# NM_007315.4(STAT1):c.1683C>T (p.Ile561=)

https://sugi.bio/variant/stat1-p-ile561

## Summary

**STAT1 p.Ile561= (c.1683C>T)** is classified **Uncertain significance** in STAT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Very rare (popmax 0.00167%, amr); Associated with Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs886055378 · 1 submitter · 1 linked condition · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the STAT1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency.

*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) | Childhood |
| Diagnostic panels | STAT1 is a diagnostic-grade gene on 4 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017462/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [STAT1](https://sugi.bio/atlas/gene/STAT1/) |
| Protein change (HGVS p.) | p.Ile561= |
| Coding change (HGVS c.) | c.1683C>T |
| MANE Select transcript | [NM_007315](https://www.ncbi.nlm.nih.gov/nuccore/NM_007315) |
| dbSNP | [rs886055378](https://www.ncbi.nlm.nih.gov/snp/rs886055378/) |
| Variant type | single nucleotide variant |
| Location | chr2:190979816-190979816 (GRCh38) |
| ClinVar | [VCV333270](https://www.ncbi.nlm.nih.gov/clinvar/variation/333270/) |

**All HGVS expressions:** `LRG_111:g.39435C>T`, `LRG_111t1:c.1683C>T`, `NC_000002.11:g.191844542G>A`, `NC_000002.12:g.190979816G>A`, `NG_008294.1:g.39435C>T`, `NM_001384880.1:c.1623C>T`, `NM_001384881.1:c.1689C>T`, `NM_001384882.1:c.1677C>T`, `NM_001384883.1:c.1584C>T`, `NM_001384884.1:c.1689C>T`, `NM_001384885.1:c.1524C>T`, `NM_001384886.1:c.1683C>T`, `NM_001384887.1:c.1590C>T`, `NM_001384888.1:c.1653C>T`, `NM_001384889.1:c.1683C>T`, `NM_001384890.1:c.1593C>T`, `NM_001384891.1:c.1719C>T`, `NM_007315.4:c.1683C>T`, `NM_139266.3:c.1683C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.20) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 5.94, GERP 0.002, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 9.889**. 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 deltas (raw): acceptor loss **0.20**, donor loss **0.20**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 50 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.26** (loss), gain 0.00 / loss 0.26. Agrees with SpliceAI. 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 **0.00167%** (amr) · FAF95 2.8e-05% · FAF99 1.1e-05% · 1/59,984 in the highest group · 3/1,613,686 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 59,984 |
| European (non-Finnish) | 0.00017% | 589,901 |

*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}

**STAT1** population constraint: LOEUF 0.271, pLI 1, missense-Z 7.0276; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *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):

- **immunodeficiency 31B** — Definitive (AR)
- **Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency** — Definitive (AD)
- **autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **561** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 87.78, 71% of residues very-high.

**10 experimental structure(s)** (PDB): [1BF5](https://www.rcsb.org/structure/1BF5), [1YVL](https://www.rcsb.org/structure/1YVL), [2KA6](https://www.rcsb.org/structure/2KA6), [3WWT](https://www.rcsb.org/structure/3WWT), [7NUF](https://www.rcsb.org/structure/7NUF), [8D3F](https://www.rcsb.org/structure/8D3F).

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

*Describes the biological roles of STAT1 (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:** STAT1's established molecular role includes RNA polymerase II transcription regulatory region sequence-specific DNA binding. In Reactome, STAT1 is annotated in disease pathway(s) including **SARS-CoV-2 activates/modulates innate and adaptive immune responses**, **Signaling by ALK fusions and activated point mutants**.

**Disease mechanism (Reactome):** STAT1 loss or alteration is curated in [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671), [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}

STAT1 participates in **31 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671) | 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 |
| [Downstream signal transduction](https://reactome.org/content/detail/R-HSA-186763) | curated |
| [ISG15 antiviral mechanism](https://reactome.org/content/detail/R-HSA-1169408) | curated |
| [Interferon alpha/beta signaling](https://reactome.org/content/detail/R-HSA-909733) | 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-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 |
| [Regulation of PD-L1(CD274) transcription](https://reactome.org/content/detail/R-HSA-9909649) | curated |
| [Signaling by SCF-KIT](https://reactome.org/content/detail/R-HSA-1433557) | curated |
| [Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells](https://reactome.org/content/detail/R-HSA-9860927) | curated |
| [Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)](https://reactome.org/content/detail/R-HSA-9942503) | other |
| [Downregulation of SMAD2/3:SMAD4 transcriptional activity](https://reactome.org/content/detail/R-HSA-2173795) | other |
| [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 |
| [Interferon gamma signaling](https://reactome.org/content/detail/R-HSA-877300) | other |
| [NOTCH3 Intracellular Domain Regulates Transcription](https://reactome.org/content/detail/R-HSA-9013508) | electronic |
| [Regulation of IFNA/IFNB signaling](https://reactome.org/content/detail/R-HSA-912694) | other |
| [Regulation of IFNG signaling](https://reactome.org/content/detail/R-HSA-877312) | other |
| [Regulation of RUNX2 expression and activity](https://reactome.org/content/detail/R-HSA-8939902) | 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 |

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

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

**Biological process:** negative regulation of endothelial cell proliferation, positive regulation of defense response to virus by host, regulation of transcription by RNA polymerase II, cell surface receptor signaling pathway via JAK-STAT, negative regulation of angiogenesis, positive regulation of interferon-alpha production.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-01-13.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |

## Associated conditions {#conditions}

[Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency](https://sugi.bio/atlas/disease/mendelian-susceptibility-to-mycobacterial-diseases-due-to-partial-stat1-deficiency/).

**Reported phenotype names (ClinVar):** Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency, IMMUNODEFICIENCY 31A, MYCOBACTERIOSIS, AUTOSOMAL DOMINANT, STAT1 DEFICIENCY, AUTOSOMAL DOMINANT, Immunodeficiency 31a.

## Similar variants {#similar}

Related STAT1 variant pages (same residue, condition, or type): [STAT1 p.Ala267Val](/variant/stat1-p-ala267val), [STAT1 p.Arg274Gln](/variant/stat1-p-arg274gln), [STAT1 p.Arg274Gly](/variant/stat1-p-arg274gly), [STAT1 p.Arg274Trp](/variant/stat1-p-arg274trp), [STAT1 p.Asp171Asn](/variant/stat1-p-asp171asn), [STAT1 p.Asp292Glu](/variant/stat1-p-asp292glu), [STAT1 p.Cys324Arg](/variant/stat1-p-cys324arg), [STAT1 p.Thr288Ile](/variant/stat1-p-thr288ile).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 333270). 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.*