Is DYSF p.Arg1756Trp (c.5266C>T) pathogenic?

DYSF p.Arg1756Trp (c.5266C>T) is classified Conflicting classifications of pathogenicity in DYSF (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-06-29). AlphaMissense: likely benign (0.0955); Rare (popmax 0.109%, nfe); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

How common is DYSF p.Arg1756Trp (c.5266C>T) in the general population?

DYSF p.Arg1756Trp (c.5266C>T) is rare (popmax 0.109%, nfe) (gnomAD).

What do computational predictors say about DYSF p.Arg1756Trp (c.5266C>T)?

AlphaMissense predicts likely benign (score 0.0955) — an in-silico prediction, not a clinical call.

DYSF p.Arg1756Trp

Q: What condition is associated with DYSF p.Arg1756Trp (c.5266C>T)?

DYSF p.Arg1756Trp (c.5266C>T) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin, autosomal recessive limb-girdle muscular dystrophy type 2B (ClinVar).

c.5266C>T · rs148541407 · VCV281237

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0955 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.109%, nfe)

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	0.0955	likely benign
REVEL	0.498	indeterminate
SaProt	LLR -9.70	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 0.79	GERP -2.5, phastCons 0.22
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	21.0	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 R1717W vs ClinVar R1756W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.109% European (non-Finnish) · 1,292/1,180,044 alleles

Filtering AF 0.105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.102%

Overall 0.0835% 1,348/1,614,180 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.109%	913
Remaining individualsnot grpmax-eligible	0.0384%	2,604
African / African-American	0.0187%	5,360
Admixed American	0.0167%	6,002
Middle Eastern	0.0165%	6,060
East Asian	0.00668%	14,961
Finnishnot grpmax-eligible	0.00469%	21,342
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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.Arg1756Trp
Coding: c.5266C>T
MANE Select: NM_001130987
dbSNP: rs148541407
Type: single nucleotide variant
Location: chr2:71665253 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1756: an α-helix

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.Arg1756Gln 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-arg1756trp (accessed [today's date]).

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