# NM_001130987.2(DYSF):c.3762del (p.Asp1255fs)

https://sugi.bio/variant/dysf-p-asp1255fs

## Summary

**DYSF p.Asp1255fs (c.3762del)** is classified **Pathogenic** in DYSF (ClinVar, Expert panel, 7 submitters; last evaluated 2025-01-08). No gnomAD frequency available for this variant; Associated with autosomal recessive limb-girdle muscular dystrophy.

**At a glance:** Pathogenic · review: Expert panel · rsID rs758107024 · 7 submitters · 3 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DYSF gene that is considered disease-causing, submitted by 7 submitters, and is linked to autosomal recessive limb-girdle 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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019825/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.Asp1255fs |
| Coding change (HGVS c.) | c.3762del |
| MANE Select transcript | [NM_001130987](https://www.ncbi.nlm.nih.gov/nuccore/NM_001130987) |
| dbSNP | [rs758107024](https://www.ncbi.nlm.nih.gov/snp/rs758107024/) |
| Variant type | Deletion |
| Location | chr2:71600707-71600707 (GRCh38) |
| ClinVar | [VCV813985](https://www.ncbi.nlm.nih.gov/clinvar/variation/813985/) |

**All HGVS expressions:** `LRG_845:g.152085del`, `LRG_845t1:c.3708del`, `LRG_845t2:c.3762del`, `NC_000002.11:g.71827837del`, `NC_000002.12:g.71600707del`, `NG_008694.1:g.152085del`, `NM_001130455.2:c.3711del`, `NM_001130976.2:c.3666del`, `NM_001130977.2:c.3666del`, `NM_001130978.2:c.3708del`, `NM_001130979.2:c.3801del`, `NM_001130980.2:c.3759del`, `NM_001130981.2:c.3759del`, `NM_001130982.2:c.3804del`, `NM_001130983.2:c.3711del`, `NM_001130984.2:c.3669del`, `NM_001130985.2:c.3762del`, `NM_001130986.2:c.3669del`, `NM_001130987.2:c.3762del`, `NM_003494.4:c.3708del`, `NM_003494.4:c.3708delA`

## 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 5.909, GERP 0.845, 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 34 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.
- 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 **1255** lies in an α-helix; the c2 4 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.Asp1255fs falls in the c2 4 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}

**Pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-01-08.

**Submitter consensus:** conflicting (5 Pathogenic, 2 Likely pathogenic).

**Submission history:** 7 submissions (2018–2025); classifications have differed over time.

**ClinGen expert panel:** Pathogenic — Limb Girdle Muscular Dystrophy VCEP (autosomal recessive limb-girdle muscular dystrophy). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PVS1`, `PM2_Supporting`, `PP4_Strong`, `PM3_Strong`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_003494.4: c.3708delA p.(Asp1237ThrfsTer24) variant in DYSF, which is also known as NM_001130987.2: c.3762del p.(Asp1255ThrfsTer24), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 34/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least three unrelated individuals with limb girdle muscular dystrophy, including in a homozygous state in two patients (1.0 pts, PMID: 25046369, 30919934) and in trans with a pathogenic variant in at least one patient (c.1662C>T p.(Arg555Trp), 1.0 pt, PMID: 19015158) (PM3_Strong). At least one patient with this variant displayed progressive limb-girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 19015158). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1, PM3_Strong, PP4_Strong, PM2_Supporting.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50061 · approved 2025-01-08 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/6847a91a-a62b-40fc-a763-5b96fa251ddb).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Likely pathogenic | criteria provided, single submitter | research | 2018-12-03 |
| Kariminejad - Najmabadi Pathology & Genetics Center | Pathogenic | criteria provided, single submitter | clinical testing | 2021-07-10 |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Likely pathogenic | no assertion criteria provided | clinical testing |  |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Pathogenic | no assertion criteria provided | clinical testing |  |
| ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen | Pathogenic | reviewed by expert panel | curation | 2025-01-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-01-13 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2024-01-01 |

## Associated conditions {#conditions}

[autosomal recessive limb-girdle muscular dystrophy](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy/), [autosomal recessive limb-girdle muscular dystrophy type 2B](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy-type-2b/), [neuromuscular disease caused by qualitative or quantitative defects of dysferlin](https://sugi.bio/atlas/disease/neuromuscular-disease-caused-by-qualitative-or-quantitative-defects-of-dysferlin/).

**Reported phenotype names (ClinVar):** Autosomal recessive limb-girdle muscular dystrophy, Autosomal recessive limb-girdle muscular dystrophy type 2B, not provided, Abnormality of the musculature, Neuromuscular disease caused by qualitative or quantitative defects of dysferlin, none provided, Qualitative or quantitative defects of dysferlin, Dysferlinopathy, MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 3, Limb-Girdle Muscular Dystrophy Type 2B (LGMD2B).

## Similar variants {#similar}

Related DYSF variant pages (same residue, condition, or type): [DYSF p.Asp1255=](/variant/dysf-p-asp1255), [DYSF c.240-159_345+1237del](/variant/dysf-c-240-minus-159-345-plus-1237del), [DYSF c.345+1del](/variant/dysf-c-345-plus-1del), [DYSF c.3756+905_3897+151del](/variant/dysf-c-3756-plus-905-3897-plus-151del), [DYSF c.5885-51_6063+50del](/variant/dysf-c-5885-minus-51-6063-plus-50del), [DYSF c.92-1496_239+950del](/variant/dysf-c-92-minus-1496-239-plus-950del), [DYSF c.951+1del](/variant/dysf-c-951-plus-1del), [DYSF p.Ala927Leufs](/variant/dysf-p-ala927leufs).

### 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 813985). 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.*