# NM_139276.3(STAT3):c.1566C>T (p.Ile522=)

https://sugi.bio/variant/stat3-p-ile522

## Summary

**STAT3 p.Ile522= (c.1566C>T)** is classified **Likely benign** in STAT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-28). Ultra-rare (popmax 0.0147%, afr); Associated with STAT3 gain of function.

**At a glance:** Likely benign · review: Single submitter · rsID rs1044069148 · 1 submitter · 2 linked conditions · ultra-rare (popmax 0.0147%, afr)

## 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 STAT3 gain of function.

*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.*

**Support & next steps:** [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.Ile522= |
| Coding change (HGVS c.) | c.1566C>T |
| MANE Select transcript | [NM_139276](https://www.ncbi.nlm.nih.gov/nuccore/NM_139276) |
| dbSNP | [rs1044069148](https://www.ncbi.nlm.nih.gov/snp/rs1044069148/) |
| Variant type | single nucleotide variant |
| Location | chr17:42324745-42324745 (GRCh38) |
| ClinVar | [VCV1640953](https://www.ncbi.nlm.nih.gov/clinvar/variation/1640953/) |

**All HGVS expressions:** `LRG_112:g.68751C>T`, `NC_000017.10:g.40476763G>A`, `NC_000017.11:g.42324745G>A`, `NG_007370.1:g.68751C>T`, `NM_001369512.1:c.1566C>T`, `NM_001369513.1:c.1566C>T`, `NM_001369514.1:c.1566C>T`, `NM_001369516.1:c.1566C>T`, `NM_001369517.1:c.1566C>T`, `NM_001369518.1:c.1566C>T`, `NM_001369519.1:c.1566C>T`, `NM_001369520.1:c.1566C>T`, `NM_001384984.1:c.1482C>T`, `NM_001384985.1:c.1488C>T`, `NM_001384986.1:c.1581C>T`, `NM_001384987.1:c.1545C>T`, `NM_001384988.1:c.1566C>T`, `NM_001384989.1:c.1470C>T`, `NM_001384990.1:c.1581C>T`, `NM_001384991.1:c.1566C>T`, `NM_001384992.1:c.1506C>T`, `NM_001384993.1:c.1566C>T`, `NM_003150.4:c.1566C>T`, `NM_139276.3:c.1566C>T`, `NM_213662.2:c.1566C>T`

## 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 -0.638, GERP -3.74 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 9.274**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.35 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Pangolin: Δ**0.22** (loss), gain 0.01 / loss 0.22. SpliceAI below 0.2. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0147%** (afr) · FAF95 0.00816% · FAF99 0.00633% · 11/74,890 in the highest group · 32/1,614,000 alleles overall — ultra-rare (popmax 0.0147%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0147% | 6,808 |
| European (non-Finnish) | 0.00178% | 56,192 |

*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}

Residue **522** lies in an α-helix.

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 2026-01-28.

**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 | 2026-01-28 |

## Associated conditions {#conditions}

[STAT3 gain of function](https://sugi.bio/atlas/disease/stat3-gain-of-function/), [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):** STAT3 gain of function, Hyper-IgE recurrent infection syndrome 1, autosomal dominant, Job's Syndrome, JOB SYNDROME, STAT3 Hyper IgE Syndrome, Hyper-IgE recurrent infection syndrome 1, HYPER-IgE SYNDROME 1, AUTOSOMAL DOMINANT, WITH RECURRENT INFECTIONS.

## 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 1640953). 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.*