# NM_198282.4(STING1):c.4C>T (p.Pro2Ser)

https://sugi.bio/variant/sting1-p-pro2ser

## Summary

**STING1 p.Pro2Ser (c.4C>T)** is classified **Uncertain significance** in STING1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-13). AlphaMissense: likely benign (0.0856); Very rare (popmax 0.00437%, nfe); Associated with STING-associated vasculopathy with onset in infancy.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1223377482 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00437%, nfe)

## For patients & families {#patients}

This is a change in the STING1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to STING-associated vasculopathy with onset in infancy.

*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) | Infancy |
| Prevalence | <1 / 1 000 000 (Worldwide) |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | STING1 is a diagnostic-grade gene on 6 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012357/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [STING1](https://sugi.bio/atlas/gene/STING1/) |
| Protein change (HGVS p.) | p.Pro2Ser |
| Coding change (HGVS c.) | c.4C>T |
| MANE Select transcript | [NM_198282](https://www.ncbi.nlm.nih.gov/nuccore/NM_198282) |
| dbSNP | [rs1223377482](https://www.ncbi.nlm.nih.gov/snp/rs1223377482/) |
| Variant type | single nucleotide variant |
| Location | chr5:139481701-139481701 (GRCh38) |
| ClinVar | [VCV948262](https://www.ncbi.nlm.nih.gov/clinvar/variation/948262/) |

**All HGVS expressions:** `LRG_1308:g.6090C>T`, `LRG_1308t1:c.4C>T`, `NC_000005.10:g.139481701G>A`, `NC_000005.9:g.138861286G>A`, `NG_034249.1:g.6090C>T`, `NM_001301738.2:c.4C>T`, `NM_001367258.1:c.-130-359C>T`, `NM_198282.4:c.4C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0856)
- REVEL 0.025 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.361 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.862, GERP -3.47, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 9.879**. 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 0.77** across the covering region of the MANE Select transcript (139,476,264–139,481,704), spanning 5,440 bp. Chi-square p 3e-07. 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 (gnomAD v4.1): grpmax **0.00437%** (nfe) · FAF95 0.00338% · FAF99 0.00305% · 51/1,166,556 in the highest group · 51/1,596,158 alleles overall — very rare (popmax 0.00437%, nfe).

*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}

**STING1** population constraint: LOEUF 0.846, pLI 0.0014813, missense-Z 2.1644. *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 **2** lies in the 'mediates interaction with zdhhc1 and zdhhc11' region.

AlphaFold model confidence (whole protein): pLDDT 84.13, 52% of residues very-high.

**125 experimental structure(s)** (PDB): [4EF4](https://www.rcsb.org/structure/4EF4), [4EF5](https://www.rcsb.org/structure/4EF5), [4EMT](https://www.rcsb.org/structure/4EMT), [4EMU](https://www.rcsb.org/structure/4EMU), [4F5D](https://www.rcsb.org/structure/4F5D), [4F5E](https://www.rcsb.org/structure/4F5E) — incl. mutant structure 6XF4.

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

*Describes the biological roles of STING1 (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:** STING1's established molecular role includes transcription coactivator activity. p.Pro2Ser falls in the mediates interaction with zdhhc1 and zdhhc11 region. In Reactome, STING1 is annotated in disease pathway(s) including **Dengue virus activates/modulates innate and adaptive immune responses**, **SARS-CoV-1 activates/modulates innate immune responses**.

**Disease mechanism (Reactome):** STING1 loss or alteration is curated in [Dengue virus activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9920588), [SARS-CoV-1 activates/modulates innate immune responses](https://reactome.org/content/detail/R-HSA-9692916), [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671).

### Pathways affected {#pathways}

STING1 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue virus activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9920588) | other |
| ⚕ [SARS-CoV-1 activates/modulates innate immune responses](https://reactome.org/content/detail/R-HSA-9692916) | other |
| ⚕ [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671) | other |
| [IRF3-mediated induction of type I IFN](https://reactome.org/content/detail/R-HSA-3270619) | other |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | other |
| [Regulation of innate immune responses to cytosolic DNA](https://reactome.org/content/detail/R-HSA-3134975) | other |
| [STAT6-mediated induction of chemokines](https://reactome.org/content/detail/R-HSA-3249367) | other |
| [STING mediated induction of host immune responses](https://reactome.org/content/detail/R-HSA-1834941) | other |

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

**Molecular function:** transcription coactivator activity, proton channel activity, protein kinase binding, cyclic-di-GMP binding, signaling adaptor activity, identical protein binding.

**Biological process:** autophagosome assembly, activation of innate immune response, pattern recognition receptor signaling pathway, positive regulation of defense response to virus by host, cytoplasmic pattern recognition receptor signaling pathway, positive regulation of macroautophagy.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-13.

**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 | 2025-01-13 |

## Associated conditions {#conditions}

[STING-associated vasculopathy with onset in infancy](https://sugi.bio/atlas/disease/sting-associated-vasculopathy-with-onset-in-infancy/).

**Reported phenotype names (ClinVar):** STING-associated vasculopathy with onset in infancy, Sting-associated vasculopathy, infantile-onset.

## Similar variants {#similar}

Related STING1 variant pages (same residue, condition, or type): [STING1 p.Pro2Leu](/variant/sting1-p-pro2leu), [STING1 p.Arg281Gln](/variant/sting1-p-arg281gln), [STING1 p.Arg284Ser](/variant/sting1-p-arg284ser), [STING1 p.Val155Met](/variant/sting1-p-val155met), [STING1 c.946+1G>T](/variant/sting1-c-946-plus-1g-t), [STING1 p.Ala22Asp](/variant/sting1-p-ala22asp), [STING1 p.Ala233Thr](/variant/sting1-p-ala233thr), [STING1 p.Ala254Val](/variant/sting1-p-ala254val).

### 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 948262). 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.*