combined immunodeficiency due to ZAP70 deficiency

Summary

combined immunodeficiency due to ZAP70 deficiency (MONDO:0010023) is a disease caused by ZAP70 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: ZAP70 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 496
• Phenotypes (HPO): 30
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0002718	Recurrent bacterial infections	Very frequent (80-99%)
HP:0004429	Recurrent viral infections	Very frequent (80-99%)
HP:0005390	Recurrent opportunistic infections	Very frequent (80-99%)
HP:0031381	Decreased lymphocyte proliferation in response to mitogen	Very frequent (80-99%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0002028	Chronic diarrhea	Frequent (30-79%)
HP:0002090	Pneumonia	Frequent (30-79%)
HP:0004798	Recurrent infection of the gastrointestinal tract	Frequent (30-79%)
HP:0005415	Decreased proportion of CD8-positive T cells	Frequent (30-79%)
HP:0005422	Absence of CD8-positive T cells	Frequent (30-79%)
HP:0009098	Chronic oral candidiasis	Frequent (30-79%)
HP:0200117	Recurrent upper and lower respiratory tract infections	Frequent (30-79%)
HP:0000100	Nephrotic syndrome	Occasional (5-29%)
HP:0000988	Skin rash	Occasional (5-29%)
HP:0001297	Stroke	Occasional (5-29%)
HP:0001433	Hepatosplenomegaly	Occasional (5-29%)
HP:0001880	Eosinophilia	Occasional (5-29%)
HP:0002583	Colitis	Occasional (5-29%)
HP:0002716	Lymphadenopathy	Occasional (5-29%)
HP:0002728	Chronic mucocutaneous candidiasis	Occasional (5-29%)
HP:0002733	Abnormality of the lymph nodes	Occasional (5-29%)
HP:0002840	Lymphadenitis	Occasional (5-29%)
HP:0005406	Recurrent bacterial skin infections	Occasional (5-29%)
HP:0010280	Stomatitis	Occasional (5-29%)
HP:0011274	Recurrent mycobacterial infections	Occasional (5-29%)
HP:0100827	Lymphocytosis	Occasional (5-29%)
HP:0001890	Autoimmune hemolytic anemia	Very rare (<1-4%)
HP:0001973	Autoimmune thrombocytopenia	Very rare (<1-4%)
HP:0002665	Lymphoma	Very rare (<1-4%)
HP:0005523	Lymphoproliferative disorder	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	combined immunodeficiency due to ZAP70 deficiency
Mondo ID	MONDO:0010023
MeSH	C536722
OMIM	269840
Orphanet	911
DOID	DOID:0111943
ICD-11	1718367094
SNOMED CT	716378008
UMLS	C2931299
MedGen	419767
GARD	0000387
Is cancer (heuristic)	no

Also known as: IMD48 · selective T-cell defect · severe combined immunodeficiency due to ZAP70 deficiency · STCD · ZAP-70 deficiency · zeta-associated-protein 70 deficiency

Data availability: 496 ClinVar variants · 4 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 › combined immunodeficiency due to ZAP70 deficiency

Related subtypes (32): ataxia telangiectasia, 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

496 retrieved; paginated sample, class counts are floors:

