# NM_004006.3(DMD):c.1956del (p.Asp652fs)

https://sugi.bio/variant/dmd-p-asp652fs

## Summary

**DMD p.Asp652fs (c.1956del)** is classified **Pathogenic/Likely pathogenic** in DMD (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-08-05). No gnomAD frequency available for this variant; Associated with neuromuscular disease caused by qualitative or quantitative defects of dystrophin.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs886043640 · 4 submitters · 4 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DMD gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to neuromuscular disease caused by qualitative or quantitative defects of dystrophin.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 7 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002031/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DMD](https://sugi.bio/atlas/gene/DMD/) |
| Protein change (HGVS p.) | p.Asp652fs |
| Coding change (HGVS c.) | c.1956del |
| MANE Select transcript | [NM_004006](https://www.ncbi.nlm.nih.gov/nuccore/NM_004006) |
| dbSNP | [rs886043640](https://www.ncbi.nlm.nih.gov/snp/rs886043640/) |
| Variant type | Deletion |
| Location | chrX:32565738-32565738 (GRCh38) |
| ClinVar | [VCV287457](https://www.ncbi.nlm.nih.gov/clinvar/variation/287457/) |

**All HGVS expressions:** `LRG_199:g.778872del`, `NC_000023.10:g.32583855del`, `NC_000023.11:g.32565738del`, `NG_012232.1:g.778872del`, `NM_000109.4:c.1932del`, `NM_004006.2:c.1956delT`, `NM_004006.3:c.1956del`, `NM_004009.3:c.1944del`, `NM_004010.3:c.1587del`

## 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 4.954, GERP 1.63, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 16 of 79**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion 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}

**DMD** population constraint: ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **progressive muscular dystrophy** — Definitive (XL)

## Protein context {#protein}


**6 experimental structure(s)** (PDB): [1DXX](https://www.rcsb.org/structure/1DXX), [1EG3](https://www.rcsb.org/structure/1EG3), [1EG4](https://www.rcsb.org/structure/1EG4), [3UUN](https://www.rcsb.org/structure/3UUN), [9D58](https://www.rcsb.org/structure/9D58), [9EC1](https://www.rcsb.org/structure/9EC1).

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

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


### Pathways affected {#pathways}

DMD participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Striated Muscle Contraction](https://reactome.org/content/detail/R-HSA-390522) | curated |
| [Formation of the dystrophin-glycoprotein complex (DGC)](https://reactome.org/content/detail/R-HSA-9913351) | electronic |
| [Non-integrin membrane-ECM interactions](https://reactome.org/content/detail/R-HSA-3000171) | electronic |

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

**Molecular function:** dystroglycan binding, actin binding, structural constituent of muscle, myosin binding, vinculin binding.

**Biological process:** regulation of heart rate, intracellular protein localization, positive regulation of neuron projection development, peptide biosynthetic process, positive regulation of neuron differentiation, cardiac muscle contraction.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-08-05.

**Submitter consensus:** conflicting (2 Likely pathogenic, 2 Pathogenic).

**Submission history:** 4 submissions (2016–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-05-01 |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2016-05-05 |
| Natera, Inc. | Likely pathogenic | no assertion criteria provided | clinical testing | 2017-03-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-08-05 |

## Associated conditions {#conditions}

[neuromuscular disease caused by qualitative or quantitative defects of dystrophin](https://sugi.bio/atlas/disease/neuromuscular-disease-caused-by-qualitative-or-quantitative-defects-of-dystrophin/), [cardiomyopathy](https://sugi.bio/atlas/disease/cardiomyopathy/), [Becker muscular dystrophy](https://sugi.bio/atlas/disease/becker-muscular-dystrophy/), [Duchenne muscular dystrophy](https://sugi.bio/atlas/disease/duchenne-muscular-dystrophy/).

**Reported phenotype names (ClinVar):** Neuromuscular disease caused by qualitative or quantitative defects of dystrophin, not provided, Becker muscular dystrophy, Cardiomyopathy, Duchenne muscular dystrophy, Dystrophin deficiency, Cardiomyopathies, MUSCULAR DYSTROPHY, PSEUDOHYPERTROPHIC PROGRESSIVE, BECKER TYPE, Becker Muscular Dystrophy (BMD), Duchenne Muscular Dystrophy (DMD).

## Similar variants {#similar}

Related DMD variant pages (same residue, condition, or type): [DMD p.Asp652Tyr](/variant/dmd-p-asp652tyr), [DMD c.1813-29_1813-2del](/variant/dmd-c-1813-minus-29-1813-minus-2del), [DMD c.2804-1del](/variant/dmd-c-2804-minus-1del), [DMD c.3433-5_3434del](/variant/dmd-c-3433-minus-5-3434del), [DMD c.4519-2_4523del](/variant/dmd-c-4519-minus-2-4523del), [DMD c.9650-4_9655del](/variant/dmd-c-9650-minus-4-9655del), [DMD p.Ala192fs](/variant/dmd-p-ala192fs), [DMD p.Ala324fs](/variant/dmd-p-ala324fs).

### 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 287457). 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.*