Is DYSF p.Glu1663fs (c.4989del) pathogenic?

DYSF p.Glu1663fs (c.4989del) is classified Pathogenic in DYSF (ClinVar, Expert panel, 5 submitters; last evaluated 2025-08-14). Very rare (popmax 0.00133%, afr); Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with DYSF p.Glu1663fs (c.4989del)?

DYSF p.Glu1663fs (c.4989del) is associated with autosomal recessive limb-girdle muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2B, distal myopathy with anterior tibial onset (ClinVar).

How common is DYSF p.Glu1663fs (c.4989del) in the general population?

DYSF p.Glu1663fs (c.4989del) is very rare (popmax 0.00133%, afr) (gnomAD).

DYSF p.Glu1663fs

c.4989del · rs1156805286 · VCV1300185

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

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.4872delG p.(Glu1624AspfsTer10) variant in DYSF, which is also known as NM_001130987.2: c.4989del (p.Glu1663AspfsTer10), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 45/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in at least 13 unrelated patients with phenotypes consistent with LGMD in a homozygous state in all individuals, with reported consanguinity in at least one family (1.0 pt, PMID: 10825360, 35723113, 17698709) (PM3). Many of these families were Jewish and from Libya. At least one of these individuals displayed muscle weakness and reduced or absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-associated LGMD (PMID: 17698709; PP4_Strong). The highest population frequency of this variant in gnomAD v4.1.0 is 0.00001335 in the African/African American population (1/74922 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; 08/14/2025): PVS1, PP4_Strong, PM3, 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 45 of 56
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,922 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,613,902 alleles · very rare exomes 6/1,461,718 · genomes 1/152,184 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,922
European (non-Finnish)	0.000509%	196,651

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.Glu1663fs
Coding: c.4989del
MANE Select: NM_001130987
dbSNP: rs1156805286
Type: Deletion
Location: chr2:71660637 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1663: a β-strand; the c2 6 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 distal myopathy with anterior tibial onset 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-glu1663fs (accessed [today's date]).

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