Is DYSF p.Gln709Ter (c.2125C>T) pathogenic?

DYSF p.Gln709Ter (c.2125C>T) is classified Pathogenic in DYSF (ClinVar, Expert panel, 5 submitters; last evaluated 2025-10-29). Very rare (popmax 0.000867%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with DYSF p.Gln709Ter (c.2125C>T)?

DYSF p.Gln709Ter (c.2125C>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.Gln709Ter (c.2125C>T) in the general population?

DYSF p.Gln709Ter (c.2125C>T) is very rare (popmax 0.000867%, nfe) (gnomAD).

DYSF p.Gln709Ter

c.2125C>T · rs756258757 · VCV963357

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000867%, 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

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.2071C>T p.(Gln691Ter) variant in DYSF, which is also known as NM_001130987.2: c.2125C>T p.(Gln709Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 22/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in two individuals with LGMD (PMID: 33610434, 36983702), including confirmed in trans in one individual with a pathogenic variant (NM_003494.4: c.3113G>A p.(Arg1038Gln), 1 pt, PMID: 36983702) (PM3). Both individuals had absent dysferlin protein expression, which is highly specific for DYSF-related LGMD, and one individual also displayed progressive muscle weakness (PP4_Strong). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.0 is 0.000014703 (10/1153648 European (non-Finnish) alleles), 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 2.0.0; 10/29/2025): 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	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 22 of 56
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.65, 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 0.000867% European (non-Finnish) · 10/1,153,648 alleles

Filtering AF 0.000438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00032%

Overall 0.00064% 10/1,563,558 alleles · very rare

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.Gln709Ter
Coding: c.2125C>T
MANE Select: NM_001130987
dbSNP: rs756258757
Type: single nucleotide variant
Location: chr2:71555980 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 709: 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.Gln709fs Likely pathogenic ★ 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
DYSF c.1149+1G>C Pathogenic ★★★ same condition
DYSF c.1149+4A>G 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-gln709ter (accessed [today's date]).

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