Is DYSF p.Arg500Cys (c.1498C>T) pathogenic?

DYSF p.Arg500Cys (c.1498C>T) is classified Conflicting classifications of pathogenicity in DYSF (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-02). AlphaMissense: likely pathogenic (0.7192); Rare (popmax 0.172%, amr); Associated with Miyoshi muscular dystrophy 1.

What condition is associated with DYSF p.Arg500Cys (c.1498C>T)?

DYSF p.Arg500Cys (c.1498C>T) is associated with Miyoshi muscular dystrophy 1, autosomal recessive limb-girdle muscular dystrophy type 2B, distal myopathy with anterior tibial onset (ClinVar).

How common is DYSF p.Arg500Cys (c.1498C>T) in the general population?

DYSF p.Arg500Cys (c.1498C>T) is rare (popmax 0.172%, amr) (gnomAD).

How is Miyoshi myopathy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DYSF p.Arg500Cys (c.1498C>T)?

AlphaMissense predicts likely pathogenic (score 0.7192) — an in-silico prediction, not a clinical call.

DYSF p.Arg500Cys

c.1498C>T · rs185119682 · VCV285813

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.7192 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.172%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Miyoshi muscular dystrophy 1

Computational evidence

Protein change
AlphaMissense	0.7192	likely pathogenic
REVEL	0.555	indeterminate
SaProt	LLR -11.23	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic
Overall
CADD	27.8	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 R468C vs ClinVar R500C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.172% Admixed American · 103/60,004 alleles

Filtering AF 0.145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.135%

Overall 0.0113% 183/1,613,970 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.172%	583
Remaining individualsnot grpmax-eligible	0.0432%	2,315
African / African-American	0.0293%	3,408
European (non-Finnish)	0.00254%	39,332
East Asian	0.00223%	44,864

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.Arg500Cys
Coding: c.1498C>T
MANE Select: NM_001130987
dbSNP: rs185119682
Type: single nucleotide variant
Location: chr2:71539161 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB

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

Disease context

Miyoshi muscular dystrophy 1 — 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

For Miyoshi myopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult
Prevalence: 1-9 / 1 000 000 (Japan)

Similar variants

DYSF p.Arg500His Uncertain significance ★★ ⚠ same residue
DYSF p.Val500Ile Uncertain significance ★ ⚠ same residue
DYSF p.Arg500_Leu501insTer 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.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-arg500cys (accessed [today's date]).

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