# NM_139276.3(STAT3):c.2307C>G (p.Pro769=)

https://sugi.bio/variant/stat3-p-pro769

## Summary

**STAT3 p.Pro769= (c.2307C>G)** is classified **Likely benign** in STAT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-12-04). Very rare (popmax 0.0011%, sas); Associated with hyper-IgE recurrent infection syndrome 1, autosomal dominant.

**At a glance:** Likely benign · review: Single submitter · rsID rs2081221437 · 1 submitter · 1 linked condition · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the STAT3 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to hyper-IgE recurrent infection syndrome 1, autosomal dominant.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 8 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | STAT3 is a diagnostic-grade gene on 13 Genomics England panels |

**Commonly reported features of Autosomal dominant hyper-IgE syndrome due to STAT3 deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Eczematoid dermatitis — Very frequent (99-80%)
- Skin rash — Very frequent (99-80%)
- Pruritus — Very frequent (99-80%)
- Recurrent respiratory infections — Very frequent (99-80%)
- Recurrent infections — Very frequent (99-80%)
- Increased circulating IgE level — Very frequent (99-80%)
- Generalized abnormality of skin — Very frequent (99-80%)
- Atelectasis — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006800/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [STAT3](https://sugi.bio/atlas/gene/STAT3/) |
| Protein change (HGVS p.) | p.Pro769= |
| Coding change (HGVS c.) | c.2307C>G |
| MANE Select transcript | [NM_139276](https://www.ncbi.nlm.nih.gov/nuccore/NM_139276) |
| dbSNP | [rs2081221437](https://www.ncbi.nlm.nih.gov/snp/rs2081221437/) |
| Variant type | single nucleotide variant |
| Location | chr17:42315751-42315751 (GRCh38) |
| ClinVar | [VCV1658924](https://www.ncbi.nlm.nih.gov/clinvar/variation/1658924/) |

**All HGVS expressions:** `LRG_112:g.77745C>G`, `NC_000017.10:g.40467769G>C`, `NC_000017.11:g.42315751G>C`, `NG_007370.1:g.77745C>G`, `NM_001369512.1:c.2307C>G`, `NM_001369513.1:c.2307C>G`, `NM_001369514.1:c.2304C>G`, `NM_001369516.1:c.2304C>G`, `NM_001369517.1:c.*88C>G`, `NM_001369518.1:c.*88C>G`, `NM_001369519.1:c.*88C>G`, `NM_001369520.1:c.*88C>G`, `NM_001384984.1:c.2223C>G`, `NM_001384985.1:c.2229C>G`, `NM_001384986.1:c.*88C>G`, `NM_001384987.1:c.2286C>G`, `NM_001384988.1:c.2211C>G`, `NM_001384989.1:c.2208C>G`, `NM_001384990.1:c.*88C>G`, `NM_001384991.1:c.2280C>G`, `NM_001384992.1:c.2247C>G`, `NM_001384993.1:c.2295C>G`, `NM_003150.4:c.2304C>G`, `NM_139276.3:c.2307C>G`, `NM_213662.2:c.*88C>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.864, GERP 0.645, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 7.361**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · 1/91,080 in the highest group · 1/1,613,888 alleles overall — very rare (popmax 0.0011%, sas).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**STAT3** population constraint: LOEUF 0.109, pLI 1, missense-Z 7.3843. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **STAT3-related early-onset multisystem autoimmune disease** — Definitive (AD)
- **hyper-IgE recurrent infection syndrome 1, autosomal dominant** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 85.80, 70% of residues very-high.

**6 experimental structure(s)** (PDB): [5AX3](https://www.rcsb.org/structure/5AX3), [5U5S](https://www.rcsb.org/structure/5U5S), [6NJS](https://www.rcsb.org/structure/6NJS), [6NUQ](https://www.rcsb.org/structure/6NUQ), [6QHD](https://www.rcsb.org/structure/6QHD), [6TLC](https://www.rcsb.org/structure/6TLC).

## What this gene does {#gene-function}

*Describes the biological roles of STAT3 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** STAT3's established molecular role includes transcription cis-regulatory region binding. In Reactome, STAT3 is annotated in disease pathway(s) including **Nuclear events stimulated by ALK signaling in cancer**, **Signaling by ALK fusions and activated point mutants**.

**Disease mechanism (Reactome):** STAT3 loss or alteration is curated in [Nuclear events stimulated by ALK signaling in cancer](https://reactome.org/content/detail/R-HSA-9725371), [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370), [Signaling by PDGFRA extracellular domain mutants](https://reactome.org/content/detail/R-HSA-9673770).

