Combined immunodeficiency

disease

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Also known as CIDcongenital combined immunodeficiencyX-linked combined immunodeficiency

Summary

Combined immunodeficiency (MONDO:0015131) is a disease (an umbrella term covering 33 Mondo subtypes) caused by variants in IL7, IRF4, and ITPR3, with 17 cohort genes and 4 clinical trials.

At a glance

Causal genes: IL7 (GenCC Strong), IRF4 (GenCC Strong), ITPR3 (GenCC Strong)
Umbrella term: 33 Mondo subtypes
Cohort genes: 17
ClinVar variants: 17
Clinical trials: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	combined immunodeficiency
Mondo ID	MONDO:0015131
Orphanet	101972
DOID	DOID:0111962, DOID:628
ICD-11	1616506198
NCIT	C27871
UMLS	C2711630
MedGen	751396
GARD	0019806
Is cancer (heuristic)	no

Also known as: CID · congenital combined immunodeficiency · X-linked combined immunodeficiency

Data availability: 17 ClinVar variants · 9 GenCC gene-disease records.

Disease family

An umbrella term covering 33 Mondo subtypes.

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

Subtypes (33): 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, severe combined immunodeficiency, 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

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

17 retrieved; paginated sample, class counts are floors:

8 pathogenic, 6 conflicting classifications of pathogenicity, 2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
424712	NM_006785.3(MALT1):c.[1019-2A>G];[1060delC]		Pathogenic	no assertion criteria provided
827687	NM_005720.4(ARPC1B):c.739_743del (p.Leu247fs)	ARPC1B	Pathogenic	criteria provided, multiple submitters, no conflicts
254673	NM_138576.4(BCL11B):c.1323T>G (p.Asn441Lys)	BCL11B	Pathogenic	no assertion criteria provided
266035	NM_001013838.3(CARMIL2):c.490dup (p.Ala164fs)	CARMIL2	Pathogenic	no assertion criteria provided
266036	NM_001013838.3(CARMIL2):c.871+1G>T	CARMIL2	Pathogenic	criteria provided, multiple submitters, no conflicts
562177	NM_001013838.3(CARMIL2):c.1590C>A (p.Asn530Lys)	CARMIL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
827694	NM_001242.5(CD27):c.250dup (p.Cys84fs)	CD27	Pathogenic	criteria provided, single submitter
827686	NC_000007.14:g.99369754_99378887del	LOC129998866	Pathogenic	criteria provided, single submitter
827753	NM_001079.4(ZAP70):c.283C>T (p.Pro95Ser)	ZAP70	Pathogenic	criteria provided, single submitter
1339546	NM_015259.6(ICOSLG):c.499C>T (p.Pro167Ser)	ICOSLG	Likely pathogenic	criteria provided, single submitter
3384076	NM_000206.3(IL2RG):c.820_823dup (p.Ser275fs)	IL2RG	Likely pathogenic	criteria provided, single submitter
354225	NM_003664.5(AP3B1):c.2769A>C (p.Lys923Asn)	AP3B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
827695	NM_001242.5(CD27):c.319C>T (p.Arg107Cys)	CD27	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
537091	NM_002691.4(POLD1):c.3244C>T (p.Arg1082Cys)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
218163	NM_001128148.3(TFRC):c.58T>C (p.Tyr20His)	TFRC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
222950	NM_001079.4(ZAP70):c.1079G>C (p.Arg360Pro)	ZAP70	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
222951	NM_001079.4(ZAP70):c.574C>T (p.Arg192Trp)	ZAP70	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · 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
IL7	Strong	Autosomal recessive	combined immunodeficiency	3
IRF4	Strong	Autosomal recessive	combined immunodeficiency	2
ITPR3	Strong	Autosomal dominant	combined immunodeficiency	6
ERBIN	Moderate	Autosomal dominant	combined immunodeficiency
SLC19A1	Moderate	Autosomal recessive	combined immunodeficiency	2
CRACR2A	Limited	Autosomal recessive	combined immunodeficiency
POLE2	Limited	Autosomal recessive	combined immunodeficiency

