DYSF p.Arg573Trp
c.1717C>T · rs377735262 · VCV94278
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 PP1 PP3
Curation rationale (ClinGen, verbatim)
The NM_003494.4: c.1663C>T variant in DYSF, which is also known as NM_001130987.2: c.1717C>T p.(Arg573Trp), is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 555 (p.Arg555Trp). This variant has been detected in at least nine unrelated individuals with limb girdle muscular dystrophy (PMID: 16010686, 17698709, 18853459, 25591676, 25143362, 19015158), including in a homozygous state in two patients (0.75 pts, PMID: 25143362,16010686) and in trans with a pathogenic variant in at least two patients (c.3708delA p.(Asp1237ThrfsTer24), 1.0 pt, PMID: 19015158; c.3220_3221delCT p.(Leu1074PheTer39), 1.0 pt, PMID: 25591676) (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: 16010686, 25143362, 19015158, 18853459). The variant has also been reported to segregate with LGMD in two affected family members from one family (PP1; PMID: 25143362). The filtering allele frequency of the variant is 0.0002685 for South Asian exome alleles in gnomAD v2.1.1 (the upper threshold of the 95% CI of 3/28874), which is greater than the LGMD VCEP threshold (<0.0001) (PM2_Supporting not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg555Trp protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). The computational predictor REVEL gives a score of 0.94, which exceeds 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 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): PM3_Strong, PP4_Strong, PP1, PS3_Moderate, PP3.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9552 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.94 | strongly pathogenic-leaning |
| SaProt | LLR -15.75 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | <0.2 | all four deltas below 0.2 · C>A here scores Δ0.29 · evaluated, not missing |
| Constraint at this position | ||
| Conservation | phyloP 1.3 | GERP 1.8, phastCons 1 |
| Regional constraint | o/e 1.02 | unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic |
| Overall | ||
| CADD | 24.8 | 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 R555W vs ClinVar R573W) — verify the residue.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.00447% | 22,363 |
| European (non-Finnish) | 0.0039% | 25,625 |
| Admixed American | 0.00337% | 29,647 |
| Finnishnot grpmax-eligible | 0.00317% | 31,511 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,324 |
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.Arg573Trp
- Coding
- c.1717C>T
- MANE Select
- NM_001130987
- dbSNP
- rs377735262
- Type
- single nucleotide variant
- Location
- chr2:71551631 (GRCh38)
- Gene constraint
- LOEUF 0.836 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 79.25 · 11 PDB
- Residue 573
- a β-strand
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.Arg573Gln Uncertain significance ★★ ⚠ 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-arg573trp (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown