# NM_001723.7(DST):c.108T>C (p.Cys36=)

https://sugi.bio/variant/dst-p-cys36

## Summary

**DST p.Cys36= (c.108T>C)** is classified **Likely benign** in DST (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). Very rare (popmax 0.00449%, nfe); Associated with hereditary sensory and autonomic neuropathy type 6.

**At a glance:** Likely benign · review: Single submitter · rsID rs766639572 · 1 submitter · 2 linked conditions · very rare (popmax 0.00449%, nfe)

## For patients & families {#patients}

This is a change in the DST gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, 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.Cys36= |
| Coding change (HGVS c.) | c.108T>C |
| MANE Select transcript | [NM_001374736](https://www.ncbi.nlm.nih.gov/nuccore/NM_001374736) (variant reported on NM_001723) |
| dbSNP | [rs766639572](https://www.ncbi.nlm.nih.gov/snp/rs766639572/) |
| Variant type | single nucleotide variant |
| Location | chr6:56642681-56642681 (GRCh38) |
| ClinVar | [VCV1152202](https://www.ncbi.nlm.nih.gov/clinvar/variation/1152202/) |

**All HGVS expressions:** `NC_000006.11:g.56507479A>G`, `NC_000006.12:g.56642681A>G`, `NG_029322.2:g.316948T>C`, `NM_001144769.5:c.1680-178T>C`, `NM_001144770.2:c.1266-178T>C`, `NM_001374722.1:c.1779-178T>C`, `NM_001374729.1:c.1146-178T>C`, `NM_001374730.1:c.1146-178T>C`, `NM_001374734.1:c.1806-178T>C`, `NM_001374736.1:c.1779-178T>C`, `NM_001386100.1:c.1146-178T>C`, `NM_001723.7:c.108T>C`, `NM_015548.5:c.108T>C`, `NM_183380.4:c.1146-178T>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 1.99, GERP -3.92, phastCons 1 — weakly conserved position
- CADD: **PHRED 12.69**. 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 (A>T, Δ0.27 acceptor 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 **0.00449%** (nfe) · FAF95 0.0035% · FAF99 0.00318% · 53/1,180,024 in the highest group · 58/1,614,070 alleles overall — very rare (popmax 0.00449%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,498 |
| European (non-Finnish) (grpmax) | 0.00449% | 22,265 |

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}

**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}

Residue **36** lies in the calponin-homology (ch) 1 domain; the 'actin-binding' region.

**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. p.Cys36= falls in the calponin-homology (ch) 1 domain.


### 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 2025-08-13.

**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 | 2025-08-13 |

## 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, HSAN VI, Neuropathy, hereditary sensory and autonomic, type VI, Epidermolysis bullosa simplex due to BP230 deficiency, Epidermolysis bullosa simplex, autosomal recessive 2.

## Similar variants {#similar}

Related DST variant pages (same residue, condition, or type): [DST p.Cys36Trp](/variant/dst-p-cys36trp), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 1152202). 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.*