STAT3 gain of function: genes and variants

Genes linked to STAT3 gain of function

• 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.

  49 disease-causing and 167 uncertain variants in STAT3 are linked to STAT3 gain of function.

Where STAT3 gain of function variants cluster

• STAT3 SH2 (positions 580–670): 17 of 49 disease-causing changes, 2.9× more than its size predicts.

Known disease-causing variants in STAT3 gain of function

Uncertain variants in STAT3 gain of function that look disease-causing

Which prediction tools work for STAT3 gain of function

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 88 out of 100
• REVEL: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 84 out of 100
• PolyPhen-2: 79 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 56 out of 100

Same protein, different disease

• Hyper-IgE recurrent infection syndrome 1, autosomal dominant is also caused by STAT3 variants; they fall in the same places as the STAT3 gain of function variants (65 disease-causing).
• STAT3-related early-onset multisystem autoimmune disease is also caused by STAT3 variants; they fall partly in the same places as the STAT3 gain of function variants (21 disease-causing).

Diseases related to STAT3 gain of function

• Hyper-IgE recurrent infection syndrome 1, autosomal dominant, also linked to STAT3
• STAT3-related early-onset multisystem autoimmune disease, also linked to STAT3
• Inherited Immunodeficiency Diseases, also linked to STAT3
• Hyper-IgE syndrome 6, autosomal dominant, with recurrent infections, also linked to STAT3

Frequently asked questions

Which genes are linked to STAT3 gain of function?

In CATVariant, STAT3 gain of function is linked to 1 analyzed protein: STAT3 (Signal transducer and activator of transcription 3).

How many genetic variants are linked to STAT3 gain of function?

246 variants: 49 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 167 are of uncertain significance or have conflicting reports.

Which uncertain variants in STAT3 gain of function look disease-causing?

2 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example STAT3 R335Q and STAT3 G421E. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for STAT3 gain of function?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.88, based on 8 disease-causing and 25 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis 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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