# NM_001374736.1(DST):c.20987_20988dup (p.Asp6997fs)

https://sugi.bio/variant/dst-p-asp6997fs

## Summary

**DST p.Asp6997fs (c.20987_20988dup)** is classified **Pathogenic** in DST (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-01). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2533826804 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DST gene that is reported as disease-causing, but on limited review, 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 | [DST](https://sugi.bio/atlas/gene/DST/) |
| Protein change (HGVS p.) | p.Asp6997fs |
| Coding change (HGVS c.) | c.20987_20988dup |
| MANE Select transcript | [NM_001374736](https://www.ncbi.nlm.nih.gov/nuccore/NM_001374736) |
| dbSNP | [rs2533826804](https://www.ncbi.nlm.nih.gov/snp/rs2533826804/) |
| Variant type | Duplication |
| Location | chr6:56487162-56487163 (GRCh38) |
| ClinVar | [VCV2499012](https://www.ncbi.nlm.nih.gov/clinvar/variation/2499012/) |

**All HGVS expressions:** `NC_000006.11:g.56351961_56351962dup`, `NC_000006.12:g.56487163_56487164dup`, `NG_029322.2:g.472465_472466dup`, `NM_001144769.5:c.14630_14631dup`, `NM_001144770.2:c.14216_14217dup`, `NM_001374722.1:c.20987_20988dup`, `NM_001374729.1:c.20027_20028dup`, `NM_001374730.1:c.13769_13770dup`, `NM_001374734.1:c.21014_21015dup`, `NM_001374736.1:c.20987_20988dup`, `NM_001386100.1:c.14096_14097dup`, `NM_015548.5:c.13118_13119dup`, `NM_183380.4:c.14096_14097dup`

## 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 0.846, GERP -3.09, phastCons 0.326 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.297, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 87 of 104**, 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: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**DST** population constraint: LOEUF 0.297, pLI 1, missense-Z 3.9467. *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):

- **hereditary sensory and autonomic neuropathy type 6** — Definitive (AR)

## Protein context {#protein}


**2 experimental structure(s)** (PDB): [3GJO](https://www.rcsb.org/structure/3GJO), [7OLG](https://www.rcsb.org/structure/7OLG).

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

*Describes the biological roles of DST (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:** DST's established molecular role includes integrin binding.


### Pathways affected {#pathways}

DST participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RHOU GTPase cycle](https://reactome.org/content/detail/R-HSA-9013420) | curated |
| [RHOV GTPase cycle](https://reactome.org/content/detail/R-HSA-9013424) | curated |
| [RND1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9696273) | curated |
| [RND2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9696270) | curated |
| [RND3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9696264) | curated |
| [Type I hemidesmosome assembly](https://reactome.org/content/detail/R-HSA-446107) | curated |
| [Assembly of collagen fibrils and other multimeric structures](https://reactome.org/content/detail/R-HSA-2022090) | other |

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

**Molecular function:** integrin binding, protein homodimerization activity, microtubule plus-end binding.

**Biological process:** microtubule cytoskeleton organization, cytoskeleton organization, response to wounding, maintenance of cell polarity, hemidesmosome assembly, intermediate filament cytoskeleton organization.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-03-01.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2023-03-01 |

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

## Similar variants {#similar}

Related DST variant pages (same residue, condition, or type): [DST p.Thr1727fs](/variant/dst-p-thr1727fs), [DST p.Tyr1196fs](/variant/dst-p-tyr1196fs), [DST p.Phe1022dup](/variant/dst-p-phe1022dup), [DST p.Ala1361fs](/variant/dst-p-ala1361fs), [DST p.Arg6274fs](/variant/dst-p-arg6274fs), [DST p.Asn2130Ter](/variant/dst-p-asn2130ter), [DST p.Asn5081fs](/variant/dst-p-asn5081fs), [DST p.Gln1818fs](/variant/dst-p-gln1818fs).

### 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 2499012). 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.*