DYSF p.Arg285Trp
c.853C>T · rs149827237 · VCV284800
ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP
Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):
PS3_Moderate PP4_Strong PM3_Strong
Curation rationale (ClinGen, verbatim)
The NM_003494.4: c.757C>T variant in DYSF, which is also known as NM_001130987.2: c.853C>T p.(Arg285Trp), is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 253, p.(Arg253Trp). This variant has been reported in at least 10 individuals with symptoms consistent with LGMD (PMID: 16010686, 18853459, 24803842, 25868377, 26404900, 27666772, 30564623, 30919934, 36983702; LOVD DYSF_000205), including in a homozygous state without reported familial consanguinity in one patient (0.5 pts; PMID: 30919934) and confirmed in trans with a likely pathogenic or pathogenic variant in two patients (NM_003494.4: c.5979dup p.(Glu1994ArgfsTer3), 1.0 pt, LOVD Individual #00215315; NM_003494.4: c.2894G>A p.(Trp965Ter), 1.0 pt, PMID: 36983702) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic DYSF variant displayed progressive proximal muscle weakness and significantly reduced or absent dysferlin protein expression in skeletal muscle or blood monocytes, which is highly specific for DYSF-associated LGMD (PP4_Strong; PMID: 36983702, 27666772, 25868377). The highest minor allele frequency for this variant in gnomAD v4.1.0 is 0.0001890 in the European (non-Finnish) population (223/1180018 alleles), which is higher than the LGMD VCEP threshold for PM2_Supporting (0.0001) (criterion not met). The computational predictor REVEL gives a score of 0.614, which is below the VCEP's threshold of 0.7 for PP3 (criterion not met). However, immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg253Trp protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). 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; 07/08/2025): PM3_Strong, PP4_Strong, PS3_Moderate.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.4127 | ambiguous |
|---|---|---|
| REVEL | 0.614 | indeterminate |
| SaProt | LLR -13.32 | damaging |
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 3.4 | GERP 1.2, phastCons 1 |
| Regional constraint | o/e 1.02 | unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic |
| Overall | ||
| CADD | 24.3 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R253W vs ClinVar R285W) — verify the residue.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Ashkenazi Jewishnot grpmax-eligible | 0.054% | 1,851 |
| European (non-Finnish)grpmax | 0.0189% | 5,292 |
| Remaining individualsnot grpmax-eligible | 0.0128% | 7,813 |
| Admixed American | 0.00667% | 15,002 |
| African / African-American | 0.00267% | 37,509 |
| East Asian | 0.00223% | 44,870 |
| Finnishnot grpmax-eligible | 0.00156% | 64,000 |
| South Asian | 0.0011% | 91,088 |
Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. 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.
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- DYSF
- Protein
- p.Arg285Trp
- Coding
- c.853C>T
- MANE Select
- NM_001130987
- dbSNP
- rs149827237
- Type
- single nucleotide variant
- Location
- chr2:71515716 (GRCh38)
- Gene constraint
- LOEUF 0.836 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 79.25 · 11 PDB
- Residue 253 UniProt numbering
- an α-helix; a UniProt-annotated variant site (found in patients with isolated hyperckemia); the c2 2 domain
Disease context
autosomal recessive limb-girdle muscular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: autosomal recessive limb-girdle muscular dystrophy type 2Bdistal myopathy with anterior tibial onsetneuromuscular disease caused by qualitative or quantitative defects of dysferlinMiyoshi muscular dystrophy 1
Similar variants
- DYSF p.Arg285Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
- DYSF c.1003-3C>A Pathogenic ★★★ same condition
- DYSF c.1033+1G>A Pathogenic ★★★ same condition
- DYSF c.1033+4A>T Likely pathogenic ★★★ same condition
- DYSF c.1033+5G>A Likely pathogenic ★★★ same condition
- DYSF c.1149+1G>A Pathogenic ★★★ same condition
- DYSF c.1149+1G>C Pathogenic ★★★ same condition
- DYSF c.1149+4A>G Pathogenic ★★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dysf-p-arg285trp (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown