Is DYSF p.Ser1191fs (c.3571dup) pathogenic?

DYSF p.Ser1191fs (c.3571dup) is classified Pathogenic in DYSF (ClinVar, Expert panel, 8 submitters; last evaluated 2025-05-14). Very rare (popmax 0.00407%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy.

How common is DYSF p.Ser1191fs (c.3571dup) in the general population?

DYSF p.Ser1191fs (c.3571dup) is very rare (popmax 0.00407%, nfe) (gnomAD).

DYSF p.Ser1191fs

Q: What condition is associated with DYSF p.Ser1191fs (c.3571dup)?

DYSF p.Ser1191fs (c.3571dup) 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.3571dup · rs766341386 · VCV370730

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00407%, 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_Strong

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.3517dup p.(Ser1173PhefsTer2) variant in DYSF, which is also known as NM_001130987.2: c.3571dup p.(Ser1191PhefsTer2), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 32/55, 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 six patients with dysferlinopathy (PMID: 19528035, 18853459, 27447704, 36983702), including in a homozygous state in two individuals without reported familial consanguinity (1.0 pts, PMID: 19528035, 27447704), confirmed in trans with a likely pathogenic or pathogenic variant (NM_003494.4: c.3113G>A p.(Arg1038Gln), 1.0 pt, PMID: 36983702), and in unknown phase with a pathogenic variant (NM_003494.4: c.5836_5839del p.(Gln1946TrpfsTer19), 0.5 pts, PMID: 36983702) (PM3_Strong). At least one of the patients with this variant and a second presumed diagnostic DYSF variant displayed progressive proximal muscle weakness and absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 18853459, 36983702). The filtering allele frequency of this variant is 0.000053899 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 47/1111990 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; 05/14/2025): PVS1, PM3_Strong, 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 32 of 56
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.2	GERP 1.1, phastCons 1
Overall
CADD	36.0	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 0.00407% European (non-Finnish) · 48/1,180,020 alleles

Filtering AF 0.00315% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00316% 51/1,614,062 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00407%	24,584
Remaining individualsnot grpmax-eligible	0.0032%	31,244
Admixed American	0.00167%	59,996

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.Ser1191fs
Coding: c.3571dup
MANE Select: NM_001130987
dbSNP: rs766341386
Type: Duplication
Location: chr2:71590280 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1191: the c2 4 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.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
DYSF p.Asp497fs Pathogenic ★★★ same condition
DYSF p.Glu2033fs Pathogenic ★★★ same condition
DYSF p.Ile1036Hisfs 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-ser1191fs (accessed [today's date]).

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