Is DYSF p.Arg1807Trp (c.5419C>T) pathogenic?

DYSF p.Arg1807Trp (c.5419C>T) is classified Pathogenic in DYSF (ClinVar, Expert panel, 15 submitters; last evaluated 2025-07-29). AlphaMissense: likely pathogenic (0.7485); Very rare (popmax 0.005%, amr); Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with DYSF p.Arg1807Trp (c.5419C>T)?

DYSF p.Arg1807Trp (c.5419C>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.Arg1807Trp (c.5419C>T) in the general population?

DYSF p.Arg1807Trp (c.5419C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about DYSF p.Arg1807Trp (c.5419C>T)?

AlphaMissense predicts likely pathogenic (score 0.7485) — an in-silico prediction, not a clinical call.

DYSF p.Arg1807Trp

c.5419C>T · rs746243052 · VCV286151

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 15 submitters

AlphaMissense

likely pathogenic

0.7485 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

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):

PS3_Moderate PP4_Strong PP1 PP3 PM3

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.5302C>T variant in DYSF, which is also known as NM_001130987.2: c.5419C>T p.(Arg1807Trp), is a missense variant predicted to cause substitution of arginine to tryptophan at amino acid 1768, p.(Arg1768Trp). This variant has been identified in at least 15 individuals with features consistent with LGMD (PMID: 17698709, 21522182, 25591676, 30564623, 32934002, 34559919; LOVD DYSF_000126), including in a homozygous state in a proband from a family without reported consanguinity (0.5 pts, PMID: 21522182) and confirmed in trans with a likely pathogenic or pathogenic variant (NM_003494.4: c.5979dup p.(Glu1994ArgfsTer3), 1.0 pt, PMID: 17698709) (PM3). This variant was identified in conjunction with another presumed diagnostic DYSF variant in at least one individual with a clinical diagnosis of LGMD and absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PMID: 25591676; PP4_Strong). It was also shown to segregate with autosomal recessive LGMD in three affected members from a single family (PMID: 21522182; PP1, capped with PP4_Strong). The filtering allele frequency of this variant is 0.0001734 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 3/44720 Admixed American chromosomes), which is greater than the LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg1768Trp protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). In addition, the computational predictor REVEL gives a score of 0.704, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). 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): PM3, PP4_Strong, PP1, PS3_Moderate, PP3.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.7485	likely pathogenic ✓ concordant with ClinVar
REVEL	0.704	pathogenic-leaning
SaProt	LLR -10.52	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 2.1, phastCons 0.99
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R1768W vs ClinVar R1807W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,004 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.0013% 21/1,614,038 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,001
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)	0.00136%	73,752

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.Arg1807Trp
Coding: c.5419C>T
MANE Select: NM_001130987
dbSNP: rs746243052
Type: single nucleotide variant
Location: chr2:71667477 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1807: the c2 7 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.Arg1807Gln Pathogenic ★★★ same residue
DYSF p.Arg1807Pro Likely pathogenic ★★ same residue
DYSF p.Arg1807= 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-arg1807trp (accessed [today's date]).

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