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ERBIN	Orphanet:656912	Autosomal dominant combined immunodeficiency due to ERBIN deficiency
IL7	Orphanet:302	Inherited epidermodysplasia verruciformis
IRF4	Orphanet:3452	Whipple disease
TFRC	Orphanet:476113	Combined immunodeficiency due to TFRC deficiency
CD27	Orphanet:238505	Combined immunodeficiency due to CD27 deficiency
ZAP70	Orphanet:911	Combined immunodeficiency due to ZAP70 deficiency
BCL11B	Orphanet:662829	Intellectual disability-speech delay-dysmorphic features-T cell abnormalities syndrome
ICOSLG	Orphanet:695191	Late-onset combined immunodeficiency due to ICOSL deficiency
CARMIL2	Orphanet:542301	EBV-induced lymphoproliferative disease due to CARMIL2 deficiency
AP3B1	Orphanet:664500	Hermansky-Pudlak syndrome due to AP3B1 deficiency
IL2RG	Orphanet:276	T-B+ severe combined immunodeficiency due to gamma chain deficiency
IL2RG	Orphanet:39041	Omenn syndrome
ARPC1B	Orphanet:714496	Immunodeficiency-congenital thrombocytopenia-hypereosinophilia-colitis-vasculitis syndrome
POLD1	Orphanet:363649	Mandibular hypoplasia-deafness-progeroid features-lipodystrophy syndrome
POLD1	Orphanet:440437	Familial colorectal cancer Type X
POLD1	Orphanet:447877	Polymerase proofreading-related polyposis

Cohort genes → proteins

17 cohort genes, 17 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	17

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC19A1	HGNC:10937	ENSG00000173638	P41440	Reduced folate transporter	gencc
ERBIN	HGNC:15842	ENSG00000112851	Q96RT1	Erbin	gencc
CRACR2A	HGNC:28657	ENSG00000130038	Q9BSW2	EF-hand calcium-binding domain-containing protein 4B	gencc
IL7	HGNC:6023	ENSG00000104432	P13232	Interleukin-7	gencc
IRF4	HGNC:6119	ENSG00000137265	Q15306	Interferon regulatory factor 4	gencc
ITPR3	HGNC:6182	ENSG00000096433	Q14573	Inositol 1,4,5-trisphosphate-gated calcium channel ITPR3	gencc
POLE2	HGNC:9178	ENSG00000100479	P56282	DNA polymerase epsilon subunit 2	gencc
TFRC	HGNC:11763	ENSG00000072274	P02786	Transferrin receptor protein 1	clinvar
CD27	HGNC:11922	ENSG00000139193	P26842	CD27 antigen	clinvar
ZAP70	HGNC:12858	ENSG00000115085	P43403	Tyrosine-protein kinase ZAP-70	clinvar
BCL11B	HGNC:13222	ENSG00000127152	Q9C0K0	B-cell lymphoma/leukemia 11B	clinvar
ICOSLG	HGNC:17087	ENSG00000160223	O75144	ICOS ligand	clinvar
CARMIL2	HGNC:27089	ENSG00000159753	Q6F5E8	Capping protein, Arp2/3 and myosin-I linker protein 2	clinvar
AP3B1	HGNC:566	ENSG00000132842	O00203	AP-3 complex subunit beta-1	clinvar
IL2RG	HGNC:6010	ENSG00000147168	P31785	Cytokine receptor common subunit gamma	clinvar
ARPC1B	HGNC:704	ENSG00000130429	O15143	Actin-related protein 2/3 complex subunit 1B	clinvar
POLD1	HGNC:9175	ENSG00000062822	P28340	DNA polymerase delta catalytic subunit	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC19A1	Reduced folate transporter	Antiporter that mediates the import of reduced folates or a subset of cyclic dinucleotides, driven by the export of organic anions.
ERBIN	Erbin	Acts as an adapter for the receptor ERBB2, in epithelia.
CRACR2A	EF-hand calcium-binding domain-containing protein 4B	Ca(2+)-binding protein that plays a key role in store-operated Ca(2+) entry (SOCE) in T-cells by regulating CRAC channel activation.
IL7	Interleukin-7	Hematopoietic cytokine that plays an essential role in the development, expansion, and survival of naive and memory T-cells and B-cells thereby regulating the number of mature lymphocytes and maintaining lymphoid homeostasis.
IRF4	Interferon regulatory factor 4	Transcriptional activator.
ITPR3	Inositol 1,4,5-trisphosphate-gated calcium channel ITPR3	Inositol 1,4,5-trisphosphate-gated calcium channel that, upon 1D-myo-inositol 1,4,5-trisphosphate binding, transports calcium from the endoplasmic reticulum lumen to cytoplasm, thus releasing the intracellular calcium and therefore partici…
POLE2	DNA polymerase epsilon subunit 2	Accessory component of the DNA polymerase epsilon complex.
TFRC	Transferrin receptor protein 1	Cellular uptake of iron occurs via receptor-mediated endocytosis of ligand-occupied transferrin receptor into specialized endosomes.
CD27	CD27 antigen	Costimulatory immune-checkpoint receptor expressed at the surface of T-cells, NK-cells and B-cells which binds to and is activated by its ligand CD70/CD27L expressed by B-cells.
ZAP70	Tyrosine-protein kinase ZAP-70	Tyrosine kinase that plays an essential role in regulation of the adaptive immune response.
BCL11B	B-cell lymphoma/leukemia 11B	Key regulator of both differentiation and survival of T-lymphocytes during thymocyte development in mammals.
ICOSLG	ICOS ligand	Ligand for the T-cell-specific cell surface receptor ICOS.
CARMIL2	Capping protein, Arp2/3 and myosin-I linker protein 2	Cell membrane-cytoskeleton-associated protein that plays a role in the regulation of actin polymerization at the barbed end of actin filaments.
AP3B1	AP-3 complex subunit beta-1	Subunit of non-clathrin- and clathrin-associated adaptor protein complex 3 (AP-3) that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes.
IL2RG	Cytokine receptor common subunit gamma	Common subunit for the receptors for a variety of interleukins.
ARPC1B	Actin-related protein 2/3 complex subunit 1B	Component of the Arp2/3 complex, a multiprotein complex that mediates actin polymerization upon stimulation by nucleation-promoting factor (NPF).
POLD1	DNA polymerase delta catalytic subunit	As the catalytic component of the trimeric (Pol-delta3 complex) and tetrameric DNA polymerase delta complexes (Pol-delta4 complex), plays a crucial role in high fidelity genome replication, including in lagging strand synthesis, and repair.

