	2.7.10.2	Death_dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
IRF2BP2	Transcription factor	no		IRF-2BP1_2-like_Znf, I2BP1/2_C3HC4-RING_sf, Zf-C3HC4_IRF-2BP1_2
RAG2	Transcription factor	no		RAG2, Znf_FYVE_PHD, Gal_Oxase/kelch_b-propeller

Expression context

Cohort genes with no expression data: 0.

13 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)	13
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	2
monocyte	2
mononuclear cell	2
calcaneal tendon	1
corpus callosum	1
tibia	1
ascending aorta	1
right coronary artery	1
thoracic aorta	1
apex of heart	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
left adrenal gland cortex	1
right adrenal gland	1
right adrenal gland cortex	1
cardiac muscle of right atrium	1
left ventricle myocardium	1
pancreatic ductal cell	1
ileal mucosa	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STXBP3	289	ubiquitous	marker	corpus callosum, calcaneal tendon, tibia
TNFSF12	134	tissue_specific	marker	right coronary artery, thoracic aorta, ascending aorta
TRIM22	285	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
TAOK2	211	ubiquitous	marker	right hemisphere of cerebellum, apex of heart, cerebellar hemisphere
LY96	252	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
TKFC	213	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland cortex
INO80	253	ubiquitous	marker	cardiac muscle of right atrium, pancreatic ductal cell, left ventricle myocardium
RC3H1	260	ubiquitous	marker	tibialis anterior, upper leg skin, ileal mucosa
NFAT5	269	ubiquitous	marker	renal medulla, nipple, caput epididymis
NFATC1	252	ubiquitous	marker	oocyte, hindlimb stylopod muscle, secondary oocyte
RIPK1	238	ubiquitous	marker	granulocyte, sural nerve, right lobe of liver
IRF2BP2	256	ubiquitous	marker	mammary duct, epithelium of mammary gland, trachea
RAG2	119	tissue_specific	marker	thymus, bone marrow, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RIPK1	4,129
INO80	3,237
NFATC1	3,147
RC3H1	3,135
RAG2	2,319
NFAT5	2,071
LY96	2,007
STXBP3	1,642
TKFC	1,606
TRIM22	1,515

Structural data

PDB: 9 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RIPK1	Q13546	39
LY96	Q9Y6Y9	9
INO80	Q9ULG1	6
RC3H1	Q5TC82	6
NFATC1	O95644	3
IRF2BP2	Q7Z5L9	3
TNFSF12	O43508	1
NFAT5	O94916	1
RAG2	P55895	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TKFC	Q3LXA3	95.40
STXBP3	O00186	89.63
TRIM22	Q8IYM9	85.38
TAOK2	Q9UL54	67.17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 93. Enrichment computed across 13 evidence-associated genes (9 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 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TRIF-mediated programmed cell death	2	282.0×	0.002	RIPK1, LY96
Caspase activation via Death Receptors in the presence of ligand	2	169.2×	0.003	RIPK1, LY96
IKK complex recruitment mediated by RIP1	2	110.3×	0.004	RIPK1, LY96
SARS-CoV-1-mediated effects on programmed cell death	1	423.0×	0.049	RIPK1
Microbial modulation of RIPK1-mediated regulated necrosis	1	317.2×	0.049	RIPK1
Disinhibition of SNARE formation	1	253.8×	0.049	STXBP3
Fructose catabolism	1	253.8×	0.049	TKFC
TLR3-mediated TICAM1-dependent programmed cell death	1	211.5×	0.049	RIPK1
Defective RIPK1-mediated regulated necrosis	1	211.5×	0.049	RIPK1
Caspase activation via extrinsic apoptotic signalling pathway	1	158.6×	0.049	LY96
Calcineurin activates NFAT	1	141.0×	0.049	NFATC1
Regulation by c-FLIP	1	115.3×	0.049	RIPK1
CASP8 activity is inhibited	1	115.3×	0.049	RIPK1
CLEC7A (Dectin-1) induces NFAT activation	1	115.3×	0.049	NFATC1
Dimerization of procaspase-8	1	115.3×	0.049	RIPK1
Diseases of Immune System	1	97.6×	0.049	LY96
Diseases associated with the TLR signaling cascade	1	97.6×	0.049	LY96
NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10	1	97.6×	0.049	RIPK1
Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)	1	97.6×	0.049	NFATC1
IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation	1	84.6×	0.049	LY96
Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7	1	84.6×	0.049	LY96
TRAF6-mediated induction of TAK1 complex within TLR4 complex	1	79.3×	0.049	LY96
Dengue virus modulates apoptosis	1	79.3×	0.049	RIPK1
RIP-mediated NFkB activation via ZBP1	1	74.6×	0.049	RIPK1
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway	1	74.6×	0.049	TNFSF12
TICAM1, RIP1-mediated IKK complex recruitment	1	66.8×	0.049	RIPK1
MyD88 deficiency (TLR2/4)	1	66.8×	0.049	LY96
Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)	1	66.8×	0.049	LY96
IRAK4 deficiency (TLR2/4)	1	63.4×	0.050	LY96
Regulation of TLR by endogenous ligand	1	55.2×	0.054	LY96

