Is DYSF p.Arg1625Ter (c.4873C>T) pathogenic?

DYSF p.Arg1625Ter (c.4873C>T) is classified Pathogenic in DYSF (ClinVar, Expert panel, 13 submitters; last evaluated 2025-04-16). Ultra-rare (popmax 0.0164%, mid); Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with DYSF p.Arg1625Ter (c.4873C>T)?

DYSF p.Arg1625Ter (c.4873C>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.Arg1625Ter (c.4873C>T) in the general population?

DYSF p.Arg1625Ter (c.4873C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

DYSF p.Arg1625Ter

c.4873C>T · rs398123789 · VCV94330

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 13 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

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 PM3_Strong

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.4756C>T p.(Arg1586Ter) variant in DYSF, which is also known as NM_001130987.2: c.4873C>T p.(Arg1625Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 43/55, 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 patients with features consistent with LGMD (PMID: 36983702; 23641709; 23530687; 11468312), including in a homozygous state in one individual without reported familial consanguinity (0.5 pts, PMID: 11468312) and in trans with a likely pathogenic or pathogenic variant in two individuals (NM_003494.4: c.265C>T p.(Arg89Ter), 1.0 pt, PMID: 23641709; NM_003494.4: c.3113G>C p.(Arg1038Pro), 1.0 pt, PMID: 36983702) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic variant in DYSF had a clinical diagnosis of LGMD (Miyoshi myopathy) and absent dysferlin protein expression in both skeletal muscle and blood monocytes, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 36983702; 33610434). The filtering allele frequency of this variant is 0.0001061 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 4/86258 South Asian chromosomes), which is greater than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting 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 ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/16/2025): PVS1, PM3_Strong, 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 44 of 56
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.1, phastCons 1
Overall
CADD	48.0	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00173% 28/1,614,006 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
South Asian	0.00439%	22,769
Admixed American	0.00333%	30,001
Remaining individualsnot grpmax-eligible	0.0032%	31,241
European (non-Finnish)	0.00153%	65,557
African / African-American	0.00134%	74,906

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.Arg1625Ter
Coding: c.4873C>T
MANE Select: NM_001130987
dbSNP: rs398123789
Type: single nucleotide variant
Location: chr2:71658995 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1625: the c2 6 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.Arg1625Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
DYSF p.Arg1625_Gly1628delinsTer 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

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-arg1625ter (accessed [today's date]).

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