Protein-family classification

Druggable: 7 · Difficult: 4 · Unknown: 6 · Druggable fraction: 0.41

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
Ion channel	1	6.6×	0.580
Transporter	1	4.6×	0.580
Antibody/Immunoglobulin	2	3.4×	0.580
Scaffold/PPI	2	2.0×	0.580
Protease	1	2.1×	0.676
Kinase	1	1.6×	0.697
Transcription factor	2	1.0×	0.807
Enzyme (other)	1	0.7×	0.869
Other/Unknown	6	0.6×	0.974

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC19A1	Transporter	yes		Folate_carrier, SLC19A1, MFS_trans_sf
ERBIN	Scaffold/PPI	no		PDZ, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp
CRACR2A	Other/Unknown	no		Small_GTPase, EF_hand_dom, Small_GTP-bd
IL7	Other/Unknown	no		IL-7, IL-7/IL-9_CS, IL7_sf
IRF4	Other/Unknown	no		Interferon_reg_fact_DNA-bd_dom, SMAD_FHA_dom_sf, SMAD-like_dom_sf
ITPR3	Ion channel	yes		InsP3_rcpt, RIH_dom, Ion_trans_dom
POLE2	Enzyme (other)	yes	2.7.7.7	DNA_pol_a/d/e_bsu, POLE2, DNA_pol_e_bsu_N
TFRC	Protease	yes		PA_domain, TFR-like_dimer_dom, Peptidase_M28
CD27	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_7, TNFRSF7_N
ZAP70	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom
BCL11B	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Dev/Hematopoietic_TF
ICOSLG	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, Ig_V-set
CARMIL2	Other/Unknown	no		Leu-rich_rpt, PH-like_dom_sf, CARMIL_C
AP3B1	Other/Unknown	no		Clathrin/coatomer_adapt-like_N, ARM-like, B-adaptin_app_sub_C
IL2RG	Antibody/Immunoglobulin	yes		Hempt_rcpt_S_F1_CS, FN3_dom, Ig-like_fold
ARPC1B	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, ARPC1
POLD1	Transcription factor	no	2.7.7.7	DNA-dir_DNA_pol_B_exonuc, DNA-dir_DNA_pol_B_multi_dom, DNA-dir_DNA_pol_B

Expression context

Cohort genes with no expression data: 0.

