DYSF p.Gly331Arg
c.991G>A · rs121908963 · VCV6681
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 PP1 PP3 PM3
Curation rationale (ClinGen, verbatim)
The NM_003494.4: c.895G>A variant in DYSF, which is also known as NM_001130987.2: c.991G>A (p.Gly331Arg), is a missense variant predicted to cause substitution of glycine by arginine at amino acid 299, p.(Gly299Arg). This variant has been reported in at least two individuals with clinical features consistent with LGMD, including confirmed in trans with a pathogenic variant in one patient (NM_003494.4: c.855+1del, 1.0 pt, PMID: 16705711, 28877744; PM3). At least one of these patients had a clinical diagnosis of LGMD and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PMID: 16705711; PP4_Strong). This variant has also been shown to co-segregate with the LGMD phenotype in one affected family member (PMID: 16705711; PP1). The frequency of this variant in the East Asian population in gnomAD v4.1.0 is 0.00002228 (1/44890 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 Gly299Arg 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 0.968, 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 1.0.0; 07/29/2025): PM3, PP4_Strong, PP1, PM2_Supporting, PS3_Moderate, PP3.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9895 | likely pathogenic ✓ concordant with ClinVar · top 3% in DYSF |
|---|---|---|
| REVEL | 0.968 | strongly pathogenic-leaning |
| SaProt | LLR -17.38 | 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 12 | GERP 1.9, phastCons 1 |
| Regional constraint | o/e 1.02 | unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic |
| Overall | ||
| CADD | 28.6 | 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 G299R vs ClinVar G331R) — verify the residue.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Ashkenazi Jewishnot grpmax-eligible | 0.00338% | 29,606 |
| East Asiangrpmax | 0.00223% | 44,890 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,490 |
| African / African-American | 0.00133% | 74,918 |
| European (non-Finnish) | 0.000254% | 393,337 |
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.Gly331Arg
- Coding
- c.991G>A
- MANE Select
- NM_001130987
- dbSNP
- rs121908963
- Type
- single nucleotide variant
- Location
- chr2:71517028 (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 2Bneuromuscular disease caused by qualitative or quantitative defects of dysferlinMiyoshi muscular dystrophy 1
Similar variants
- DYSF p.Gly331Trp Pathogenic ★★★ same residue
- DYSF p.Gly331Glu 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-gly331arg (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown