Is DYSF p.Phe451fs (c.1350del) pathogenic?

DYSF p.Phe451fs (c.1350del) is classified Pathogenic in DYSF (ClinVar, Expert panel, 4 submitters; last evaluated 2025-09-17). Very rare (popmax 8.47e-05%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy.

How common is DYSF p.Phe451fs (c.1350del) in the general population?

DYSF p.Phe451fs (c.1350del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

DYSF p.Phe451fs

Q: What condition is associated with DYSF p.Phe451fs (c.1350del)?

DYSF p.Phe451fs (c.1350del) 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.1350del · rs766936914 · VCV551669

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, 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 PM3_Supporting PM2_Supporting PP4_Strong

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.1254del p.(Phe419LeufsTer41) variant in DYSF, which is also known as NM_001130987.2: c.1350del p.(Phe451LeufsTer41), is a frameshift variant expected to introduce a premature stop codon in exon 15/55, leading to nonsense mediated decay in a gene in which loss of function is a known mechanism of disease (PVS1). In the literature, this variant has also been described as p.(Pro418ProfsTer123). This variant has been reported in at least three patients with features consistent with LGMD (PMID: 27647186, 26404900, 26404900), including in a homozygous state without reported familial consanguinity (0.5 pts, PMID: 17994539; PM3_Supporting). This homozygous individual had both progressive limb girdle muscle weakness and absent dysferlin expression in skeletal muscle via both immunohistochemistry and Western blot (PMID: 17994539; PP4_Strong). The highest population allele frequency for this variant is 8.475e-7 in gnomAD v4.1.0 (1/1180008 European (non-Finnish) alleles), which is less than the threshold of 0.0001 for PM2_Supporting, meeting this criterion (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 2.0.0; 09/17/2025): PVS1, PM3_Supporting, 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 14 of 56
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,008 alleles

Overall 6.84e-05% 1/1,461,836 alleles · very rare

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.Phe451fs
Coding: c.1350del
MANE Select: NM_001130987
dbSNP: rs766936914
Type: Deletion
Location: chr2:71528368 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 451: a β-strand; the c2 3 domain

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 c.240-159_345+1237del Pathogenic ★★★ same condition
DYSF c.345+1del Pathogenic ★★★ same condition
DYSF c.3756+905_3897+151del Pathogenic ★★★ same condition
DYSF c.5885-51_6063+50del Pathogenic ★★★ same condition
DYSF c.92-1496_239+950del Pathogenic ★★★ same condition
DYSF c.951+1del Pathogenic ★★★ same condition
DYSF p.Ala927Leufs Pathogenic ★★★ same condition
DYSF p.Arg1759fs 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-phe451fs (accessed [today's date]).

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