# NM_004006.3(DMD):c.88del (p.Ser30fs)

https://sugi.bio/variant/dmd-p-ser30fs

## Summary

**DMD p.Ser30fs (c.88del)** is classified **Pathogenic** in DMD (ClinVar, Single submitter, 2 submitters; last evaluated 2022-12-02). No gnomAD frequency available for this variant; Associated with Duchenne muscular dystrophy.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2093885666 · 2 submitters · 3 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DMD gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to Duchenne muscular dystrophy.

*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) | X-linked recessive |
| Age of onset (of this condition) | Childhood |
| Prevalence | 1-9 / 100 000 (Worldwide) |
| Clinical trials | 373 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DMD is a diagnostic-grade gene on 17 Genomics England panels |

**Commonly reported features of Duchenne muscular dystrophy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Delayed speech and language development — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Motor delay — Very frequent (99-80%)
- Specific learning disability — Very frequent (99-80%)
- Flexion contracture — Very frequent (99-80%)
- Cardiomyopathy — Very frequent (99-80%)
- Respiratory insufficiency — Very frequent (99-80%)
- Waddling gait — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006291/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.Ser30fs |
| Coding change (HGVS c.) | c.88del |
| MANE Select transcript | [NM_004006](https://www.ncbi.nlm.nih.gov/nuccore/NM_004006) |
| dbSNP | [rs2093885666](https://www.ncbi.nlm.nih.gov/snp/rs2093885666/) |
| Variant type | Deletion |
| Location | chrX:33020144-33020144 (GRCh38) |
| ClinVar | [VCV948835](https://www.ncbi.nlm.nih.gov/clinvar/variation/948835/) |

**All HGVS expressions:** `LRG_199:g.324466del`, `LRG_199t1:c.88del`, `NC_000023.10:g.33038264del`, `NC_000023.11:g.33020147del`, `NG_012232.1:g.324466del`, `NM_000109.4:c.64del`, `NM_004006.3:c.88del`, `NM_004009.3:c.76del`, `NM_004010.3:c.-282del`

## 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 11.552, GERP 1.85, 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 2 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, triplosensitivity 0 (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):

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

## Protein context {#protein}

Residue **30** lies in the calponin-homology (ch) 1 domain; an α-helix; the 'actin-binding' region.

**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. p.Ser30fs falls in the calponin-homology (ch) 1 domain.


### 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** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-12-02.

**Submitter consensus:** conflicting (1 not provided, 1 Pathogenic).

**Submission history:** 2 submissions (2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GenomeConnect - Invitae Patient Insights Network | not provided | no classification provided | phenotyping only |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-12-02 |

## Associated conditions {#conditions}

[Duchenne muscular dystrophy](https://sugi.bio/atlas/disease/duchenne-muscular-dystrophy/), [Becker muscular dystrophy](https://sugi.bio/atlas/disease/becker-muscular-dystrophy/), [dilated cardiomyopathy 3B](https://sugi.bio/atlas/disease/dilated-cardiomyopathy-3b/).

**Reported phenotype names (ClinVar):** Duchenne muscular dystrophy, Becker muscular dystrophy, Dilated cardiomyopathy 3B, MUSCULAR DYSTROPHY, PSEUDOHYPERTROPHIC PROGRESSIVE, DUCHENNE TYPE, Duchenne Muscular Dystrophy (DMD), MUSCULAR DYSTROPHY, PSEUDOHYPERTROPHIC PROGRESSIVE, BECKER TYPE, Becker Muscular Dystrophy (BMD), CMD3B: DMD-Related Dilated Cardiomyopathy, CARDIOMYOPATHY, DILATED, X-LINKED, DMD-Associated Dilated Cardiomyopathy.

## Similar variants {#similar}

Related DMD variant pages (same residue, condition, or type): [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), [DMD p.Ala3522fs](/variant/dmd-p-ala3522fs).

### 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 2026-07-14); 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 948835). 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.*