# NM_005419.4(STAT2):c.1045_1046insCA (p.Arg349fs)

https://sugi.bio/variant/stat2-p-arg349fs

## Summary

**STAT2 p.Arg349fs (c.1045_1046insCA)** is classified **Pathogenic** in STAT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-09-01). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1878353719 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the STAT2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter.

*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 | [STAT2](https://sugi.bio/atlas/gene/STAT2/) |
| Protein change (HGVS p.) | p.Arg349fs |
| Coding change (HGVS c.) | c.1045_1046insCA |
| MANE Select transcript | [NM_005419](https://www.ncbi.nlm.nih.gov/nuccore/NM_005419) |
| dbSNP | [rs1878353719](https://www.ncbi.nlm.nih.gov/snp/rs1878353719/) |
| Variant type | Insertion |
| Location | chr12:56350877-56350878 (GRCh38) |
| ClinVar | [VCV872172](https://www.ncbi.nlm.nih.gov/clinvar/variation/872172/) |

**All HGVS expressions:** `LRG_1329:g.14376_14377insCA`, `LRG_1329t1:c.1045_1046insCA`, `NC_000012.11:g.56744662_56744663insGT`, `NC_000012.12:g.56350878_56350879insGT`, `NG_046314.1:g.14376_14377insCA`, `NM_005419.4:c.1045_1046insCA`, `NM_198332.2:c.1033_1034insCA`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 2.186, GERP 1.37, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.497, pLI 0.80697. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 11 of 24**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no insertion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**STAT2** population constraint: LOEUF 0.497, pLI 0.80697, missense-Z 3.6539. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **349** lies in the 'mediates interaction with usp18' region; the 'interaction with heartland virus nss' region; the 'interaction with sftsv virus nss' region.

AlphaFold model confidence (whole protein): pLDDT 78.45, 49% of residues very-high.

**6 experimental structure(s)** (PDB): [2KA4](https://www.rcsb.org/structure/2KA4), [6UX2](https://www.rcsb.org/structure/6UX2), [6WCZ](https://www.rcsb.org/structure/6WCZ), [8T12](https://www.rcsb.org/structure/8T12), [8T13](https://www.rcsb.org/structure/8T13), [9ZFO](https://www.rcsb.org/structure/9ZFO).

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

*Describes the biological roles of STAT2 (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:** STAT2's established molecular role includes DNA-binding transcription factor activity, RNA polymerase II-specific. p.Arg349fs falls in the mediates interaction with usp18 region. In Reactome, STAT2 is annotated in disease pathway(s) including **Dengue virus activates/modulates innate and adaptive immune responses**, **Evasion by RSV of host interferon responses**.

**Disease mechanism (Reactome):** STAT2 loss or alteration is curated in [Dengue virus activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9920588), [Evasion by RSV of host interferon responses](https://reactome.org/content/detail/R-HSA-9833109), [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191).

### Pathways affected {#pathways}

STAT2 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue virus activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9920588) | curated |
| ⚕ [Evasion by RSV of host interferon responses](https://reactome.org/content/detail/R-HSA-9833109) | curated |
| ⚕ [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191) | curated |
| ⚕ [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671) | 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 |
| [Regulation of IFNA/IFNB signaling](https://reactome.org/content/detail/R-HSA-912694) | electronic |

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

**Molecular function:** DNA-binding transcription factor activity, RNA polymerase II-specific, DNA-binding transcription factor activity, identical protein binding, ubiquitin-like protein ligase binding.

**Biological process:** regulation of protein phosphorylation, regulation of transcription by RNA polymerase II, cell surface receptor signaling pathway via JAK-STAT, positive regulation of transcription by RNA polymerase II, defense response to virus, type I interferon-mediated signaling pathway.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-09-01.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2018-09-01 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related STAT2 variant pages (same residue, condition, or type): [STAT2 p.Met58fs](/variant/stat2-p-met58fs).

### 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 872172). 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.*