# NM_013352.4(DSE):c.406C>T (p.Gln136Ter)

https://sugi.bio/variant/dse-p-gln136ter

## Summary

**DSE p.Gln136Ter (c.406C>T)** is classified **Pathogenic** in DSE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-04). Very rare (popmax 8.48e-05%, nfe); Associated with Ehlers-Danlos syndrome, musculocontractural type 2.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the DSE gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Ehlers-Danlos syndrome, musculocontractural type 2.

*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 | DSE is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Musculocontractural Ehlers-Danlos syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Cryptorchidism — Very frequent (99-80%)
- Narrow mouth — Very frequent (99-80%)
- High palate — Very frequent (99-80%)
- Thin upper lip vermilion — Very frequent (99-80%)
- Large fontanelles — Very frequent (99-80%)
- Hypertelorism — Very frequent (99-80%)
- Long philtrum — Very frequent (99-80%)
- Macrotia — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015982/index) · [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.Gln136Ter |
| Coding change (HGVS c.) | c.406C>T |
| MANE Select transcript | [NM_013352](https://www.ncbi.nlm.nih.gov/nuccore/NM_013352) |
| Variant type | single nucleotide variant |
| Location | chr6:116399656-116399656 (GRCh38) |
| ClinVar | [VCV4807721](https://www.ncbi.nlm.nih.gov/clinvar/variation/4807721/) |

**All HGVS expressions:** `LRG_1184:g.150486C>T`, `LRG_1184t1:c.406C>T`, `NC_000006.11:g.116720819C>T`, `NC_000006.12:g.116399656C>T`, `NG_033266.4:g.150486C>T`, `NG_109095.1:g.305C>T`, `NM_001080976.3:c.406C>T`, `NM_001322937.2:c.406C>T`, `NM_001322938.2:c.406C>T`, `NM_001322939.2:c.463C>T`, `NM_001322940.2:c.-152C>T`, `NM_001322941.2:c.-152C>T`, `NM_001322943.2:c.406C>T`, `NM_001322944.2:c.406C>T`, `NM_001374520.1:c.-495C>T`, `NM_001374521.1:c.-182C>T`, `NM_001374522.1:c.406C>T`, `NM_013352.4:c.406C>T`, `NR_136524.2:n.634C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.23) — consistent with the pathogenic call
- Conservation: phyloP 7.683, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — 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.
- CADD: **PHRED 37.0**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.23**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 6 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.20** (loss), gain 0.08 / loss 0.20. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,178,906 in the highest group · 1/1,460,266 alleles overall — very rare (popmax 8.48e-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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-04.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-04 |

## Associated conditions {#conditions}

[Ehlers-Danlos syndrome, musculocontractural type 2](https://sugi.bio/atlas/disease/ehlers-danlos-syndrome-musculocontractural-type-2/).

**Reported phenotype names (ClinVar):** Ehlers-Danlos syndrome, musculocontractural type 2.

## Similar variants {#similar}

Related DSE variant pages (same residue, condition, or type): [DSE c.416+1G>A](/variant/dse-c-416-plus-1g-a), [DSE p.Ala122Thr](/variant/dse-p-ala122thr), [DSE p.Ala135Val](/variant/dse-p-ala135val), [DSE p.Ala408Thr](/variant/dse-p-ala408thr), [DSE p.Ala54Val](/variant/dse-p-ala54val), [DSE p.Ala584Val](/variant/dse-p-ala584val), [DSE p.Ala688Val](/variant/dse-p-ala688val), [DSE p.Ala710Val](/variant/dse-p-ala710val).

### 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 4807721). 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.*