# NM_013352.4(DSE):c.22dup (p.Ala8fs)

https://sugi.bio/variant/dse-p-ala8fs

## Summary

**DSE p.Ala8fs (c.22dup)** is classified **Likely pathogenic** in DSE (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-25). Very rare (popmax 8.47e-05%, nfe).

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2482082556 · 1 submitter · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the DSE gene that is considered likely disease-causing, 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 | [DSE](https://sugi.bio/atlas/gene/DSE/) |
| Protein change (HGVS p.) | p.Ala8fs |
| Coding change (HGVS c.) | c.22dup |
| MANE Select transcript | [NM_013352](https://www.ncbi.nlm.nih.gov/nuccore/NM_013352) |
| dbSNP | [rs2482082556](https://www.ncbi.nlm.nih.gov/snp/rs2482082556/) |
| Variant type | Duplication |
| Location | chr6:116399266-116399267 (GRCh38) |
| ClinVar | [VCV2503345](https://www.ncbi.nlm.nih.gov/clinvar/variation/2503345/) |

**All HGVS expressions:** `LRG_1184:g.150102dup`, `LRG_1184t1:c.22dup`, `NC_000006.11:g.116720435dup`, `NC_000006.12:g.116399272dup`, `NG_033266.4:g.150102dup`, `NG_109094.1:g.422dup`, `NM_001080976.3:c.22dup`, `NM_001322937.2:c.22dup`, `NM_001322938.2:c.22dup`, `NM_001322939.2:c.79dup`, `NM_001322940.2:c.-536dup`, `NM_001322941.2:c.-536dup`, `NM_001322943.2:c.22dup`, `NM_001322944.2:c.22dup`, `NM_001374520.1:c.-879dup`, `NM_001374521.1:c.-566dup`, `NM_001374522.1:c.22dup`, `NM_013352.4:c.22dup`, `NR_136524.2:n.250dup`

## 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 5.958, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.563, pLI 0.062098. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 6**, so the transcript is predicted to undergo NMD.
- 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 **8.47e-05%** (nfe) · 1/1,180,032 in the highest group · 1/1,461,640 alleles overall — very rare (popmax 8.47e-05%, 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}

**DSE** population constraint: LOEUF 0.563, pLI 0.062098, missense-Z 3.703; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *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):

- **Ehlers-Danlos syndrome, musculocontractural type 2** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 86.59, 70% of residues very-high.

**1 experimental structure(s)** (PDB): [6HZN](https://www.rcsb.org/structure/6HZN).

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

*Describes the biological roles of DSE (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:** DSE's established molecular role includes chondroitin-glucuronate 5-epimerase activity.


### Pathways affected {#pathways}

DSE participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [DS-GAG biosynthesis](https://reactome.org/content/detail/R-HSA-2022923) | curated |

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

**Molecular function:** chondroitin-glucuronate 5-epimerase activity.

**Biological process:** dermatan sulfate proteoglycan biosynthetic process.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-11-25.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-11-25 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related DSE variant pages (same residue, condition, or type): [DSE c.671-165dup](/variant/dse-c-671-minus-165dup), [TSPYL1 p.Glu154fs](/variant/tspyl1-p-glu154fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2503345). 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.*