Autoimmune disease, multisystem, infantile-onset, 2

Summary

Autoimmune disease, multisystem, infantile-onset, 2 (MONDO:0014861) is a disease caused by ZAP70 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ZAP70 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 13

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autoimmune disease, multisystem, infantile-onset, 2
Mondo ID	MONDO:0014861
OMIM	617006
DOID	DOID:0061161
UMLS	C4310768
MedGen	934735
Is cancer (heuristic)	no

Also known as: ADMIO2 · autoimmune disease, multisystem, infantile-onset caused by mutation in ZAP70 · autoimmune disease, multisystem, infantile-onset, 2 · autoimmune disease, multisystem, infantile-onset, 2; ADMIO2 · autoimmune disease, multisystem, infantile-onset, type 2 · ZAP70 autoimmune disease, multisystem, infantile-onset

Data availability: 13 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autoimmune disease, multisystem, infantile-onset › autoimmune disease, multisystem, infantile-onset, 2

Related subtypes (3): STAT3-related early-onset multisystem autoimmune disease, autoimmune disease, multisystem, infantile-onset, 3, autoimmune disease, multisystem, infantile-onset, 5

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

13 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 4 conflicting classifications of pathogenicity, 2 benign/likely benign, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3587022	NM_001079.4(ZAP70):c.83dup (p.Met29fs)	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
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
2500111	NM_001079.4(ZAP70):c.939C>T (p.Ser313=)	ZAP70	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
471240	NM_001079.4(ZAP70):c.1082+8C>T	ZAP70	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1008659	NM_001079.4(ZAP70):c.1153C>T (p.Arg385Cys)	ZAP70	Uncertain significance	criteria provided, multiple submitters, no conflicts
1028508	NM_001079.4(ZAP70):c.440C>T (p.Pro147Leu)	ZAP70	Uncertain significance	criteria provided, single submitter
1033248	NM_001079.4(ZAP70):c.692C>T (p.Thr231Met)	ZAP70	Uncertain significance	criteria provided, multiple submitters, no conflicts
337637	NM_001079.4(ZAP70):c.1645A>G (p.Met549Val)	ZAP70	Uncertain significance	criteria provided, multiple submitters, no conflicts
659011	NM_001079.4(ZAP70):c.988C>T (p.Leu330Phe)	ZAP70	Uncertain significance	criteria provided, multiple submitters, no conflicts
1587005	NM_001079.4(ZAP70):c.732C>T (p.Asp244=)	ZAP70	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
898231	NM_001079.4(ZAP70):c.512A>G (p.Glu171Gly)	ZAP70	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

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	Strong	Autosomal recessive	autoimmune disease, multisystem, infantile-onset, 2	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: 0.