Is DYSF p.Pro809Leu (c.2426C>T) pathogenic?

DYSF p.Pro809Leu (c.2426C>T) is classified Uncertain significance in DYSF (ClinVar, Expert panel, 3 submitters; last evaluated 2026-04-30). AlphaMissense: likely pathogenic (0.9012); Very rare (popmax 0.000847%, nfe); Associated with limb-girdle muscular dystrophy.

What condition is associated with DYSF p.Pro809Leu (c.2426C>T)?

DYSF p.Pro809Leu (c.2426C>T) is associated with limb-girdle muscular dystrophy, neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

How common is DYSF p.Pro809Leu (c.2426C>T) in the general population?

DYSF p.Pro809Leu (c.2426C>T) is very rare (popmax 0.000847%, nfe) (gnomAD).

What do computational predictors say about DYSF p.Pro809Leu (c.2426C>T)?

AlphaMissense predicts likely pathogenic (score 0.9012) — an in-silico prediction, not a clinical call.

DYSF p.Pro809Leu

c.2426C>T · rs121908956 · VCV566085

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9012 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

limb-girdle muscular dystrophy

ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP

Uncertain Significance for limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):

PM2_Supporting PM5_Supporting PP3

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.2372C>T variant in DYSF, which is also known as NM_001130987.2: c.2426C>T p.(Pro809Leu) is a missense variant expected to cause the substitution of proline for leucine at amino acid 791, p.(Pro791Leu). To our knowledge, this variant has not been reported in association with limb girdle muscular dystrophy. The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.0 is 0.000014 (10/1180030 European (non-Finnish) chromosomes), which is less than the LGMD VCEP threshold (0.0001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.86, which exceeds the threshold of ≥0.70, evidence that correlates with impact to DYSF function. In addition, another missense variant at this position, NM_003494.4: c.2372C>G p.(Pro791Arg), has been classified as likely pathogenic for limb girdle muscular dystrophy by the LGMD VCEP (PM5_Supporting). In summary, at this time there is insufficient evidence to classify this variant as pathogenic or benign, and it remains a variant of uncertain significance 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 2.0.0; 04/30/2026): PM2_Supporting, PP3, PM5_Supporting.

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

Computational evidence

Protein change
AlphaMissense	0.9012	likely pathogenic
REVEL	0.856	moderately pathogenic-leaning
SaProt	LLR -12.61	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 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 18 kb · p 4.1e-05 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P791L vs ClinVar P809L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000847% European (non-Finnish) · 10/1,180,030 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.00062% 10/1,614,090 alleles · very rare

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.Pro809Leu
Coding: c.2426C>T
MANE Select: NM_001130987
dbSNP: rs121908956
Type: single nucleotide variant
Location: chr2:71564074 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 809: a β-strand

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

Disease context

limb-girdle muscular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Similar variants

DYSF p.Pro809Arg Likely pathogenic ★★★ same residue
DYSF p.Pro809Gln Likely pathogenic ★ same residue
DYSF p.Pro809= 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.1149+1G>A Pathogenic ★★★ same condition
DYSF c.1149+4A>G 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-pro809leu (accessed [today's date]).

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