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 13 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 T-helper cell differentiation	1	1296.3×	0.016	RC3H1
ripoptosome assembly	1	1296.3×	0.016	RIPK1
basal dendrite morphogenesis	1	1296.3×	0.016	TAOK2
regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	1	1296.3×	0.016	RC3H1
positive regulation of miRNA processing	1	1296.3×	0.016	RIPK1
calcineurin-NFAT signaling cascade	2	129.6×	0.016	NFAT5, NFATC1
positive regulation of extrinsic apoptotic signaling pathway	2	70.1×	0.016	RIPK1, TNFSF12
extrinsic apoptotic signaling pathway	2	47.1×	0.016	RIPK1, TNFSF12
positive regulation of canonical NF-kappaB signal transduction	3	16.8×	0.016	RIPK1, TRIM22, NFAT5
B cell homeostatic proliferation	1	648.1×	0.021	RAG2
negative regulation of germinal center formation	1	648.1×	0.021	RC3H1
pre-B cell allelic exclusion	1	432.1×	0.021	RAG2
obsolete fructose catabolic process to hydroxyacetone phosphate and glyceraldehyde-3-phosphate	1	432.1×	0.021	TKFC
positive regulation of interleukin-6-mediated signaling pathway	1	432.1×	0.021	RIPK1
basal dendrite arborization	1	432.1×	0.021	TAOK2
ripoptosome assembly involved in necroptotic process	1	432.1×	0.021	RIPK1
regulation of miRNA metabolic process	1	432.1×	0.021	RC3H1
mature B cell differentiation involved in immune response	1	324.1×	0.021	RAG2
negative regulation of MDA-5 signaling pathway	1	324.1×	0.021	TKFC
regulation of T cell receptor signaling pathway	1	324.1×	0.021	RC3H1
positive regulation of programmed necrotic cell death	1	324.1×	0.021	RIPK1
regulation of calcineurin-NFAT signaling cascade	1	324.1×	0.021	NFAT5
presynaptic dense core vesicle exocytosis	1	324.1×	0.021	STXBP3
DN2 thymocyte differentiation	1	324.1×	0.021	RAG2
B cell lineage commitment	1	259.3×	0.021	RAG2
T cell lineage commitment	1	259.3×	0.021	RAG2
protein to membrane docking	1	259.3×	0.021	STXBP3
detection of lipopolysaccharide	1	259.3×	0.021	LY96
peptidyl-serine autophosphorylation	1	259.3×	0.021	RIPK1
neutrophil degranulation	1	259.3×	0.021	STXBP3

Therapeutics

Drugs indicated or in trials for this disease

1 approved drug — disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Status
Human Immunoglobulin G	Approved (phase 4)

8 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Anise Oil	Phase 2
Busulfan	Phase 2
Fludarabine	Phase 2
Licorice	Phase 2
Mycophenolate Mofetil	Phase 2
OMEGA-3 FATTY ACIDS	Phase 2
Quinine	Phase 2
Sirolimus	Phase 2

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 3 · Undrugged: 10

Druggability breadth: 8 of 13 evidence-associated genes (62%) 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
TAOK2	FEDRATINIB
RIPK1	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TAOK2	29	4
RIPK1	24	4
INO80	1	2
STXBP3	0	0
TNFSF12	0	0
TRIM22	0	0
LY96	0	0
TKFC	0	0
RC3H1	0	0
NFAT5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	RIPK1, TAOK2
SORAFENIB	4	RIPK1, TAOK2
RUXOLITINIB	4	TAOK2
PALBOCICLIB	4	TAOK2
PACRITINIB	4	TAOK2
BOSUTINIB	4	TAOK2
GILTERITINIB	4	TAOK2
PAZOPANIB	4	RIPK1, TAOK2
DASATINIB	4	TAOK2
CRIZOTINIB	4	RIPK1, TAOK2
PONATINIB	4	RIPK1
AXITINIB	4	RIPK1
DABRAFENIB	4	RIPK1
NINTEDANIB	4	RIPK1
SUNITINIB	4	RIPK1
QUIZARTINIB	4	RIPK1
DINACICLIB	3	TAOK2
ALVOCIDIB	3	TAOK2
CEDIRANIB	3	TAOK2
LESTAURTINIB	3	TAOK2
RUBOXISTAURIN	3	TAOK2
LINIFANIB	3	RIPK1
DOVITINIB	3	RIPK1
FORETINIB	2	RIPK1, TAOK2
ZOTIRACICLIB	2	TAOK2
GOLVATINIB	2	TAOK2
RG-547	2	TAOK2
AT-7519	2	TAOK2
R-406	2	TAOK2
RAF-265	2	RIPK1, TAOK2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
RIPK1	400	Binding:391, ADMET:7, Functional:2
TAOK2	232	Binding:232
LY96	87	Binding:86, ADMET:1
NFATC1	15	Binding:15
INO80	7	Binding:7
TKFC	1	Binding:1
IRF2BP2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TRIM22	2.3.2.27	RING-type E3 ubiquitin transferase
TKFC	2.7.1.28, 2.7.1.29, 4.6.1.15	triokinase, glycerone kinase, FAD-AMP lyase (cyclizing)
RIPK1	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
TAOK2	232
RIPK1	400

