Autosomal dominant hyper-IgE syndrome: genes and variants
Explore variant evidence for Autosomal dominant hyper-IgE syndrome across 3 analyzed proteins (STAT3, IL6R, DOCK8). Linked ClinVar records include 65 pathogenic or likely pathogenic variants, 231 variants of uncertain significance and 35 with conflicting classifications.
Coverage includes proteins already analyzed in CATVariant, not every gene involved in this condition. Database links are associations, not an assessment of clinical gene–disease validity. Computable evidence prioritizes variants for expert review and does not reclassify them. Source labels are pooled across this disease family.
Data updated 2026-10-10. Automated aggregation, not a clinical review date.
Download variant evidence (CSV)
Genes linked to Autosomal dominant hyper-IgE syndrome
STAT3: Signal transducer and activator of transcription 3
It translates cytokine and growth-factor signals into transcriptional programs governing immune regulation, survival, proliferation, and tissue repair. Dominant-negative variants cause hyper-IgE syndrome, while activating germline variants cause early autoimmunity and lymphoproliferation and somatic activation contributes to cancer.
65 ClinVar pathogenic / likely pathogenic and 177 uncertain variants in STAT3 have source records linked to Autosomal dominant hyper-IgE syndrome. Association strength is not clinical gene validity.
IL6R: Interleukin-6 receptor subunit alpha
It binds IL-6 and signals through gp130 either from the cell surface or as a soluble receptor, allowing both classical and trans-signaling. Genetic and pharmacologic reduction of IL-6 receptor signaling lowers inflammatory activity and is therapeutically useful in several immune-mediated diseases.
0 ClinVar pathogenic / likely pathogenic and 3 uncertain variants in IL6R have source records linked to Autosomal dominant hyper-IgE syndrome. Association strength is not clinical gene validity.
DOCK8: Dedicator of cytokinesis protein 8
It coordinates actin remodeling and signaling required for migration, survival, and immune synapse formation in lymphocytes. Biallelic loss-of-function variants cause DOCK8 deficiency, a combined immunodeficiency characterized by severe viral infections, allergy, eczema, and malignancy risk.
0 ClinVar pathogenic / likely pathogenic and 86 uncertain variants in DOCK8 have source records linked to Autosomal dominant hyper-IgE syndrome. Association strength is not clinical gene validity.
Weakly linked (only a few uncertain records): ITGB3.
Where Autosomal dominant hyper-IgE syndrome variants cluster
- STAT3 SH2 (positions 580–670): 22 of 65 ClinVar pathogenic / likely pathogenic variants, 2.9× more than its size predicts.
ClinVar pathogenic and likely pathogenic variants linked to Autosomal dominant hyper-IgE syndrome
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| STAT3 R382W | 382 | Pathogenic / likely pathogenic (★★) | |
| STAT3 R382Q | 382 | Pathogenic / likely pathogenic (★★) | |
| STAT3 F621L | 621 | SH2 | Pathogenic / likely pathogenic (★★) |
| STAT3 V637M | 637 | SH2 | Pathogenic / likely pathogenic (★★) |
| STAT3 L706P | 706 | Pathogenic / likely pathogenic (★★) | |
| STAT3 I711V | 711 | Pathogenic / likely pathogenic (★★) | |
| STAT3 R278C | 278 | Pathogenic / likely pathogenic (★★) | |
| STAT3 T389A | 389 | Pathogenic / likely pathogenic (★★) | |
| STAT3 G421R | 421 | Pathogenic / likely pathogenic (★★) | |
| STAT3 R423Q | 423 | Pathogenic / likely pathogenic (★★) | |
| STAT3 N466S | 466 | Pathogenic / likely pathogenic (★★) | |
| STAT3 N466T | 466 | Pathogenic / likely pathogenic (★★) | |
| STAT3 Y657C | 657 | SH2 | Pathogenic / likely pathogenic (★★) |
| STAT3 I659N | 659 | SH2 | Pathogenic / likely pathogenic (★★) |
| STAT3 M660T | 660 | SH2 | Pathogenic / likely pathogenic (★★) |
| STAT3 K709E | 709 | Pathogenic / likely pathogenic (★★) | |
| STAT3 P715L | 715 | Pathogenic / likely pathogenic (★★) | |
| STAT3 R152W | 152 | Essential for nuclear import | Pathogenic / likely pathogenic (★★) |
| STAT3 H332Y | 332 | Pathogenic / likely pathogenic (★★) | |
| STAT3 R335W | 335 | Pathogenic / likely pathogenic (★★) | |
| STAT3 E415K | 415 | Pathogenic / likely pathogenic (★★) | |
| STAT3 E594K | 594 | SH2 | Pathogenic / likely pathogenic (★★) |
| STAT3 T716M | 716 | Pathogenic / likely pathogenic (★★) | |
| STAT3 L673P | 673 | Pathogenic / likely pathogenic (★★) | |
| STAT3 P695L | 695 | Pathogenic / likely pathogenic (★★) | |
| STAT3 M329K | 329 | Pathogenic / likely pathogenic (★) | |
| STAT3 R382P | 382 | Pathogenic / likely pathogenic (★) | |
| STAT3 F621V | 621 | SH2 | Pathogenic / likely pathogenic (★) |
| STAT3 S636F | 636 | SH2 | Pathogenic / likely pathogenic (★) |
| STAT3 S636Y | 636 | SH2 | Pathogenic / likely pathogenic (★) |
| STAT3 V637L | 637 | SH2 | Pathogenic / likely pathogenic (★) |
| STAT3 P639A | 639 | SH2 | Pathogenic / likely pathogenic (★) |
| STAT3 P639T | 639 | SH2 | Pathogenic / likely pathogenic (★) |
| STAT3 Y705H | 705 | Pathogenic / likely pathogenic (★) | |
| STAT3 I711S | 711 | Pathogenic / likely pathogenic (★) | |
