Is DYSF p.Arg419Trp (c.1255C>T) pathogenic?

DYSF p.Arg419Trp (c.1255C>T) is classified Conflicting classifications of pathogenicity in DYSF (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-04-09). AlphaMissense: likely pathogenic (0.5716); Ultra-rare (popmax 0.0793%, mid); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

What condition is associated with DYSF p.Arg419Trp (c.1255C>T)?

DYSF p.Arg419Trp (c.1255C>T) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin, restrictive cardiomyopathy, autosomal recessive limb-girdle muscular dystrophy type 2B (ClinVar).

How common is DYSF p.Arg419Trp (c.1255C>T) in the general population?

DYSF p.Arg419Trp (c.1255C>T) is ultra-rare (popmax 0.0793%, mid) (gnomAD).

What do computational predictors say about DYSF p.Arg419Trp (c.1255C>T)?

AlphaMissense predicts likely pathogenic (score 0.5716) — an in-silico prediction, not a clinical call.

DYSF p.Arg419Trp

c.1255C>T · rs527435707 · VCV287943

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.5716 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0793%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Computational evidence

Protein change
AlphaMissense	0.5716	likely pathogenic
REVEL	0.655	pathogenic-leaning
SaProt	LLR -13.52	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 1.2	GERP -2.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic
Overall
CADD	23.3	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 R387W vs ClinVar R419W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0793% Middle Eastern · 4/5,046 alleles

Filtering AF 0.048% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0433%

Overall 0.00805% 114/1,416,250 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0793%	1,262
South Asian	0.061%	1,639
Remaining individualsnot grpmax-eligible	0.0121%	8,289
European (non-Finnish)	0.00454%	22,007
Admixed American	0.00375%	26,689

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.Arg419Trp
Coding: c.1255C>T
MANE Select: NM_001130987
dbSNP: rs527435707
Type: single nucleotide variant
Location: chr2:71526325 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 419: a β-strand; the c2 3 domain

Full DYSF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuromuscular disease caused by qualitative or quantitative defects of dysferlin — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: restrictive cardiomyopathy autosomal recessive limb-girdle muscular dystrophy type 2B

Similar variants

DYSF p.Arg419Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
DYSF p.Arg419Pro Uncertain significance ★★★ ⚠ same residue
DYSF p.Arg419Leu 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.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-arg419trp (accessed [today's date]).

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