# NM_001374736.1(DST):c.13191G>C (p.Val4397=)

https://sugi.bio/variant/dst-p-val4397

## Summary

**DST p.Val4397= (c.13191G>C)** is classified **Likely benign** in DST (ClinVar, Single submitter, 2 submitters; last evaluated 2024-04-26). Ultra-rare (popmax 0.056%, afr); Associated with hereditary sensory and autonomic neuropathy type 6.

**At a glance:** Likely benign · review: Single submitter · rsID rs371033457 · 2 submitters · 2 linked conditions · ultra-rare (popmax 0.056%, afr)

## For patients & families {#patients}

This is a change in the DST gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to hereditary sensory and autonomic neuropathy type 6.

*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 recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | DST is a diagnostic-grade gene on 8 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012987/index) · [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.Val4397= |
| Coding change (HGVS c.) | c.13191G>C |
| MANE Select transcript | [NM_001374736](https://www.ncbi.nlm.nih.gov/nuccore/NM_001374736) |
| dbSNP | [rs371033457](https://www.ncbi.nlm.nih.gov/snp/rs371033457/) |
| Variant type | single nucleotide variant |
| Location | chr6:56573724-56573724 (GRCh38) |
| ClinVar | [VCV1099054](https://www.ncbi.nlm.nih.gov/clinvar/variation/1099054/) |

**All HGVS expressions:** `NC_000006.11:g.56438522C>G`, `NC_000006.12:g.56573724C>G`, `NG_029322.2:g.385905G>C`, `NM_001144769.2:c.6834G>C`, `NM_001144769.5:c.6834G>C`, `NM_001144770.2:c.6420G>C`, `NM_001374722.1:c.13191G>C`, `NM_001374729.1:c.12558G>C`, `NM_001374730.1:c.6300G>C`, `NM_001374734.1:c.13218G>C`, `NM_001374736.1:c.13191G>C`, `NM_001386100.1:c.6300G>C`, `NM_015548.5:c.5322G>C`, `NM_183380.4:c.6300G>C`

## 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 2.249, GERP 0.029, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 6.554**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.38 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.056%** (afr) · FAF95 0.0425% · FAF99 0.0378% · 42/75,012 in the highest group · 51/1,613,612 alleles overall — ultra-rare (popmax 0.056%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.056% | 1,786 |
| Admixed American | 0.01% | 9,994 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,239 |
| European (non-Finnish) | 8.48e-05% | 1,179,668 |

*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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-26.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2019–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-02-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-04-26 |

## Associated conditions {#conditions}

[hereditary sensory and autonomic neuropathy type 6](https://sugi.bio/atlas/disease/hereditary-sensory-and-autonomic-neuropathy-type-6/), [epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency](https://sugi.bio/atlas/disease/epidermolysis-bullosa-simplex-3-localized-or-generalized-intermediate-with-bp230-deficiency/).

**Reported phenotype names (ClinVar):** Hereditary sensory and autonomic neuropathy type 6, Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency, DST-related disorder, Neuropathy, hereditary sensory and autonomic, type VI, HSAN VI, Epidermolysis bullosa simplex, autosomal recessive 2, Epidermolysis bullosa simplex due to BP230 deficiency, DST-related condition, DST-related disorders.

## Similar variants {#similar}

Related DST variant pages (same residue, condition, or type): [DST c.22959+1G>A](/variant/dst-c-22959-plus-1g-a), [DST p.Arg1512Ter](/variant/dst-p-arg1512ter), [DST p.Arg1696Ter](/variant/dst-p-arg1696ter), [DST p.Arg22Ter](/variant/dst-p-arg22ter), [DST p.Arg7329Ter](/variant/dst-p-arg7329ter), [DST p.Cys1828Ter](/variant/dst-p-cys1828ter), [DST p.Gln1124Ter](/variant/dst-p-gln1124ter), [DST p.Gln1366Ter](/variant/dst-p-gln1366ter).

### 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 1099054). 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.*