| STAT3 T714I | 714 | Pathogenic / likely pathogenic (★) | |
| STAT3 T714K | 714 | Pathogenic / likely pathogenic (★) | |
| STAT3 T620S | 620 | SH2 | Pathogenic / likely pathogenic (★) |
| STAT3 P639L | 639 | SH2 | Pathogenic / likely pathogenic (★) |
| STAT3 Y705C | 705 | Pathogenic / likely pathogenic (★) | |
| STAT3 L706M | 706 | Pathogenic / likely pathogenic (★) | |
| STAT3 R278H | 278 | Pathogenic / likely pathogenic (★) | |
| STAT3 M394T | 394 | Pathogenic / likely pathogenic (★) | |
| STAT3 M394I | 394 | Pathogenic / likely pathogenic (★) | |
| STAT3 H437Q | 437 | Pathogenic / likely pathogenic (★) | |
| STAT3 T600S | 600 | SH2 | Pathogenic / likely pathogenic (★) |
| STAT3 T622I | 622 | SH2 | Pathogenic / likely pathogenic (★) |
| STAT3 K642E | 642 | SH2 | Pathogenic / likely pathogenic (★) |
| STAT3 Y672C | 672 | Pathogenic / likely pathogenic (★) | |
| STAT3 T708S | 708 | Pathogenic / likely pathogenic (★) | |
| STAT3 C712R | 712 | Pathogenic / likely pathogenic (★) | |
| STAT3 H437Y | 437 | Pathogenic / likely pathogenic (★) | |
| STAT3 V713L | 713 | Pathogenic / likely pathogenic (★) | |
| STAT3 R103W | 103 | Pathogenic / likely pathogenic (★) | |
| STAT3 L287F | 287 | Pathogenic / likely pathogenic (★) | |
| STAT3 H410Y | 410 | Pathogenic / likely pathogenic (★) | |
| STAT3 N567D | 567 | Pathogenic / likely pathogenic (★) | |
| STAT3 L645Q | 645 | SH2 | Pathogenic / likely pathogenic (★) |
| STAT3 R382L | 382 | Pathogenic / likely pathogenic | |
| STAT3 T620A | 620 | SH2 | Pathogenic / likely pathogenic |
Showing 60 of 65.
Uncertain variants prioritized for review in Autosomal dominant hyper-IgE syndrome
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| STAT3 G618R | 618 | SH2 | Conflicting reports (★) | +7: 5 other pathogenic changes within 3 positions; G618D at the same position is pathogenic; seen in 0 of gnomAD DNA copies; REVEL 0.903 |
| STAT3 R335Q | 335 | Conflicting reports (★) | +7: 2 other pathogenic changes within 3 positions; R335W at the same position is pathogenic; seen in 4.1e-06 of gnomAD DNA copies; REVEL 0.818 | |
| STAT3 G421E | 421 | Uncertain (★) | +6: 2 other pathogenic changes within 3 positions; G421R at the same position is pathogenic; seen in 6.8e-07 of gnomAD DNA copies; REVEL 0.700 |
Which prediction tools work for Autosomal dominant hyper-IgE syndrome
Observed separation of ClinVar pathogenic / likely pathogenic from benign / likely benign variants (AUROC × 100). This benchmark is not a clinical recommendation.
- AlphaMissense: 97 out of 100
- MetaLR: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- REVEL: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CATVariant: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CADD: 86 out of 100
- MutPred2: 83 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- SIFT: 80 out of 100
- PolyPhen-2: 75 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- phyloP: 69 out of 100
- EVE: 64 out of 100
Same protein, different disease
- STAT3-related early-onset multisystem autoimmune disease also has ClinVar records linked to STAT3 variants; they fall partly in the same places as the Autosomal dominant hyper-IgE syndrome variants (21 pathogenic / likely pathogenic).
Diseases related to Autosomal dominant hyper-IgE syndrome
- Inherited Immunodeficiency Diseases, also linked to DOCK8 and STAT3
- STAT3 gain of function, also linked to STAT3
- Severe combined immunodeficiency, also linked to DOCK8
- STAT3-related early-onset multisystem autoimmune disease, also linked to STAT3
- Crohn disease, also linked to STAT3
- Hyper-IgE syndrome 6, autosomal dominant, with recurrent infections, also linked to STAT3
- Combined immunodeficiency due to DOCK8 deficiency, also linked to DOCK8
Frequently asked questions
Which genes have records linked to Autosomal dominant hyper-IgE syndrome?
This view contains 3 analyzed proteins: STAT3, IL6R, DOCK8. Links come from clinical records and association databases. They do not imply that every listed gene is a validated cause, and missing genes may not yet be analyzed.
What do the clinical classifications mean?
Linked records include 65 pathogenic or likely pathogenic variants, 231 variants of uncertain significance and 35 with conflicting classifications. Labels summarize source records; multi-condition records may not make a separate assertion for this disease. Check the original record and review status.
Does the evidence score change a VUS classification?
No. 3 VUS or conflicting variants reach the likely-pathogenic points range on the computable criteria available here. This is a research prioritization signal, not a clinical classification. Patient, family and other required evidence may be missing.
Can I download the variant evidence?
Download the CSV for all 366 variants in the selected disease scope, including clinical labels, review status, evidence criteria, predictor scores, functional measurements and population frequency where available.
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from eligible public CATVariant analyses of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.
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