Is DYSF p.Arg1944Ter (c.5830C>T) pathogenic?

DYSF p.Arg1944Ter (c.5830C>T) is classified Pathogenic in DYSF (ClinVar, Expert panel, 16 submitters; last evaluated 2026-01-23). Very rare (popmax 0.0033%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with DYSF p.Arg1944Ter (c.5830C>T)?

DYSF p.Arg1944Ter (c.5830C>T) 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.Arg1944Ter (c.5830C>T) in the general population?

DYSF p.Arg1944Ter (c.5830C>T) is very rare (popmax 0.0033%, nfe) (gnomAD).

DYSF p.Arg1944Ter

c.5830C>T · rs121908959 · VCV6676

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 16 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0033%, 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.5713C>T p.(Arg1905Ter) variant in DYSF, which is also known as NM_001130987.2: c.5830C>T p.(Arg1944Ter), is a nonsense variant predicted to cause a premature stop codon in exon 51/55, leading to nonsense mediated decay in a gene in which loss of function is a known mechanism of disease (PVS1). There is also a chance for missplicing (SpliceAI delta score 0.23 for acceptor loss and 0.21 for donor loss), but exon skipping would be expected to introduce a frameshift and nonsense mediated decay. Across a selection of the available literature, this variant has been reported in at least seven individuals with suspected LGMD (PMID: 27602406, 33927379, 39548682), including in a homozygous state in at least two individuals with no reported familial consanguinity (1.0 pt, PMID: 39548682, LOVD individuals #00219410 and #00220156) and four with a second pathogenic variant in unknown phase (c.2779del p.(Ala927LeufsTer21), 0.5 pts, and c.3517dup p.(Ser1173PhefsTer2), 0.5 pts, PMID: 33927379; c.1392dupA p.(Asp465ArgfsTer9), 0.5 pts, and c.1481-1G>A, 0.5 pts, PMID: 27602406) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic DYSF variant had suspected LGMD and absent dysferlin protein expression in blood monocytes, which is highly specific for DYSF-associated LGMD (PMID: 27602406; PP4_Strong). The filtering allele frequency for this variant is 0.000043167 in gnomAD v4.1.0 (the upper bound of the 95% CI of 39/1180060 European (non-Finnish) chromosomes), which is lower than the LGMD VCEP threshold 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 (specifications v2.0.0; 01/23/2026): PVS1, PP4_Strong, PM3_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/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 52 of 56
Splicing
SpliceAI	Δ0.23	acceptor loss, 45 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 1.8	GERP -1.1, phastCons 0.003
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 0.0033% European (non-Finnish) · 39/1,180,060 alleles

Filtering AF 0.00247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00279% 45/1,614,122 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0033%	30,258
South Asian	0.00329%	30,361
Remaining individualsnot grpmax-eligible	0.0032%	31,243
Admixed American	0.00167%	60,014

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.Arg1944Ter
Coding: c.5830C>T
MANE Select: NM_001130987
dbSNP: rs121908959
Type: single nucleotide variant
Location: chr2:71674242 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1944: 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 distal myopathy with anterior tibial onset neuromuscular disease caused by qualitative or quantitative defects of dysferlin Miyoshi muscular dystrophy 1

Similar variants

DYSF p.Arg1944Gln Uncertain significance ★★ ⚠ same residue
DYSF p.Arg1944fs Pathogenic/Likely pathogenic ★★ same residue
DYSF p.Arg1944Pro Uncertain significance ★ ⚠ 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-arg1944ter (accessed [today's date]).

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