Pharmacogenomics

Cohort genes with a PharmGKB record: 13; 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)
FEDRATINIB	4	RIPK1, TAOK2
SORAFENIB	4	RIPK1, TAOK2
RUXOLITINIB	4	TAOK2
PALBOCICLIB	4	TAOK2
PACRITINIB	4	TAOK2
BOSUTINIB	4	TAOK2
GILTERITINIB	4	TAOK2
PAZOPANIB	4	RIPK1, TAOK2
DASATINIB	4	TAOK2
CRIZOTINIB	4	RIPK1, TAOK2
PONATINIB	4	RIPK1
AXITINIB	4	RIPK1
DABRAFENIB	4	RIPK1
NINTEDANIB	4	RIPK1
SUNITINIB	4	RIPK1
QUIZARTINIB	4	RIPK1
DINACICLIB	3	TAOK2
ALVOCIDIB	3	TAOK2
CEDIRANIB	3	TAOK2
LESTAURTINIB	3	TAOK2
RUBOXISTAURIN	3	TAOK2
LINIFANIB	3	RIPK1
DOVITINIB	3	RIPK1
FORETINIB	2	RIPK1, TAOK2
ZOTIRACICLIB	2	TAOK2
GOLVATINIB	2	TAOK2
RG-547	2	TAOK2
AT-7519	2	TAOK2
R-406	2	TAOK2
RAF-265	2	RIPK1, TAOK2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	TAOK2, RIPK1
B	Phased (≥1) drug, not yet approved	1	INO80
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	TKFC
E	Difficult family or no structure, no drug	9	STXBP3, TNFSF12, TRIM22, LY96, RC3H1, NFAT5, NFATC1, IRF2BP2, RAG2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
STXBP3	0	—
TNFSF12	0	—
TRIM22	0	—
LY96	87	—
TKFC	1	—
RC3H1	0	—
NFAT5	0	—
NFATC1	15	—
IRF2BP2	1	—
RAG2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 48.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	26
PHASE3	15
PHASE2	6
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03677557	PHASE4	UNKNOWN	Safety, Tolerability, Patient Satisfaction and Cost of 16.5% Subcutaneous Immunoglobulin (Cutaquig®) Treatment
NCT04944979	PHASE3	ACTIVE_NOT_RECRUITING	Clinical Assessment of Pharmacokinetics, Efficacy, and Safety of 10% IVIg in Pediatric PID Patients (KIDCARES10)
NCT07346859	PHASE3	RECRUITING	Study of BP-SCIG 20% in Patients With Primary Immunodeficiency (PID)
NCT00001646	PHASE3	COMPLETED	Voriconazole vs. Amphotericin B in the Treatment of Invasive Aspergillosis
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT00468273	PHASE3	COMPLETED	A Clinical Study of Intravenous Immunoglobulin
NCT00811174	PHASE3	TERMINATED	Efficacy, Safety and Kinetics Study of Octagam 10% in Primary Immunodeficiency Diseases
NCT01012323	PHASE3	COMPLETED	A Study of NewGam, Human Immunoglobulin 10%, in Patients With Primary Immunodeficiency Diseases
NCT01313507	PHASE3	COMPLETED	High Infusion Rate Study of Immunoglobulin Intravenous (Human) 10% (NewGam)
NCT01406470	PHASE3	COMPLETED	Phase 3 Study of Immune Globulin Intravenous (Human)IVIG-SN™ in Subjects With Primary Immunodeficiency
NCT02783482	PHASE3	COMPLETED	Study of Immune Globulin Intravenous (Human) GC5107 in Subjects With Primary Humoral Immunodeficiency
NCT02810444	PHASE3	COMPLETED	Study to Investigate Efficacy, Safety and Pharmacokinetics of BT595 in Subjects With PID
NCT03961009	PHASE3	COMPLETED	Clinical Assessment of Pharmacokinetics, Efficacy, and Safety of 10% IVIg in PID Patients
NCT04842643	PHASE3	COMPLETED	An Extension Study of TAK-664 for Japanese People With Primary Immunodeficiency Disease
NCT06089122	PHASE3	UNKNOWN	Efficacy, Safety, and Pharmacokinetics of Shu Yang IVIG
NCT06150833	PHASE3	UNKNOWN	Efficacy and Safety and Pharmacokinetics of Boya IVIG
NCT06199427	PHASE2	RECRUITING	PTCy and and Ruxolitinib for GVHD Prophylaxis After HSCT With Thymoglobulin in Conditioning Regimen in Patients With Inborn Errors of Immunity
