# NM_001130987.2(DYSF):c.2125_2128del (p.Gln709fs)

https://sugi.bio/variant/dysf-p-gln709fs

## Summary

**DYSF p.Gln709fs (c.2125_2128del)** is classified **Likely pathogenic** in DYSF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-10). Associated with Miyoshi muscular dystrophy 1.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## 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.Gln709fs |
| Coding change (HGVS c.) | c.2125_2128del |
| MANE Select transcript | [NM_001130987](https://www.ncbi.nlm.nih.gov/nuccore/NM_001130987) |
| Variant type | Deletion |
| Location | chr2:71555979-71555982 (GRCh38) |
| ClinVar | [VCV4294100](https://www.ncbi.nlm.nih.gov/clinvar/variation/4294100/) |

**All HGVS expressions:** `LRG_845:g.107358_107361del`, `LRG_845t1:c.2071_2074del`, `LRG_845t2:c.2125_2128del`, `NC_000002.11:g.71783110_71783113del`, `NC_000002.12:g.71555980_71555983del`, `NG_008694.1:g.107358_107361del`, `NM_001130455.2:c.2074_2077del`, `NM_001130976.2:c.2029_2032del`, `NM_001130977.2:c.2029_2032del`, `NM_001130978.2:c.2071_2074del`, `NM_001130979.2:c.2164_2167del`, `NM_001130980.2:c.2122_2125del`, `NM_001130981.2:c.2122_2125del`, `NM_001130982.2:c.2167_2170del`, `NM_001130983.2:c.2074_2077del`, `NM_001130984.2:c.2032_2035del`, `NM_001130985.2:c.2125_2128del`, `NM_001130986.2:c.2032_2035del`, `NM_001130987.2:c.2125_2128del`, `NM_003494.4:c.2071_2074del`

## 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 7.965, GERP 0.606, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.836, pLI 3.6575e-52. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 22 of 56**, 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.

*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 **709** lies in an α-helix.

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.


### 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 2024-12-10.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 3billion | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-12-10 |

## Associated conditions {#conditions}

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

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

## Same-residue context {#hotspot}

Residue **709** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DYSF p.Gln709Ter](/variant/dysf-p-gln709ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DYSF variant pages (same residue, condition, or type): [DYSF p.Gln709Ter](/variant/dysf-p-gln709ter), [DYSF c.951+1del](/variant/dysf-c-951-plus-1del), [DYSF p.Ala927Leufs](/variant/dysf-p-ala927leufs), [DYSF p.Gln1985fs](/variant/dysf-p-gln1985fs), [DYSF p.Glu1143fs](/variant/dysf-p-glu1143fs), [DYSF p.Glu1663fs](/variant/dysf-p-glu1663fs), [DYSF p.Gly1904fs](/variant/dysf-p-gly1904fs), [DYSF p.Lys37fs](/variant/dysf-p-lys37fs).

### 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 4294100). 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.*