248 likely benign, 170 uncertain significance, 21 conflicting classifications of pathogenicity, 20 pathogenic, 19 benign, 9 likely pathogenic, 6 benign/likely benign, 2 not provided, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1072344	NM_001079.4(ZAP70):c.475G>T (p.Glu159Ter)	ZAP70	Pathogenic	criteria provided, single submitter
13253	NM_001079.4(ZAP70):c.1624-11G>A	ZAP70	Pathogenic	criteria provided, multiple submitters, no conflicts
13255	NM_001079.4(ZAP70):c.1554C>A (p.Ser518Arg)	ZAP70	Pathogenic	no assertion criteria provided
13256	NM_001079.4(ZAP70):c.1510_1522del (p.Lys504fs)	ZAP70	Pathogenic	criteria provided, single submitter
1390316	NM_001079.4(ZAP70):c.1518C>A (p.Tyr506Ter)	ZAP70	Pathogenic	criteria provided, single submitter
1394530	NM_001079.4(ZAP70):c.703-1G>A	ZAP70	Pathogenic	criteria provided, single submitter
1455724	NM_001079.4(ZAP70):c.847C>T (p.Arg283Ter)	ZAP70	Pathogenic	criteria provided, single submitter
2088832	NM_001079.4(ZAP70):c.1450A>T (p.Lys484Ter)	ZAP70	Pathogenic	criteria provided, single submitter
2501785	NM_001079.4(ZAP70):c.493del (p.His165fs)	ZAP70	Pathogenic	criteria provided, single submitter
2697762	NM_001079.4(ZAP70):c.747C>A (p.Cys249Ter)	ZAP70	Pathogenic	criteria provided, single submitter
2745505	NM_001079.4(ZAP70):c.1120_1135dup (p.Asp379fs)	ZAP70	Pathogenic	criteria provided, single submitter
3622427	NM_001079.4(ZAP70):c.392G>A (p.Trp131Ter)	ZAP70	Pathogenic	criteria provided, single submitter
3640729	NM_001079.4(ZAP70):c.1228del (p.Leu410fs)	ZAP70	Pathogenic	criteria provided, single submitter
3664651	NM_001079.4(ZAP70):c.1258_1261del (p.Gly420fs)	ZAP70	Pathogenic	criteria provided, single submitter
3674567	NM_001079.4(ZAP70):c.845_846del (p.Arg282fs)	ZAP70	Pathogenic	criteria provided, single submitter
3721398	NM_001079.4(ZAP70):c.252C>A (p.Cys84Ter)	ZAP70	Pathogenic	criteria provided, single submitter
4769503	NM_001079.4(ZAP70):c.1244_1253del (p.Glu415fs)	ZAP70	Pathogenic	criteria provided, single submitter
567226	NM_001079.4(ZAP70):c.1247dup (p.Met416fs)	ZAP70	Pathogenic	criteria provided, single submitter
659957	NM_001079.4(ZAP70):c.1529_1532dup (p.Ile511fs)	ZAP70	Pathogenic	criteria provided, single submitter
659958	NM_001079.4(ZAP70):c.109C>G (p.Arg37Gly)	ZAP70	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
954252	NM_001079.4(ZAP70):c.261C>G (p.Tyr87Ter)	ZAP70	Pathogenic	criteria provided, single submitter
1300183	NM_001079.4(ZAP70):c.1065C>T (p.Gly355=)	ZAP70	Likely pathogenic	criteria provided, single submitter
2767977	NM_001079.4(ZAP70):c.890-1_891del	ZAP70	Likely pathogenic	criteria provided, single submitter
3587022	NM_001079.4(ZAP70):c.83dup (p.Met29fs)	ZAP70	Likely pathogenic	criteria provided, single submitter
3666897	NM_001079.4(ZAP70):c.1083-1G>A	ZAP70	Likely pathogenic	criteria provided, single submitter
3720353	NM_001079.4(ZAP70):c.1690T>C (p.Cys564Arg)	ZAP70	Likely pathogenic	criteria provided, single submitter
3775169	NM_001079.4(ZAP70):c.1505C>T (p.Pro502Leu)	ZAP70	Likely pathogenic	criteria provided, single submitter
38912	NM_001079.4(ZAP70):c.1393C>T (p.Arg465Cys)	ZAP70	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4723863	NM_001079.4(ZAP70):c.402+1G>A	ZAP70	Likely pathogenic	criteria provided, single submitter
861386	NM_001079.4(ZAP70):c.791-1G>A	ZAP70	Likely 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
ZAP70	Definitive	Autosomal recessive	combined immunodeficiency due to ZAP70 deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZAP70	Orphanet:911	Combined immunodeficiency due to ZAP70 deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ZAP70	HGNC:12858	ENSG00000115085	P43403	Tyrosine-protein kinase ZAP-70	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZAP70	Tyrosine-protein kinase ZAP-70	Tyrosine kinase that plays an essential role in regulation of the adaptive immune response.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZAP70	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
granulocyte	1
lymph node	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZAP70	182	broad	marker	granulocyte, lymph node, blood

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ZAP70	3,648

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ZAP70	P43403	15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Translocation of ZAP-70 to Immunological synapse	1	634.4×	0.003	ZAP70
Generation of second messenger molecules	1	346.1×	0.003	ZAP70
Nuclear events stimulated by ALK signaling in cancer	1	326.3×	0.003	ZAP70
RHOH GTPase cycle	1	308.6×	0.003	ZAP70

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
T cell aggregation	1	8426.0×	0.002	ZAP70
beta selection	1	5617.3×	0.002	ZAP70
positive regulation of alpha-beta T cell proliferation	1	2808.7×	0.002	ZAP70
positive regulation of alpha-beta T cell differentiation	1	1685.2×	0.002	ZAP70
positive thymic T cell selection	1	1404.3×	0.002	ZAP70
negative thymic T cell selection	1	1404.3×	0.002	ZAP70
T cell migration	1	1404.3×	0.002	ZAP70
B cell activation	1	455.5×	0.004	ZAP70
positive regulation of T cell differentiation	1	455.5×	0.004	ZAP70
peptidyl-tyrosine phosphorylation	1	421.3×	0.004	ZAP70
positive regulation of calcium-mediated signaling	1	421.3×	0.004	ZAP70
T cell differentiation	1	383.0×	0.004	ZAP70
T cell activation	1	259.3×	0.006	ZAP70
calcium-mediated signaling	1	183.2×	0.007	ZAP70
T cell receptor signaling pathway	1	151.8×	0.008	ZAP70
adaptive immune response	1	84.3×	0.014	ZAP70
protein phosphorylation	1	68.0×	0.016	ZAP70
immune response	1	47.1×	0.022	ZAP70
intracellular signal transduction	1	38.1×	0.026	ZAP70

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
ZAP70	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ZAP70	14	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
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
KW-2449	1	ZAP70

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ZAP70	451	Binding:448, Functional:2, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ZAP70	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
ZAP70	451

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

14 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	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
KW-2449	1	ZAP70

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ZAP70
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: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns