Is DYSF p.Asp497fs (c.1488dup) pathogenic?

DYSF p.Asp497fs (c.1488dup) is classified Pathogenic in DYSF (ClinVar, Expert panel, 9 submitters; last evaluated 2025-07-29). Very rare (popmax 0.000678%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy.

How common is DYSF p.Asp497fs (c.1488dup) in the general population?

DYSF p.Asp497fs (c.1488dup) is very rare (popmax 0.000678%, nfe) (gnomAD).

DYSF p.Asp497fs

Q: What condition is associated with DYSF p.Asp497fs (c.1488dup)?

DYSF p.Asp497fs (c.1488dup) is associated with autosomal recessive limb-girdle muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2B, neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

c.1488dup · rs398123767 · VCV94271

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 9 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Conditions

autosomal recessive limb-girdle muscular dystrophy

ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP

Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):

PVS1 PM2_Supporting PP4_Strong PM3

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.1392dup p.(Asp465ArgfsTer9) variant in DYSF, which is also known as NM_001130987.2: c.1488dup (p.Asp497ArgfsTer9), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 16/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least five individuals with features of LGMD (PMID: 27602406, 36983702), including in a homozygous state in one patient without reported familial consanguinity (0.5 pts, PMID: 27602406) and in unknown phase with a pathogenic variant in two patients (NM_003494.4: c.5698_5699del p.(Ser1900GlnfsTer14), 0.5 pts, PMID: 27602406; NM_003494.4: c.1481-1G>A, 0.5 pts, PMID: 27602406) (PM3). At least one patient with this variant displayed a clinical suspicion of LGMD and severely reduced or absent dysferlin protein expression in skeletal muscle or blood monocytes, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 27602406, 33610434). The filtering allele frequency of this variant is 0.000012981 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 8/1111992 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). 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): PVS1, PM3, PP4_Strong, PM2_Supporting.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 16 of 56
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.5	GERP 0.86, phastCons 0.59

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000678% European (non-Finnish) · 8/1,180,014 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000616% 9/1,461,874 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)grpmax	0.000678%	147,502

Remaining individuals 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.Asp497fs
Coding: c.1488dup
MANE Select: NM_001130987
dbSNP: rs398123767
Type: Duplication
Location: chr2:71535305 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB

Full DYSF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive limb-girdle muscular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2B neuromuscular disease caused by qualitative or quantitative defects of dysferlin Miyoshi muscular dystrophy 1

Similar variants

DYSF p.Asp497Val Uncertain significance ★ ⚠ same residue
DYSF p.Ala497= Likely benign ★ same residue
DYSF p.Asp497= Likely benign ★ same residue
DYSF c.1267_1276+4dup Pathogenic ★★★ same condition
DYSF c.1274_1276+4dup Likely pathogenic ★★★ same condition
DYSF c.1493+2dup Pathogenic ★★★ same condition
DYSF p.Asn44fs Pathogenic ★★★ same condition
DYSF p.Asp320fs 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-asp497fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown