Is DYSF p.Arg1759Cys (c.5275C>T) pathogenic?

DYSF p.Arg1759Cys (c.5275C>T) is classified Conflicting classifications of pathogenicity in DYSF (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-09). AlphaMissense: likely benign (0.0829); Very rare (popmax 0.00801%, afr); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

How common is DYSF p.Arg1759Cys (c.5275C>T) in the general population?

DYSF p.Arg1759Cys (c.5275C>T) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about DYSF p.Arg1759Cys (c.5275C>T)?

AlphaMissense predicts likely benign (score 0.0829) — an in-silico prediction, not a clinical call.

DYSF p.Arg1759Cys

Q: What condition is associated with DYSF p.Arg1759Cys (c.5275C>T)?

DYSF p.Arg1759Cys (c.5275C>T) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin, autosomal recessive limb-girdle muscular dystrophy type 2B (ClinVar).

c.5275C>T · rs757240900 · VCV643300

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0829 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Computational evidence

Protein change
AlphaMissense	0.0829	likely benign
REVEL	0.49	indeterminate
SaProt	LLR -8.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.068	GERP -2.3, phastCons 0.007
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	17.92	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 R1720C vs ClinVar R1759C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00801% African / African-American · 6/74,926 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.000991% 16/1,614,046 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,488
Admixed American	0.005%	20,001
Finnishnot grpmax-eligible	0.00156%	64,016
European (non-Finnish)	0.000508%	196,673

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.Arg1759Cys
Coding: c.5275C>T
MANE Select: NM_001130987
dbSNP: rs757240900
Type: single nucleotide variant
Location: chr2:71665262 (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

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

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

Similar variants

DYSF p.Arg1759His Conflicting classifications of pathogenicity ★ ⚠ 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
DYSF c.1149+4A>G Pathogenic ★★★ same condition
DYSF c.1276+5G>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-arg1759cys (accessed [today's date]).

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