DYSF p.Ser321Pro
c.961T>C · rs398123808 · VCV94366
ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP
Likely Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):
PM3_Supporting PM2_Supporting PS3_Moderate PP3 PP4
Curation rationale (ClinGen, verbatim)
The NM_003494.4: c.865T>C variant in DYSF, which is also known as NM_001130987.2: c.961T>C p.(Ser321Pro), is a missense variant predicted to cause substitution of serine by proline at amino acid 289, p.(Ser289Pro). This variant has been reported in two patients with features consistent with LGMD (PMID: 36983702; PMID: 30564623; LOVD DYSF_000780), including in unconfirmed phase with a pathogenic variant (NM_003494.4: c.757C>T p.(Arg253Trp), 0.5 pts; PMID: 0564623, LOVD Individual #00222734) (PM3_Supporting). One of the patients with this variant and a second presumed diagnostic DYSF variant displayed progressive limb girdle muscle weakness and reduced range dysferlin by blood monocyte assay (PP4; PMID: 36983702). The filtering allele frequency of this variant is 0.000007 in the European (non-Finnish) population of gnomAD v4.1.0 (the upper threshold of the 95% CI of 3/1112008 exome 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 Ser289Pro 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 0.71, 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 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 1.0.0; 06/24/2025): PM3_Supporting, PP4, PM2_Supporting, PS3_Moderate, PP3.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.8088 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.707 | pathogenic-leaning |
| SaProt | LLR -11.85 | 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 6.1 | GERP 1.9, phastCons 1 |
| Regional constraint | o/e 1.02 | unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic |
| Overall | ||
| CADD | 23.9 | 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 S289P vs ClinVar S321P) — verify the residue.
Population frequency
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.Ser321Pro
- Coding
- c.961T>C
- MANE Select
- NM_001130987
- dbSNP
- rs398123808
- Type
- single nucleotide variant
- Location
- chr2:71516998 (GRCh38)
- Gene constraint
- LOEUF 0.836 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 79.25 · 11 PDB
- Residue 321
- a β-strand; the c2 2 domain
Similar variants
- DYSF p.Ser321Cys Uncertain significance ★★ ⚠ same residue
- DYSF p.Ser321Phe Uncertain significance ★★ ⚠ same residue
- DYSF p.Ser321= Likely benign ★ 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
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-ser321pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown