# NM_024928.5(STN1):c.894dup (p.Asp299fs)

https://sugi.bio/variant/stn1-p-asp299fs

## Summary

**STN1 p.Asp299fs (c.894dup)** is classified **Conflicting classifications of pathogenicity** in STN1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-02-17). Very rare (popmax 0.00246%, nfe); Associated with brain disorder.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs753230146 · 2 submitters · 1 linked condition · very rare (popmax 0.00246%, nfe)

## For patients & families {#patients}

This is a change in the STN1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to brain disorder.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 259 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [STN1](https://sugi.bio/atlas/gene/STN1/) |
| Protein change (HGVS p.) | p.Asp299fs |
| Coding change (HGVS c.) | c.894dup |
| MANE Select transcript | [NM_024928](https://www.ncbi.nlm.nih.gov/nuccore/NM_024928) |
| dbSNP | [rs753230146](https://www.ncbi.nlm.nih.gov/snp/rs753230146/) |
| Variant type | Duplication |
| Location | chr10:103889126-103889127 (GRCh38) |
| ClinVar | [VCV1346494](https://www.ncbi.nlm.nih.gov/clinvar/variation/1346494/) |

**All HGVS expressions:** `NC_000010.10:g.105648887dup`, `NC_000010.11:g.103889129dup`, `NM_024928.5:c.894dup`

## 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 4.818, GERP 1.49, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.975, pLI 3.0373e-05. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 9 of 10**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 33.0**. 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.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00246%** (nfe) · FAF95 0.00172% · FAF99 0.00149% · 29/1,179,320 in the highest group · 32/1,613,182 alleles overall — very rare (popmax 0.00246%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,818 |
| European (non-Finnish) (grpmax) | 0.00246% | 40,666 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**STN1** population constraint: LOEUF 0.975, pLI 3.0373e-05, missense-Z 1.2158. *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):

- **cerebroretinal microangiopathy with calcifications and cysts 2** — Moderate (AR)

## Protein context {#protein}

Residue **299** lies in the 'winged helix-turn-helix (whth) 2' region; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 87.67, 68% of residues very-high.

**8 experimental structure(s)** (PDB): [4JOI](https://www.rcsb.org/structure/4JOI), [4JQF](https://www.rcsb.org/structure/4JQF), [6W6W](https://www.rcsb.org/structure/6W6W), [7U5C](https://www.rcsb.org/structure/7U5C), [8D0B](https://www.rcsb.org/structure/8D0B), [8D0K](https://www.rcsb.org/structure/8D0K).

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

*Describes the biological roles of STN1 (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:** STN1's established molecular role includes telomeric repeat DNA binding. p.Asp299fs falls in the winged helix-turn-helix (whth) 2 region.


### Pathways affected {#pathways}

STN1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Polymerase switching on the C-strand of the telomere](https://reactome.org/content/detail/R-HSA-174411) | curated |
| [Telomere C-strand synthesis initiation](https://reactome.org/content/detail/R-HSA-174430) | curated |

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

**Molecular function:** telomeric repeat DNA binding, single-stranded telomeric DNA binding.

**Biological process:** telomere maintenance, telomere maintenance via telomere lengthening, negative regulation of telomere maintenance via telomerase.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2022-02-17.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely pathogenic).

**Submission history:** 2 submissions (2019–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-02-17 |
| Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-10-10 |

## Associated conditions {#conditions}

[brain disorder](https://sugi.bio/atlas/disease/brain-disorder/).

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

## Similar variants {#similar}

Related STN1 variant pages (same residue, condition, or type): [STN1 p.Asp299Glu](/variant/stn1-p-asp299glu), [STN1 p.Leu236Pro](/variant/stn1-p-leu236pro), [STN1 c.133+2dup](/variant/stn1-c-133-plus-2dup), [STN1 c.581+2dup](/variant/stn1-c-581-plus-2dup), [STN1 p.Ala27fs](/variant/stn1-p-ala27fs), [STN1 p.Ile271fs](/variant/stn1-p-ile271fs), [STN1 p.Tyr75Ter](/variant/stn1-p-tyr75ter).

### 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 1346494). 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.*