# NM_001130987.2(DYSF):c.2426C>G (p.Pro809Arg)

https://sugi.bio/variant/dysf-p-pro809arg

## Summary

**DYSF p.Pro809Arg (c.2426C>G)** is classified **Likely pathogenic** in DYSF (ClinVar, Expert panel, 8 submitters; last evaluated 2026-04-30). AlphaMissense: likely pathogenic (0.9874); Absent from gnomAD v4.1; Associated with limb-girdle muscular dystrophy.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs121908956 · 8 submitters · 5 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DYSF gene that is considered likely disease-causing, submitted by 8 submitters, and is linked to 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.*

|  |  |
| --- | --- |
| Clinical trials | 40 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006907/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.Pro809Arg |
| Coding change (HGVS c.) | c.2426C>G |
| MANE Select transcript | [NM_001130987](https://www.ncbi.nlm.nih.gov/nuccore/NM_001130987) |
| dbSNP | [rs121908956](https://www.ncbi.nlm.nih.gov/snp/rs121908956/) |
| Variant type | single nucleotide variant |
| Location | chr2:71564074-71564074 (GRCh38) |
| ClinVar | [VCV6671](https://www.ncbi.nlm.nih.gov/clinvar/variation/6671/) |

**All HGVS expressions:** `LRG_845:g.115452C>G`, `LRG_845t1:c.2372C>G`, `LRG_845t2:c.2426C>G`, `NC_000002.11:g.71791204C>G`, `NC_000002.12:g.71564074C>G`, `NG_008694.1:g.115452C>G`, `NM_001130455.2:c.2375C>G`, `NM_001130976.2:c.2330C>G`, `NM_001130977.2:c.2330C>G`, `NM_001130978.2:c.2372C>G`, `NM_001130979.2:c.2465C>G`, `NM_001130980.2:c.2423C>G`, `NM_001130981.2:c.2423C>G`, `NM_001130982.2:c.2468C>G`, `NM_001130983.2:c.2375C>G`, `NM_001130984.2:c.2333C>G`, `NM_001130985.2:c.2426C>G`, `NM_001130986.2:c.2333C>G`, `NM_001130987.2:c.2426C>G`, `NM_003494.4:c.2372C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9874) — concordant with the pathogenic call
- REVEL 0.902 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.419 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.66, GERP 2.24, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **P791R** vs ClinVar **P809R**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- AlphaMissense ranks this among the **top 4%** most-pathogenic-predicted substitutions in DYSF (of 12,318 modeled).
- CADD: **PHRED 24.4**. 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 0.82** across the covering region of the MANE Select transcript (71,551,716–71,569,909), spanning 18,193 bp. Chi-square p 4.1e-05. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **809** 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}

**Likely pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2026-04-30.

**Submitter consensus:** conflicting (6 Pathogenic, 2 Likely pathogenic, 1 Likely Pathogenic).

**Submission history:** 9 submissions (1999–2026); classifications have differed over time.

**ClinGen expert panel:** Likely Pathogenic — Limb Girdle Muscular Dystrophy VCEP (limb-girdle muscular dystrophy). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`, `PP4_Strong`, `PP1_Supporting`, `PP3`, `PM3`.
*Considered but not met:* `PS1`, `PS3`, `PM5`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_003494.4: c.2372C>G variant in DYSF, which is also known as NM_001130987.2: c.2426C>G p.(Pro809Arg), is a missense variant predicted to cause substitution of proline by arginine at amino acid position 809, p.(Pro791Arg). This variant has been detected in a homozygous state in at least five seemingly unrelated individuals with features consistent with limb girdle muscular dystrophy (1 pt; PMID: 30564623, 16996541, 10196377; PM3). It has also been reported in unconfirmed phase with a VUS in an individual with undetectable dysferlin protein expression (Jain Foundation Dysferlin Registry internal data communication). At least one patient with this variant in a homozygous state displayed progressive limb girdle muscle weakness and significantly reduced DYSF protein expression, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 16996541, 10196377). This variant was also shown to co-segregate with autosomal recessive LGMD in at least 10 affected family members from three Canadian Indigenous families sharing the same haplotype, suggesting it is a founder variant in that population (PMID: 10196377; PP1_Supporting, capped with PP4_Strong). This variant is absent from gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.902, which meets the VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Likely 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 2.0.0; 04/30/2026): PM3, PP4_Strong, PP1, PM2_Supporting, PP3.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50061 · approved 2026-04-30 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/2366548f-6ee9-4d1a-96a0-c9352c48ed67).*
*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 |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2017-03-03 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1999-05-01 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-09-28 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-06-12 |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-04-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-09 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-05-20 |
| ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen | Likely Pathogenic | reviewed by expert panel | curation | 2026-04-30 |

## Associated conditions {#conditions}

[limb-girdle muscular dystrophy](https://sugi.bio/atlas/disease/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/), [autosomal recessive limb-girdle muscular dystrophy](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy/), [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):** Limb-girdle muscular dystrophy, Autosomal recessive limb-girdle muscular dystrophy type 2B, Miyoshi muscular dystrophy 1, not provided, Neuromuscular disease caused by qualitative or quantitative defects of dysferlin, Autosomal recessive limb-girdle muscular dystrophy, DYSF-related disorder, DYSF-related disorders, DYSF-related condition, Qualitative or quantitative defects of dysferlin.

## Same-residue context {#hotspot}

Residue **809** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DYSF p.Pro809Gln](/variant/dysf-p-pro809gln). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DYSF variant pages (same residue, condition, or type): [DYSF p.Pro809Leu](/variant/dysf-p-pro809leu), [DYSF p.Pro809Gln](/variant/dysf-p-pro809gln), [DYSF p.Pro809=](/variant/dysf-p-pro809), [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.1033+5G>A](/variant/dysf-c-1033-plus-5g-a), [DYSF c.1149+1G>A](/variant/dysf-c-1149-plus-1g-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 6671). 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.*