hyper-IgE syndrome 6, autosomal dominant, with recurrent infections

Summary

hyper-IgE syndrome 6, autosomal dominant, with recurrent infections (MONDO:0957807) is a disease caused by STAT6 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: STAT6 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 8

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyper-IgE syndrome 6, autosomal dominant, with recurrent infections
Mondo ID	MONDO:0957807
OMIM	620532
UMLS	C5848786
MedGen	1851769
GARD	0026874
Is cancer (heuristic)	no

Data availability: 8 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › B cell deficiency › hyperimmunoglobulin syndrome › hyper-IgE syndrome › hyper-IgE syndrome 6, autosomal dominant, with recurrent infections

Related subtypes (13): hyper-IgE recurrent infection syndrome 1, autosomal dominant, combined immunodeficiency due to DOCK8 deficiency, Netherton syndrome, hyper-IgE recurrent infection syndrome 5, autosomal recessive, immunodeficiency 94 with autoinflammation and dysmorphic facies, hyper-IgE recurrent infection syndrome 3, autosomal recessive, hyper-IgE recurrent infection syndrome 4, autosomal recessive, hyper-IgE recurrent infection syndrome 4A, autosomal dominant, 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

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

8 retrieved; paginated sample, class counts are floors:

5 pathogenic, 2 uncertain significance, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2582687	NM_003153.5(STAT6):c.1256A>G (p.Asp419Gly)	STAT6	Pathogenic	no assertion criteria provided
2582688	NM_003153.5(STAT6):c.1255G>T (p.Asp419Tyr)	STAT6	Pathogenic	no assertion criteria provided
2582690	NM_003153.5(STAT6):c.1144G>C (p.Glu382Gln)	STAT6	Pathogenic	no assertion criteria provided
2582691	NM_003153.5(STAT6):c.1555G>C (p.Asp519His)	STAT6	Pathogenic	no assertion criteria provided
2582692	NM_003153.5(STAT6):c.1114G>A (p.Glu372Lys)	STAT6	Pathogenic	no assertion criteria provided
2582689	NM_003153.5(STAT6):c.1255G>C (p.Asp419His)	STAT6	Likely pathogenic	criteria provided, single submitter
4291806	NM_003153.5(STAT6):c.866T>A (p.Phe289Tyr)	STAT6	Uncertain significance	criteria provided, single submitter
4293117	NM_003153.5(STAT6):c.2285G>A (p.Cys762Tyr)	STAT6	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · 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
STAT6	Strong	Autosomal dominant	hyper-IgE syndrome 6, autosomal dominant, with recurrent infections	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STAT6	Orphanet:2126	Solitary fibrous tumor

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
STAT6	HGNC:11368	ENSG00000166888	P42226	Signal transducer and activator of transcription 6	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
STAT6	Signal transducer and activator of transcription 6	Carries out a dual function: signal transduction and activation of transcription.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STAT6	Transcription factor	no		SH2, STAT, p53-like_TF_DNA-bd_sf

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
granulocyte	1
left ovary	1
right ovary	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STAT6	292	ubiquitous	marker	granulocyte, right ovary, left ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STAT6	3,345

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
STAT6	P42226	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
STAT6-mediated induction of chemokines	1	3806.7×	0.003	STAT6
STING mediated induction of host immune responses	1	1038.2×	0.006	STAT6
Downstream signal transduction	1	380.7×	0.010	STAT6
Cytosolic sensors of pathogen-associated DNA	1	285.5×	0.010	STAT6
Signaling by PDGF	1	253.8×	0.010	STAT6
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	1	146.4×	0.015	STAT6
Interleukin-4 and Interleukin-13 signaling	1	102.9×	0.018	STAT6
Signaling by Interleukins	1	64.2×	0.025	STAT6
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.028	STAT6
Cytokine Signaling in Immune system	1	40.8×	0.032	STAT6
Innate Immune System	1	25.5×	0.046	STAT6
Immune System	1	13.0×	0.084	STAT6
Signal Transduction	1	10.2×	0.098	STAT6

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
regulation of mast cell proliferation	1	16852.0×	9e-04	STAT6
mammary gland morphogenesis	1	8426.0×	9e-04	STAT6
isotype switching to IgE isotypes	1	5617.3×	9e-04	STAT6
T-helper 1 cell lineage commitment	1	4213.0×	9e-04	STAT6
positive regulation of isotype switching to IgE isotypes	1	4213.0×	9e-04	STAT6
negative regulation of type 2 immune response	1	2808.7×	0.001	STAT6
interleukin-4-mediated signaling pathway	1	2407.4×	0.001	STAT6
mammary gland epithelial cell proliferation	1	1532.0×	0.001	STAT6
growth hormone receptor signaling pathway via JAK-STAT	1	1532.0×	0.001	STAT6
response to peptide hormone	1	391.9×	0.005	STAT6
cell surface receptor signaling pathway via JAK-STAT	1	290.6×	0.006	STAT6
defense response	1	216.1×	0.007	STAT6
positive regulation of cold-induced thermogenesis	1	163.6×	0.008	STAT6
cytokine-mediated signaling pathway	1	130.6×	0.010	STAT6
regulation of cell population proliferation	1	115.4×	0.010	STAT6
negative regulation of transcription by RNA polymerase II	1	17.7×	0.063	STAT6
positive regulation of transcription by RNA polymerase II	1	14.9×	0.071	STAT6
regulation of transcription by RNA polymerase II	1	11.7×	0.086	STAT6

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
STAT6	THIORIDAZINE HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
STAT6	11	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
THIORIDAZINE HYDROCHLORIDE	4	STAT6
DOXORUBICIN HYDROCHLORIDE	4	STAT6
AMSACRINE	4	STAT6
ADENOSINE	4	STAT6
AMANTADINE	4	STAT6
BISACODYL	4	STAT6
QUERCETIN	3	STAT6
TIAPRIDE	3	STAT6
HYCANTHONE	2	STAT6
SANGUINARIUM	2	STAT6
IODOQUINOL	2	STAT6

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
STAT6	81	Binding:77, Functional:4

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

11 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)
THIORIDAZINE HYDROCHLORIDE	4	STAT6
DOXORUBICIN HYDROCHLORIDE	4	STAT6
AMSACRINE	4	STAT6
ADENOSINE	4	STAT6
AMANTADINE	4	STAT6
BISACODYL	4	STAT6
QUERCETIN	3	STAT6
TIAPRIDE	3	STAT6
HYCANTHONE	2	STAT6
SANGUINARIUM	2	STAT6
IODOQUINOL	2	STAT6

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	STAT6
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.