# NM_139276.3(STAT3):c.979C>T (p.Pro327Ser)

https://sugi.bio/variant/stat3-p-pro327ser

## Summary

**STAT3 p.Pro327Ser (c.979C>T)** is classified **Uncertain significance** in STAT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-15). AlphaMissense: likely pathogenic (0.9992); Absent from gnomAD v4.1; Associated with STAT3 gain of function.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs759527569 · 1 submitter · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the STAT3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Pro327Ser |
| Coding change (HGVS c.) | c.979C>T |
| MANE Select transcript | [NM_139276](https://www.ncbi.nlm.nih.gov/nuccore/NM_139276) |
| dbSNP | [rs759527569](https://www.ncbi.nlm.nih.gov/snp/rs759527569/) |
| Variant type | single nucleotide variant |
| Location | chr17:42333743-42333743 (GRCh38) |
| ClinVar | [VCV2953919](https://www.ncbi.nlm.nih.gov/clinvar/variation/2953919/) |

**All HGVS expressions:** `LRG_112:g.59753C>T`, `LRG_112t1:c.979C>T`, `NC_000017.10:g.40485761G>A`, `NC_000017.11:g.42333743G>A`, `NG_007370.1:g.59753C>T`, `NM_001369512.1:c.979C>T`, `NM_001369513.1:c.979C>T`, `NM_001369514.1:c.979C>T`, `NM_001369516.1:c.979C>T`, `NM_001369517.1:c.979C>T`, `NM_001369518.1:c.979C>T`, `NM_001369519.1:c.979C>T`, `NM_001369520.1:c.979C>T`, `NM_001384984.1:c.979C>T`, `NM_001384985.1:c.901C>T`, `NM_001384986.1:c.979C>T`, `NM_001384987.1:c.979C>T`, `NM_001384988.1:c.979C>T`, `NM_001384989.1:c.883C>T`, `NM_001384990.1:c.979C>T`, `NM_001384991.1:c.979C>T`, `NM_001384992.1:c.979C>T`, `NM_001384993.1:c.979C>T`, `NM_003150.4:c.979C>T`, `NM_139276.3:c.979C>T`, `NM_213662.2:c.979C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9992)
- REVEL 0.847 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -7.97 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 11.831, GERP 1.72, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 3%** most-pathogenic-predicted substitutions in STAT3 (of 4,517 modeled).
- CADD: **PHRED 28.6**. 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.*
- Regional missense constraint: **o/e 0.39** across the covering region of the MANE Select transcript (42,323,088–42,348,516), spanning 25,428 bp. Chi-square p 2.4e-61. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **327** lies in a β-strand.

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-11-15.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-11-15 |

## 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, STAT3 Hyper IgE Syndrome, Hyper-IgE recurrent infection syndrome 1, JOB SYNDROME, HYPER-IgE SYNDROME 1, AUTOSOMAL DOMINANT, WITH RECURRENT INFECTIONS, Job's Syndrome.

## Similar variants {#similar}

Related STAT3 variant pages (same residue, condition, or type): [STAT3 p.Pro327=](/variant/stat3-p-pro327), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2953919). 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.*