# NM_005419.4(STAT2):c.1034G>A (p.Arg345Lys)

https://sugi.bio/variant/stat2-p-arg345lys

## Summary

**STAT2 p.Arg345Lys (c.1034G>A)** is classified **Uncertain significance** in STAT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-21). AlphaMissense: ambiguous (0.4478); Absent from gnomAD v4.1; Associated with pseudo-TORCH syndrome 3.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2547256124 · 1 submitter · 1 linked condition · AlphaMissense ambiguous · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the STAT2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to pseudo-TORCH syndrome 3.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025516/index) · [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.Arg345Lys |
| Coding change (HGVS c.) | c.1034G>A |
| MANE Select transcript | [NM_005419](https://www.ncbi.nlm.nih.gov/nuccore/NM_005419) |
| dbSNP | [rs2547256124](https://www.ncbi.nlm.nih.gov/snp/rs2547256124/) |
| Variant type | single nucleotide variant |
| Location | chr12:56351098-56351098 (GRCh38) |
| ClinVar | [VCV2671942](https://www.ncbi.nlm.nih.gov/clinvar/variation/2671942/) |

**All HGVS expressions:** `LRG_1329:g.14156G>A`, `LRG_1329t1:c.1034G>A`, `NC_000012.11:g.56744882C>T`, `NC_000012.12:g.56351098C>T`, `NG_046314.1:g.14156G>A`, `NM_001385110.1:c.1022G>A`, `NM_001385111.1:c.1034G>A`, `NM_001385113.1:c.1034G>A`, `NM_001385114.1:c.1034G>A`, `NM_001385115.1:c.1022G>A`, `NM_005419.4:c.1034G>A`, `NM_198332.2:c.1022G>A`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.4478) — no call either way
- REVEL 0.85 (moderately pathogenic-leaning)
- SaProt LLR -8.412 (tolerated)
- → **In-silico consensus:** REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate
- SpliceAI predicts **donor loss** (Δ 0.54) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 5.912, GERP 1.7, phastCons 1 — highly conserved
- CADD: **PHRED 34.0**. 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 0.73** across the covering region of the MANE Select transcript (56,343,392–56,356,571), spanning 13,179 bp. Chi-square p 6.2e-18. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.54**, acceptor gain **0.00**, donor gain **0.01**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.01**.
  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**0.70** (loss), gain 0.02 / loss 0.70. 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: **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}

**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 **345** lies in the 'mediates interaction with usp18' region; the 'interaction with heartland virus nss' region; the 'interaction with sftsv virus nss' region; a β-strand.

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.Arg345Lys 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-09-21.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-09-21 |

## Associated conditions {#conditions}

[pseudo-TORCH syndrome 3](https://sugi.bio/atlas/disease/pseudo-torch-syndrome-3/).

**Reported phenotype names (ClinVar):** Pseudo-TORCH syndrome 3.

## Similar variants {#similar}

Related STAT2 variant pages (same residue, condition, or type): [STAT2 p.Arg667Gln](/variant/stat2-p-arg667gln), [STAT2 p.Ser12Gly](/variant/stat2-p-ser12gly), [STAT2 p.Arg148Gln](/variant/stat2-p-arg148gln), [STAT2 p.Arg374Gln](/variant/stat2-p-arg374gln), [STAT2 p.Arg148Trp](/variant/stat2-p-arg148trp), [STAT2 p.Arg667Ter](/variant/stat2-p-arg667ter), [STAT2 p.Gln274Ter](/variant/stat2-p-gln274ter), [STAT2 p.Ala219Thr](/variant/stat2-p-ala219thr).

### 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 2671942). 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.*