# NM_001130987.2(DYSF):c.6025C>T (p.Pro2009Ser)

https://sugi.bio/variant/dysf-p-pro2009ser

## Summary

**DYSF p.Pro2009Ser (c.6025C>T)** is classified **Pathogenic/Likely pathogenic** in DYSF (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-25). AlphaMissense: likely pathogenic (0.8426); Very rare (popmax 0.0011%, sas); Associated with Miyoshi muscular dystrophy 1.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1057521141 · 6 submitters · 4 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the DYSF gene that is considered likely disease-causing, submitted by 6 submitters, 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.Pro2009Ser |
| Coding change (HGVS c.) | c.6025C>T |
| MANE Select transcript | [NM_001130987](https://www.ncbi.nlm.nih.gov/nuccore/NM_001130987) |
| dbSNP | [rs1057521141](https://www.ncbi.nlm.nih.gov/snp/rs1057521141/) |
| Variant type | single nucleotide variant |
| Location | chr2:71679197-71679197 (GRCh38) |
| ClinVar | [VCV381677](https://www.ncbi.nlm.nih.gov/clinvar/variation/381677/) |

**All HGVS expressions:** `LRG_845:g.230575C>T`, `LRG_845t1:c.5908C>T`, `LRG_845t2:c.6025C>T`, `NC_000002.11:g.71906327C>T`, `NC_000002.12:g.71679197C>T`, `NG_008694.1:g.230575C>T`, `NM_001130455.2:c.5911C>T`, `NM_001130976.2:c.5866C>T`, `NM_001130977.2:c.5929C>T`, `NM_001130978.2:c.5971C>T`, `NM_001130979.2:c.6001C>T`, `NM_001130980.2:c.5959C>T`, `NM_001130981.2:c.6022C>T`, `NM_001130982.2:c.6004C>T`, `NM_001130983.2:c.5974C>T`, `NM_001130984.2:c.5932C>T`, `NM_001130985.2:c.5962C>T`, `NM_001130986.2:c.5869C>T`, `NM_001130987.2:c.6025C>T`, `NM_003494.4:c.5908C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.8426) — concordant with the pathogenic call
- REVEL 0.947 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.978 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 5.964, GERP 2.24, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **P1970S** vs ClinVar **P2009S**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 25.1**. 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.*
- Regional missense constraint: **o/e 0.97** across the covering region of the MANE Select transcript (71,569,910–71,686,489), spanning 116,579 bp. Chi-square p 0.28. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · FAF95 0.000183% · FAF99 0.00012% · 1/91,072 in the highest group · 9/1,461,782 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,249 |
| South Asian (grpmax) | 0.0011% | 91,072 |
| European (non-Finnish) | 0.000508% | 196,659 |

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 **2009** lies in the 'disordered' region.

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.Pro2009Ser falls in the disordered region.


### 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/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-25.

**Submitter consensus:** conflicting (4 Likely pathogenic, 2 Pathogenic).

**Submission history:** 6 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2016-02-29 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-01-30 |
| Counsyl | Likely pathogenic | no assertion criteria provided | clinical testing | 2017-12-07 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-11-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-25 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-10-27 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Miyoshi muscular dystrophy 1, not provided, Neuromuscular disease caused by qualitative or quantitative defects of dysferlin, Autosomal recessive limb-girdle muscular dystrophy type 2B, Distal myopathy with anterior tibial onset, MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 3, MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2, Limb-girdle muscular dystrophy, type 2B, Limb-Girdle Muscular Dystrophy Type 2B (LGMD2B), Qualitative or quantitative defects of dysferlin.

## Similar variants {#similar}

Related DYSF variant pages (same residue, condition, or type): [DYSF p.Pro2009=](/variant/dysf-p-pro2009), [DYSF c.1003-3C>A](/variant/dysf-c-1003-minus-3c-a), [DYSF c.1033+1G>A](/variant/dysf-c-1033-plus-1g-a), [DYSF c.1033+4A>T](/variant/dysf-c-1033-plus-4a-t), [DYSF c.1149+1G>A](/variant/dysf-c-1149-plus-1g-a), [DYSF c.1149+1G>C](/variant/dysf-c-1149-plus-1g-c), [DYSF c.1149+4A>G](/variant/dysf-c-1149-plus-4a-g), [DYSF c.1276+5G>A](/variant/dysf-c-1276-plus-5g-a).

### 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 381677). 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.*