NCT00001438	PHASE2	COMPLETED	A Pilot Study of the Combination of Retinoic Acid and Interferon-Alpha2a for the Treatment of Lymphoproliferative Disorders in Children With Immunodeficiency Syndromes
NCT00176865	PHASE2	COMPLETED	Stem Cell Transplant for Immunologic or Histiocytic Disorders
NCT00389324	PHASE2	COMPLETED	A Trial of the Pharmacokinetics, Safety, and Tolerability of Subcutaneous Gamunex® in Primary Immunodeficiency
NCT00598481	PHASE2	COMPLETED	ADA Gene Transfer Into Hematopoietic Stem/Progenitor Cells for the Treatment of ADA-SCID
NCT01856582	PHASE2	TERMINATED	CD34+ Stem Cell Infusion to Augment Graft Function
NCT02417740	Not specified	RECRUITING	Natural History of Noncirrhotic Portal Hypertension
NCT02735824	Not specified	RECRUITING	Genetic Study of Immunodeficiency: Search for New Genetic Causes for Primary Immunodeficiencies
NCT03478670	Not specified	ENROLLING_BY_INVITATION	Strimvelis Registry Study to Follow-up Patients With Adenosine Deaminase Severe Combined Immunodeficiency (ADA-SCID)
NCT03835312	Not specified	RECRUITING	Sequential Transplantation of UCBSCs and Islet Cells in Children and Adolescents With Monogenic Immunodeficiency T1DM
NCT05236764	Not specified	ACTIVE_NOT_RECRUITING	Haploidentical Hematopoietic Cell Transplantation Using TCR Alpha/Beta and CD19 Depletion
NCT06773546	Not specified	RECRUITING	Immunodysregulation As an Expression of Underlying Inborn Errors of Immunity: Implementation of Diagnostics and Management of Pediatric and Adult Patients with Immune System Disorders
NCT07019857	Not specified	RECRUITING	Impact of Thymectomy on Immunity in Infants After Cardiac Surgery
NCT07516002	Not specified	NOT_YET_RECRUITING	Immunoglobulin Efficacy and Immune Profiling in Antibody Immunodeficiency
NCT00001158	Not specified	COMPLETED	Studies of the Immune Response in Normal Subjects and Patients With Disorders of the Immune System
NCT00001336	Not specified	COMPLETED	In Vitro Studies of Immunological and Stem Cell Function in Peripheral Blood Mononuclear Cells in Patients
NCT00001788	Not specified	TERMINATED	Genetic Basis of Primary Immunodeficiencies
NCT00006054	Not specified	TERMINATED	Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies
NCT00006131	Not specified	COMPLETED	Randomized Study of Two Doses of Oral Valacyclovir in Immunocompromised Patients With Uncomplicated Herpes Zoster
NCT01150240	Not specified	UNKNOWN	Clinical and Laboratory Online Patient- and Research Database for Primary Immunodeficiencies in Switzerland
NCT01727895	Not specified	COMPLETED	Effects of Orally Administered Beta-glucan on Leukocyte Function in Humans
NCT02176239	Not specified	COMPLETED	Monitoring of 5% Treatment Naïve Intravenous Immunoglobulin (IVIg) Primary Immunodeficiency Disease (PIDD) Patients Using the CareExchange® System: A Pilot Study Using 5% Gammaplex® IVIg in the Home Setting
NCT02554630	Not specified	COMPLETED	Novel Mechanisms and Approaches to Treat Neonatal Sepsis
NCT02630082	Not specified	COMPLETED	Feasibility of Measuring Immune Resp, Activation in Foreskin/Mucosa in HIV-, Uncircumcised High-HIV-risk MSM, Lima Peru

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
HUMAN IMMUNOGLOBULIN G	4	5
AMPHOTERICIN B	4	1
AUTOLOGOUS CD34+ ENRICHED CELL FRACTION THAT CONTAINS CD34+ CELLS TRANSDUCED WITH RETROVIRAL VECTOR THAT ENCODES FOR THE HUMAN ADA CDNA SEQUENCE	4	1
DEXTROSE	4	1
VORICONAZOLE	4	1
CHEMBL423707	0	1