# NM_003494.4(DYSF):c.42_43del (p.Pro15fs)

https://sugi.bio/variant/dysf-p-pro15fs

## Summary

**DYSF p.Pro15fs (c.42_43del)** is classified **Likely pathogenic** in DYSF (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-23). No gnomAD frequency available for this variant; Associated with Miyoshi muscular dystrophy 1.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2466863398 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DYSF gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Miyoshi muscular dystrophy 1.

*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) | Adult |
| Prevalence | 1-9 / 1 000 000 (Japan) |
| Diagnostic panels | DYSF is a diagnostic-grade gene on 4 Genomics England panels |

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

- Gait disturbance — Frequent (79-30%)
- Shoulder girdle muscle weakness — Frequent (79-30%)
- Difficulty climbing stairs — Frequent (79-30%)
- Difficulty standing — Frequent (79-30%)
- Quadriceps muscle weakness — Frequent (79-30%)
- Exercise-induced myalgia — Frequent (79-30%)
- Pelvic girdle muscle weakness — Frequent (79-30%)
- Proximal amyotrophy — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025425/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DYSF](https://sugi.bio/atlas/gene/DYSF/) |
| Protein change (HGVS p.) | p.Pro15fs |
| Coding change (HGVS c.) | c.42_43del |
| MANE Select transcript | [NM_001130987](https://www.ncbi.nlm.nih.gov/nuccore/NM_001130987) (variant reported on NM_003494) |
| dbSNP | [rs2466863398](https://www.ncbi.nlm.nih.gov/snp/rs2466863398/) |
| Variant type | Microsatellite |
| Location | chr2:71454035-71454036 (GRCh38) |
| ClinVar | [VCV2674985](https://www.ncbi.nlm.nih.gov/clinvar/variation/2674985/) |

**All HGVS expressions:** `LRG_845:g.5414AC[2]`, `LRG_845t1:c.42_43del`, `NC_000002.11:g.71681166AC[2]`, `NC_000002.12:g.71454036AC[2]`, `NG_008694.1:g.5414AC[2]`, `NG_095499.1:g.718AC[2]`, `NM_001130976.2:c.42_43del`, `NM_001130977.2:c.42_43del`, `NM_001130978.2:c.42_43del`, `NM_001130979.2:c.42_43del`, `NM_001130980.2:c.42_43del`, `NM_001130981.2:c.42_43del`, `NM_003494.4:c.42_43del`

## 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 1.114, GERP -0.739, phastCons 0.994 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.836, pLI 3.6575e-52. For a truncating variant the loss-of-function impact is position-dependent — C-terminal / last-exon truncations may escape nonsense-mediated decay. *Descriptive; not an applied PVS1 code.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite 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}

**DYSF** population constraint: LOEUF 0.836, pLI 3.6575e-52, missense-Z 1.3979. *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):

- **autosomal recessive limb-girdle muscular dystrophy** — Definitive (AR)

## Protein context {#protein}

Residue **15** lies in a β-strand; the c2 1 domain.

AlphaFold model confidence (whole protein): pLDDT 79.25, 28% of residues very-high.

**11 experimental structure(s)** (PDB): [4CAH](https://www.rcsb.org/structure/4CAH), [4CAI](https://www.rcsb.org/structure/4CAI), [4IHB](https://www.rcsb.org/structure/4IHB), [4IQH](https://www.rcsb.org/structure/4IQH), [7JOF](https://www.rcsb.org/structure/7JOF), [7K6B](https://www.rcsb.org/structure/7K6B) — incl. mutant structure 4IQH.

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

*Describes the biological roles of DYSF (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:** DYSF's established molecular role includes calcium ion binding. p.Pro15fs falls in the c2 1 domain.


### Pathways affected {#pathways}

DYSF participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Smooth Muscle Contraction](https://reactome.org/content/detail/R-HSA-445355) | electronic |

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

**Molecular function:** calcium ion binding, phospholipid binding, calcium-dependent phospholipid binding.

**Biological process:** monocyte activation involved in immune response, macrophage activation involved in immune response, negative regulation of phagocytosis.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-03-23.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-03-23 |

## Associated conditions {#conditions}

[Miyoshi muscular dystrophy 1](https://sugi.bio/atlas/disease/miyoshi-muscular-dystrophy-1/).

**Reported phenotype names (ClinVar):** Miyoshi muscular dystrophy 1.

## Similar variants {#similar}

Related DYSF variant pages (same residue, condition, or type): [DYSF p.Leu1092fs](/variant/dysf-p-leu1092fs), [DYSF p.Phe1128fs](/variant/dysf-p-phe1128fs), [DYSF p.Ser1939fs](/variant/dysf-p-ser1939fs), [DYSF p.1080AE[3]](/variant/dysf-p-1080ae-3), [DYSF p.Leu298fs](/variant/dysf-p-leu298fs), [DYSF p.Ser1189fs](/variant/dysf-p-ser1189fs), [DYSF p.2087ILFI[1]](/variant/dysf-p-2087ilfi-1), [DYSF p.His1055fs](/variant/dysf-p-his1055fs).

### 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 2674985). 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.*