# NM_198282.4(STING1):c.276C>A (p.Pro92=)

https://sugi.bio/variant/sting1-p-pro92

## Summary

**STING1 p.Pro92= (c.276C>A)** is classified **Likely benign** in STING1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-16). Very rare (popmax 0.000424%, nfe); Associated with STING-associated vasculopathy with onset in infancy.

**At a glance:** Likely benign · review: Single submitter · rsID rs544170120 · 1 submitter · 1 linked condition · very rare (popmax 0.000424%, nfe)

## For patients & families {#patients}

This is a change in the STING1 gene that is classified as likely benign — not considered disease-causing, 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.Pro92= |
| Coding change (HGVS c.) | c.276C>A |
| MANE Select transcript | [NM_198282](https://www.ncbi.nlm.nih.gov/nuccore/NM_198282) |
| dbSNP | [rs544170120](https://www.ncbi.nlm.nih.gov/snp/rs544170120/) |
| Variant type | single nucleotide variant |
| Location | chr5:139481294-139481294 (GRCh38) |
| ClinVar | [VCV2977709](https://www.ncbi.nlm.nih.gov/clinvar/variation/2977709/) |

**All HGVS expressions:** `LRG_1308:g.6497C>A`, `LRG_1308t1:c.276C>A`, `NC_000005.10:g.139481294G>T`, `NC_000005.9:g.138860879G>T`, `NG_034249.1:g.6497C>A`, `NG_077832.1:g.371G>T`, `NM_001301738.2:c.276C>A`, `NM_001367258.1:c.-82C>A`, `NM_198282.4:c.276C>A`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 0.055, GERP -2.77, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 2.228**. 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: **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 **0.000424%** (nfe) · FAF95 0.000124% · FAF99 9e-05% · 5/1,179,106 in the highest group · 5/1,459,856 alleles overall — very rare (popmax 0.000424%, 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 **92** lies in the 'mediates interaction with zdhhc1 and zdhhc11' region; an α-helix.

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.Pro92= 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-08-16.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-08-16 |

## 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.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), [STING1 p.Ala262Thr](/variant/sting1-p-ala262thr).

### 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 2026-07-14); 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 2977709). 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.*