16 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)	17
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lymph node	4
vermiform appendix	3
granulocyte	3
blood	2
endothelial cell	2
cartilage tissue	2
upper arm skin	2
primordial germ cell in gonad	2
ventricular zone	2
jejunal mucosa	1
corpus callosum	1
cranial nerve II	1
lateral globus pallidus	1
ileal mucosa	1
mucosa of sigmoid colon	1
parotid gland	1
bronchial epithelial cell	1
male germ cell	1
sperm	1
endocervix	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC19A1	238	ubiquitous	marker	jejunal mucosa, blood, endothelial cell
ERBIN	296	ubiquitous	marker	corpus callosum, lateral globus pallidus, cranial nerve II
CRACR2A	210	broad	marker	parotid gland, ileal mucosa, mucosa of sigmoid colon
IL7	217	broad	marker	sperm, male germ cell, bronchial epithelial cell
IRF4	180	broad	marker	lymph node, endocervix, vermiform appendix
ITPR3	262	ubiquitous	marker	cartilage tissue, pylorus, upper arm skin
POLE2	197	ubiquitous	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, ventricular zone
TFRC	295	ubiquitous	marker	endothelial cell, trabecular bone tissue, tibia
CD27	132	tissue_specific	marker	lymph node, spleen, vermiform appendix
ZAP70	182	broad	marker	granulocyte, lymph node, blood
BCL11B	211	broad	marker	thymus, upper leg skin, cortical plate
ICOSLG	166	tissue_specific	marker	cartilage tissue, upper arm skin, apex of heart
CARMIL2	183	ubiquitous	yes	right frontal lobe, anterior cingulate cortex, right hemisphere of cerebellum
AP3B1	289	ubiquitous	marker	tendon of biceps brachii, calcaneal tendon, tendon
IL2RG	213	broad	marker	granulocyte, lymph node, vermiform appendix
ARPC1B	136	ubiquitous	marker	monocyte, leukocyte, granulocyte
POLD1	134	ubiquitous	marker	mucosa of transverse colon, ventricular zone, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TFRC	6,725
POLD1	4,000
ZAP70	3,648
ERBIN	3,503
IRF4	3,450
ITPR3	3,135
IL7	2,611
AP3B1	2,527
ARPC1B	2,526
BCL11B	2,523

Intra-cohort edges

A	B	Sources
CD27	ICOSLG	string_interaction
IL2RG	IL7	intact, string_interaction
POLD1	POLE2	string_interaction

Structural data

PDB: 15 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ITPR3	Q14573	24
TFRC	P02786	24
SLC19A1	P41440	19
IRF4	Q15306	19
ZAP70	P43403	15
IL2RG	P31785	14
ERBIN	Q96RT1	11
POLD1	P28340	6
CD27	P26842	5
AP3B1	O00203	5
POLE2	P56282	4
ARPC1B	O15143	4
IL7	P13232	2
ICOSLG	O75144	2
CRACR2A	Q9BSW2	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CARMIL2	Q6F5E8	61.50
BCL11B	Q9C0K0	51.76

