Is DYSF p.Arg409Ter (c.1225C>T) pathogenic?

DYSF p.Arg409Ter (c.1225C>T) is classified Pathogenic in DYSF (ClinVar, Expert panel, 11 submitters; last evaluated 2026-05-01). Very rare (popmax 0.00833%, amr); Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with DYSF p.Arg409Ter (c.1225C>T)?

DYSF p.Arg409Ter (c.1225C>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.Arg409Ter (c.1225C>T) in the general population?

DYSF p.Arg409Ter (c.1225C>T) is very rare (popmax 0.00833%, amr) (gnomAD).

DYSF p.Arg409Ter

c.1225C>T · rs758180890 · VCV265487

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 11 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

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 PP4_Strong

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.1129C>T p.(Arg377Ter) variant in DYSF, which is also known as NM_001130987.2: c.1225C>T p.(Arg409Ter), is a nonsense variant that introduces a premature stop codon in exon 12/55, 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 three unrelated individuals with LGMD (PMID: 33250842, 22297152; ClinVar SCV004292580.2 internal data communication), including in unconfirmed phase with a presumed diagnostic variant in two patients and in a homozygous state in one patient with possible familial consanguinity (0.25 pts, PMID: 33250842). At least one patient homozygous for this variant showed both progressive proximal muscle weakness and absent dysferlin expression in skeletal muscle, which is highly specific for DYSF-associated LGMD (PMID: 33250842; PP4_Strong). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency is 0.00017529 in gnomAD v4.1.0 (5/60010 Admixed American alleles), which is greater than the threshold for PM2_Supporting (criterion not met). 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 LGMD VCEP (specifications v2.0.0; 05/01/2026): PVS1, PP4_Strong.

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 13 of 56
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 0.076, phastCons 0.99
Overall
CADD	39.0	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 0.00833% Admixed American · 5/60,010 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000867% 14/1,614,078 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00937%	10,673
Admixed Americangrpmax	0.00833%	12,002
East Asian	0.00223%	44,888
European (non-Finnish)	0.000169%	590,023

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg409Ter
Coding: c.1225C>T
MANE Select: NM_001130987
dbSNP: rs758180890
Type: single nucleotide variant
Location: chr2:71526295 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 409: 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 distal myopathy with anterior tibial onset neuromuscular disease caused by qualitative or quantitative defects of dysferlin Miyoshi muscular dystrophy 1

Similar variants

DYSF p.Arg409Leu Uncertain significance ★ ⚠ same residue
DYSF p.Arg409= Likely benign ★ same residue
DYSF p.Arg409Gln Likely benign ★ ⚠ same residue
DYSF p.Arg409Gly 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

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-arg409ter (accessed [today's date]).

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