### Pathways affected {#pathways}

STAT3 participates in **42 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Nuclear events stimulated by ALK signaling in cancer](https://reactome.org/content/detail/R-HSA-9725371) | curated |
| ⚕ [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370) | curated |
| ⚕ [Signaling by PDGFRA extracellular domain mutants](https://reactome.org/content/detail/R-HSA-9673770) | curated |
| ⚕ [Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants](https://reactome.org/content/detail/R-HSA-9673767) | curated |
| ⚕ [Signaling by cytosolic FGFR1 fusion mutants](https://reactome.org/content/detail/R-HSA-1839117) | curated |
| ⚕ [Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants](https://reactome.org/content/detail/R-HSA-9670439) | curated |
| [BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members](https://reactome.org/content/detail/R-HSA-111453) | curated |
| [Downstream signal transduction](https://reactome.org/content/detail/R-HSA-186763) | curated |
| [Interleukin-10 signaling](https://reactome.org/content/detail/R-HSA-6783783) | curated |
| [Interleukin-15 signaling](https://reactome.org/content/detail/R-HSA-8983432) | curated |
| [Interleukin-20 family signaling](https://reactome.org/content/detail/R-HSA-8854691) | curated |
| [Interleukin-21 signaling](https://reactome.org/content/detail/R-HSA-9020958) | curated |
| [Interleukin-27 signaling](https://reactome.org/content/detail/R-HSA-9020956) | curated |
| [Interleukin-35 Signalling](https://reactome.org/content/detail/R-HSA-8984722) | curated |
| [Interleukin-37 signaling](https://reactome.org/content/detail/R-HSA-9008059) | curated |
| [Interleukin-4 and Interleukin-13 signaling](https://reactome.org/content/detail/R-HSA-6785807) | curated |
| [Interleukin-6 signaling](https://reactome.org/content/detail/R-HSA-1059683) | curated |
| [Interleukin-9 signaling](https://reactome.org/content/detail/R-HSA-8985947) | curated |
| [PKR-mediated signaling](https://reactome.org/content/detail/R-HSA-9833482) | curated |
| [POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation](https://reactome.org/content/detail/R-HSA-2892247) | curated |
| [Regulation of PD-L1(CD274) transcription](https://reactome.org/content/detail/R-HSA-9909649) | curated |
| [STAT3 nuclear events downstream of ALK signaling](https://reactome.org/content/detail/R-HSA-9701898) | curated |
| [Senescence-Associated Secretory Phenotype (SASP)](https://reactome.org/content/detail/R-HSA-2559582) | curated |
| [Signaling by ALK](https://reactome.org/content/detail/R-HSA-201556) | curated |
| [Signaling by SCF-KIT](https://reactome.org/content/detail/R-HSA-1433557) | curated |
| [Transcriptional regulation of pluripotent stem cells](https://reactome.org/content/detail/R-HSA-452723) | curated |
| [Activation of STAT3 by cadherin engagement](https://reactome.org/content/detail/R-HSA-9958825) | electronic |
| [Affinity selection of immunoglobulins](https://reactome.org/content/detail/R-HSA-9938027) | electronic |
| [Association of TriC/CCT with target proteins during biosynthesis](https://reactome.org/content/detail/R-HSA-390471) | electronic |
| [Cytoprotection by HMOX1](https://reactome.org/content/detail/R-HSA-9707564) | electronic |
| [Growth hormone receptor signaling](https://reactome.org/content/detail/R-HSA-982772) | electronic |
| [Inactivation of CSF3 (G-CSF) signaling](https://reactome.org/content/detail/R-HSA-9705462) | electronic |
| [Interleukin-23 signaling](https://reactome.org/content/detail/R-HSA-9020933) | electronic |
| [Interleukin-7 signaling](https://reactome.org/content/detail/R-HSA-1266695) | electronic |
| [MET activates STAT3](https://reactome.org/content/detail/R-HSA-8875791) | electronic |
| [PTK6 Activates STAT3](https://reactome.org/content/detail/R-HSA-8849474) | electronic |
| [Signaling by CSF1 (M-CSF) in myeloid cells](https://reactome.org/content/detail/R-HSA-9680350) | electronic |
| [Signaling by CSF3 (G-CSF)](https://reactome.org/content/detail/R-HSA-9674555) | electronic |
| [Signaling by Leptin](https://reactome.org/content/detail/R-HSA-2586552) | electronic |
| [Signalling to STAT3](https://reactome.org/content/detail/R-HSA-198745) | electronic |
| [Somatic hypermutation of immunoglobulin genes](https://reactome.org/content/detail/R-HSA-9938024) | electronic |
| [Transcriptional regulation of granulopoiesis](https://reactome.org/content/detail/R-HSA-9616222) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** transcription cis-regulatory region binding, RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription factor activity, RNA polymerase II-specific, DNA-binding transcription activator activity, RNA polymerase II-specific, DNA-binding transcription factor activity, RNA binding.

**Biological process:** regulation of DNA-templated transcription, protein import into nucleus, transforming growth factor beta receptor signaling pathway, cell surface receptor signaling pathway via JAK-STAT, negative regulation of autophagy, positive regulation of vascular endothelial growth factor production.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-12-04.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2020-12-04 |

## Associated conditions {#conditions}

[hyper-IgE recurrent infection syndrome 1, autosomal dominant](https://sugi.bio/atlas/disease/hyper-ige-recurrent-infection-syndrome-1-autosomal-dominant/).

**Reported phenotype names (ClinVar):** Hyper-IgE recurrent infection syndrome 1, autosomal dominant, STAT3 gain of function, JOB SYNDROME, Hyper-IgE recurrent infection syndrome 1, HYPER-IgE SYNDROME 1, AUTOSOMAL DOMINANT, WITH RECURRENT INFECTIONS, STAT3 Hyper IgE Syndrome, Job's Syndrome.

## Similar variants {#similar}

Related STAT3 variant pages (same residue, condition, or type): [STAT3 p.Arg152Trp](/variant/stat3-p-arg152trp), [STAT3 p.Arg278Cys](/variant/stat3-p-arg278cys), [STAT3 p.Arg335Trp](/variant/stat3-p-arg335trp), [STAT3 p.Arg382Gln](/variant/stat3-p-arg382gln), [STAT3 p.Arg382Trp](/variant/stat3-p-arg382trp), [STAT3 p.Arg423Gln](/variant/stat3-p-arg423gln), [STAT3 p.Asn466Ser](/variant/stat3-p-asn466ser), [STAT3 p.Asn466Thr](/variant/stat3-p-asn466thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1658924). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*