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 161. Enrichment computed across 17 evidence-associated genes (16 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 16 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
PCNA-Dependent Long Patch Base Excision Repair	2	64.9×	0.027	POLD1, POLE2
Gap-filling DNA repair synthesis and ligation in GG-NER	2	54.9×	0.027	POLD1, POLE2
Recognition of DNA damage by PCNA-containing replication complex	2	47.6×	0.027	POLD1, POLE2
Termination of translesion DNA synthesis	2	43.3×	0.027	POLD1, POLE2
Nuclear events stimulated by ALK signaling in cancer	2	40.8×	0.027	ZAP70, IRF4
Interleukin-7 signaling	2	39.6×	0.027	IL2RG, IL7
RHOH GTPase cycle	2	38.6×	0.027	TFRC, ZAP70
Fcgamma receptor (FCGR) dependent phagocytosis	2	34.8×	0.028	ITPR3, ARPC1B
Dual Incision in GG-NER	2	32.4×	0.028	POLD1, POLE2
trans-Golgi Network Vesicle Budding	2	31.7×	0.028	TFRC, AP3B1
Drug-mediated inhibition of ERBB2 signaling	1	178.4×	0.031	ERBIN
Resistance of ERBB2 KD mutants to trastuzumab	1	178.4×	0.031	ERBIN
Resistance of ERBB2 KD mutants to sapitinib	1	178.4×	0.031	ERBIN
Resistance of ERBB2 KD mutants to tesevatinib	1	178.4×	0.031	ERBIN
Resistance of ERBB2 KD mutants to neratinib	1	178.4×	0.031	ERBIN
Resistance of ERBB2 KD mutants to osimertinib	1	178.4×	0.031	ERBIN
Resistance of ERBB2 KD mutants to afatinib	1	178.4×	0.031	ERBIN
Resistance of ERBB2 KD mutants to AEE788	1	178.4×	0.031	ERBIN
Resistance of ERBB2 KD mutants to lapatinib	1	178.4×	0.031	ERBIN
Drug resistance in ERBB2 TMD/JMD mutants	1	178.4×	0.031	ERBIN
Golgi Associated Vesicle Biogenesis	2	25.0×	0.031	TFRC, AP3B1
HDR through Homologous Recombination (HRR)	2	23.8×	0.031	POLD1, POLE2
Gap-filling DNA repair synthesis and ligation in TC-NER	2	22.3×	0.031	POLD1, POLE2
Dual incision in TC-NER	2	21.6×	0.031	POLD1, POLE2
Leishmania infection	2	20.4×	0.031	ITPR3, ARPC1B
Parasitic Infection Pathways	2	20.4×	0.031	ITPR3, ARPC1B
RHOB GTPase cycle	2	19.3×	0.031	TFRC, ERBIN
RHOG GTPase cycle	2	18.5×	0.031	TFRC, ERBIN
RHOC GTPase cycle	2	18.3×	0.031	TFRC, ERBIN
RAC2 GTPase cycle	2	15.9×	0.037	TFRC, ERBIN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 17 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of B cell differentiation	3	198.3×	5e-05	CD27, IL2RG, IL7
T cell activation	4	61.0×	5e-05	CD27, ZAP70, ICOSLG, IRF4
positive regulation of T cell differentiation	3	80.4×	5e-04	CD27, ZAP70, IL7
interleukin-7-mediated signaling pathway	2	247.8×	0.002	IL2RG, IL7
DNA-templated DNA replication	2	66.1×	0.019	POLD1, POLE2
mature B cell differentiation	1	991.3×	0.019	IL2RG
establishment or maintenance of monopolar cell polarity	1	991.3×	0.019	CARMIL2
olfactory bulb axon guidance	1	991.3×	0.019	BCL11B
regulation of postsynaptic membrane neurotransmitter receptor levels	2	58.3×	0.019	TFRC, ERBIN
B cell activation	2	53.6×	0.019	ZAP70, ICOSLG
T cell differentiation in thymus	2	48.4×	0.019	BCL11B, IL2RG
adaptive immune response	3	14.9×	0.019	ZAP70, ICOSLG, CRACR2A
positive regulation of B cell proliferation	2	40.5×	0.019	TFRC, IL7
positive T cell selection	1	495.6×	0.022	BCL11B
basal protein localization	1	495.6×	0.022	ERBIN
methotrexate transport	1	495.6×	0.022	SLC19A1
T cell aggregation	1	495.6×	0.022	ZAP70
obsolete establishment of protein localization to mitochondrial membrane involved in mitochondrial fission	1	495.6×	0.022	AP3B1
lymphoid lineage cell migration into thymus	1	495.6×	0.022	BCL11B
positive regulation of lamellipodium organization	1	495.6×	0.022	CARMIL2
extrinsic apoptotic signaling pathway	2	36.0×	0.022	CD27, IL7
CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation	1	330.4×	0.024	IL2RG
beta selection	1	330.4×	0.024	ZAP70
DNA replication proofreading	1	330.4×	0.024	POLD1
adaptive immune memory response involving T cells and B cells	1	330.4×	0.024	CD27
striatal medium spiny neuron differentiation	1	247.8×	0.024	BCL11B
post-embryonic camera-type eye development	1	247.8×	0.024	BCL11B
T cell receptor V(D)J recombination	1	247.8×	0.024	BCL11B
response to histamine	1	247.8×	0.024	CRACR2A
hematopoietic stem cell migration	1	247.8×	0.024	BCL11B

