Is DYSF p.Arg1056Ter (c.3166C>T) pathogenic?

DYSF p.Arg1056Ter (c.3166C>T) is classified Pathogenic in DYSF (ClinVar, Expert panel, 15 submitters; last evaluated 2025-07-29). Very rare (popmax 0.00934%, afr); Associated with autosomal recessive limb-girdle muscular dystrophy.

How common is DYSF p.Arg1056Ter (c.3166C>T) in the general population?

DYSF p.Arg1056Ter (c.3166C>T) is very rare (popmax 0.00934%, afr) (gnomAD).

DYSF p.Arg1056Ter

Q: What condition is associated with DYSF p.Arg1056Ter (c.3166C>T)?

DYSF p.Arg1056Ter (c.3166C>T) 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.3166C>T · rs369607332 · VCV217225

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 15 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00934%, 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_Strong

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.3112C>T p.(Arg1038Ter) variant in DYSF, which is also known as NM_001130987.2: c.3166C>T p.(Arg1056Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 29/55, 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 five individuals with signs of dysferlinopathy (PMID: 36983702, 23243261, 17698709, 16010686), including confirmed in trans with a likely pathogenic or pathogenic DYSF variant in three patients (NM_003494.4: c.2643+1G>A, 1.0 pt, PMID: 36983702; NM_003494.4: c.4497del p.(Phe1499LeufsTer4), 1.0 pt, PMID: 23243261; NM_003494.4: c.3832C>T p.(Gln1278Ter), 1.0 pt, PMID: 16010686, 7698709). At least one of the patients with this variant and a second presumed diagnostic DYSF allele displayed progressive limb girdle muscle weakness and disease range dysferlin expression in blood monocytes, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 36983702). The filtering allele frequency for this variant is 0.00005974 in gnomAD v4.1.0 exomes (the upper bound of the 95% confidence interval for 57/1111956 European (non-Finnish) chromosomes, which is less than the VCEP threshold of 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_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	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 29 of 56
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -3.5, phastCons 1
Overall
CADD	38.0	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 0.00934% African / African-American · 7/74,916 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00353%

Overall 0.00434% 70/1,613,960 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00934%	10,702
Admixed American	0.005%	20,000
European (non-Finnish)	0.00492%	20,345
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Arg1056Ter
Coding: c.3166C>T
MANE Select: NM_001130987
dbSNP: rs369607332
Type: single nucleotide variant
Location: chr2:71570679 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1056: an α-helix

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.Arg1056Gln Pathogenic ★★★ same residue
DYSF p.Arg1056Pro Pathogenic ★★★ same residue
DYSF p.Arg1056= Likely benign ★★ 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

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-arg1056ter (accessed [today's date]).

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