# NM_001130987.2(DYSF):c.356del (p.Val119fs)

https://sugi.bio/variant/dysf-p-val119fs

## Summary

**DYSF p.Val119fs (c.356del)** is classified **Pathogenic** in DYSF (ClinVar, Multiple submitters, 12 submitters; last evaluated 2025-12-01). Very rare (popmax 0.00637%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs398123782 · 12 submitters · 5 linked conditions · very rare (popmax 0.00637%, nfe)

## For patients & families {#patients}

This is a change in the DYSF gene that is considered disease-causing, submitted by 12 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.Val119fs |
| Coding change (HGVS c.) | c.356del |
| MANE Select transcript | [NM_001130987](https://www.ncbi.nlm.nih.gov/nuccore/NM_001130987) |
| dbSNP | [rs398123782](https://www.ncbi.nlm.nih.gov/snp/rs398123782/) |
| Variant type | Deletion |
| Location | chr2:71511817-71511817 (GRCh38) |
| ClinVar | [VCV94308](https://www.ncbi.nlm.nih.gov/clinvar/variation/94308/) |

**All HGVS expressions:** `LRG_845:g.63195del`, `LRG_845t1:c.353del`, `LRG_845t2:c.356del`, `NC_000002.11:g.71738947del`, `NC_000002.12:g.71511817del`, `NG_008694.1:g.63195del`, `NM_001130455.2:c.356del`, `NM_001130976.2:c.353del`, `NM_001130977.2:c.353del`, `NM_001130978.2:c.353del`, `NM_001130979.2:c.353del`, `NM_001130980.2:c.353del`, `NM_001130981.2:c.353del`, `NM_001130982.2:c.356del`, `NM_001130983.2:c.356del`, `NM_001130984.2:c.356del`, `NM_001130985.2:c.356del`, `NM_001130986.2:c.356del`, `NM_001130987.2:c.356del`, `NM_003494.4:c.353del`, `NM_003494.4:c.353delT`

## 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 8.373, GERP 1.5, 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 5 of 56**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 33.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- 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 (gnomAD v4.1): grpmax **0.00637%** (nfe) · FAF95 0.00518% · FAF99 0.00476% · 73/1,146,258 in the highest group · 80/1,550,606 alleles overall — very rare (popmax 0.00637%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00999% | 10,014 |
| European (non-Finnish) (grpmax) | 0.00637% | 15,702 |
| Admixed American | 0.00196% | 50,998 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **119** lies in a β-strand.

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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-01.

**Submitter consensus:** conflicting (11 Pathogenic, 1 Likely pathogenic).

**Submission history:** 12 submissions (2012–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Athena Diagnostics | Pathogenic | criteria provided, single submitter | clinical testing | 2014-06-11 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2018-02-05 |
| Genomics England Pilot Project, Genomics England | Likely pathogenic | no assertion criteria provided | clinical testing |  |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2021-11-02 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-04 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-05-07 |
| Counsyl | Pathogenic | no assertion criteria provided | clinical testing | 2017-03-15 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-05-02 |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-10-10 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-01 |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2012-10-11 |

## 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/), [distal myopathy with anterior tibial onset](https://sugi.bio/atlas/disease/distal-myopathy-with-anterior-tibial-onset/), [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/), [Miyoshi muscular dystrophy 1](https://sugi.bio/atlas/disease/miyoshi-muscular-dystrophy-1/).

**Reported phenotype names (ClinVar):** Autosomal recessive limb-girdle muscular dystrophy, Autosomal recessive limb-girdle muscular dystrophy type 2B, not provided, Neuromuscular disease caused by qualitative or quantitative defects of dysferlin, Miyoshi muscular dystrophy 1, Distal myopathy with anterior tibial onset, Dysferlinopathy, Qualitative or quantitative defects of dysferlin, MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2, Limb-Girdle Muscular Dystrophy Type 2B (LGMD2B).

## Similar variants {#similar}

Related DYSF variant pages (same residue, condition, or type): [DYSF p.Val119=](/variant/dysf-p-val119), [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 2026-10-11); 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 94308). 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.*