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 4 · Undrugged: 13

Druggability breadth: 14 of 17 evidence-associated genes (82%) 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
SLC19A1	PRALATREXATE
ZAP70	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ZAP70	14	4
SLC19A1	4	4
AP3B1	1	2
ARPC1B	1	2
ERBIN	0	0
CRACR2A	0	0
IL7	0	0
IRF4	0	0
ITPR3	0	0
POLE2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PRALATREXATE	4	SLC19A1
RALTITREXED	4	SLC19A1
PEMETREXED	4	SLC19A1
METHOTREXATE	4	SLC19A1
FEDRATINIB	4	ZAP70
CERITINIB	4	ZAP70
BOSUTINIB	4	ZAP70
NINTEDANIB	4	ZAP70
QUIZARTINIB	4	ZAP70
CRIZOTINIB	4	ZAP70
MIDOSTAURIN	4	ZAP70
ORANTINIB	3	ZAP70
SEMAXANIB	3	ZAP70
LESTAURTINIB	3	ZAP70
DEFOSBARASERTIB	2	ZAP70
MIVAVOTINIB	2	ZAP70
R-406	2	ZAP70
MOLIBRESIB	2	AP3B1, ARPC1B
KW-2449	1	ZAP70

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
ZAP70	451	Binding:448, Functional:2, ADMET:1
SLC19A1	18	Binding:18
ITPR3	11	Binding:9, Functional:2
AP3B1	8	Binding:8
ARPC1B	8	Binding:8
POLD1	8	Binding:8
ICOSLG	6	Binding:6
IRF4	3	Binding:3
ERBIN	1	Binding:1
CRACR2A	1	Binding:1
TFRC	1	Binding:1
CD27	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
POLE2	2.7.7.7	DNA-directed DNA polymerase
ZAP70	2.7.10.2	non-specific protein-tyrosine kinase
POLD1	2.7.7.7	DNA-directed DNA polymerase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
ZAP70	451

Pharmacogenomics

Cohort genes with a PharmGKB record: 17; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

19 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)
PRALATREXATE	4	SLC19A1
RALTITREXED	4	SLC19A1
PEMETREXED	4	SLC19A1
METHOTREXATE	4	SLC19A1
FEDRATINIB	4	ZAP70
CERITINIB	4	ZAP70
BOSUTINIB	4	ZAP70
NINTEDANIB	4	ZAP70
QUIZARTINIB	4	ZAP70
CRIZOTINIB	4	ZAP70
MIDOSTAURIN	4	ZAP70
ORANTINIB	3	ZAP70
SEMAXANIB	3	ZAP70
LESTAURTINIB	3	ZAP70
DEFOSBARASERTIB	2	ZAP70
MIVAVOTINIB	2	ZAP70
R-406	2	ZAP70
MOLIBRESIB	2	AP3B1, ARPC1B
KW-2449	1	ZAP70

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SLC19A1, ZAP70
B	Phased (≥1) drug, not yet approved	2	AP3B1, ARPC1B
C	Druggable family + PDB, no drug	5	ITPR3, POLE2, TFRC, ICOSLG, IL2RG
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	8	ERBIN, CRACR2A, IL7, IRF4, CD27, BCL11B, CARMIL2, POLD1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ERBIN	1	—
CRACR2A	1	—
IL7	0	—
IRF4	3	—
ITPR3	11	—
POLE2	0	—
TFRC	1	—
CD27	1	—
BCL11B	0	—
ICOSLG	6	—
CARMIL2	0	—
IL2RG	0	—
POLD1	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02737384	PHASE2	TERMINATED	Hematopoietic Stem Cells Transplantation in Children With Combined Immunodeficiency (CID)
NCT04902807	Not specified	RECRUITING	Conception of a Diagnosis, Prognosis and Therapeutic Decision Tool for Patients With Autoimmunity and Inflammation
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
NCT02915406	Not specified	NO_LONGER_AVAILABLE	cliniMACs HUD for T Cell Depletion

Cohort genes: SLC19A1, ERBIN, CRACR2A, IL7, IRF4, ITPR3, POLE2, TFRC, CD27, ZAP70, BCL11B, ICOSLG, CARMIL2, AP3B1, IL2RG, ARPC1B, POLD1