DYSF p.Arg977Trp
c.2929C>T · rs202218890 · VCV284254
ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP
Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):
PM2_Supporting PS3_Moderate PP4_Strong PM3_Strong PP1 PP3
Curation rationale (ClinGen, verbatim)
The NM_003494.4: c.2875C>T variant in DYSF, which is also known as NM_001130987.2: c.2929C>T p.(Arg977Trp), is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 959, p.(Arg959Trp). This variant has been reported in at least ten patients with dysferlinopathy (PMID: 14678801, 19528035, 21522182, 27602406, 33715265, 36983702), including in a homozygous state in four unrelated individuals without reported familial consanguinity (1 pt; PMID: 21522182, 27602406, 33715265), confirmed in trans with a pathogenic variant in two affected siblings (NM_003494.4: c.4003G>A p.(Glu1335Lys), 1.0 pt, PMID: 14678801), and in unconfirmed phase with a pathogenic variant in one case (NM_003494.4: c.3517dup p.(Ser1173PhefsTer2), 0.5 pts, PMID: 19528035) (PM3_Strong). At least one of the patients with this variant displayed progressive muscle weakness and absent or reduced dysferlin expression in muscle biopsy or monocytes, which is highly specific for DYSF-related LGMD (PMID: 14678801, 21522182, 27602406, 36983702) (PP4_Strong). This variant was also shown to co-segregate with autosomal recessive LGMD in one affected family member (PMID: 14678801; PP1). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.0 is 0.000052686 (49/1180020 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg959Trp protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). In addition, the computational predictor REVEL gives a score of 0.77, which is above the LGMD 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 2.0.0; 10/06/2025): PM3_Strong, PP4_Strong, PP1, PS3_Moderate, PM2_Supporting, PP3.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.8955 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.773 | moderately pathogenic-leaning |
| SaProt | LLR -11.19 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 4.8 | GERP 2.1, phastCons 1 |
| Regional constraint | o/e 0.82 | unconstrained · MANE · 18 kb · p 4.1e-05 · regional, not allelic |
| Overall | ||
| CADD | 26.3 | 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 R959W vs ClinVar R977W) — verify the residue.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.00415% | 24,082 |
| South Asian | 0.00329% | 30,352 |
| Remaining individualsnot grpmax-eligible | 0.0032% | 31,245 |
| East Asian | 0.00223% | 44,880 |
| Finnishnot grpmax-eligible | 0.00156% | 64,006 |
| African / African-American | 0.00133% | 74,926 |
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.Arg977Trp
- Coding
- c.2929C>T
- MANE Select
- NM_001130987
- dbSNP
- rs202218890
- Type
- single nucleotide variant
- Location
- chr2:71569884 (GRCh38)
- Gene constraint
- LOEUF 0.836 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 79.25 · 11 PDB
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.Arg977Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
- DYSF p.Arg977Pro 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
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-arg977trp (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown