Is DYSF p.Leu354Pro (c.1061T>C) pathogenic?

DYSF p.Leu354Pro (c.1061T>C) is classified Pathogenic in DYSF (ClinVar, Expert panel, 6 submitters; last evaluated 2025-11-17). AlphaMissense: likely pathogenic (0.991); Ultra-rare (popmax 0.0178%, eas); Associated with autosomal recessive limb-girdle muscular dystrophy.

How common is DYSF p.Leu354Pro (c.1061T>C) in the general population?

DYSF p.Leu354Pro (c.1061T>C) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about DYSF p.Leu354Pro (c.1061T>C)?

AlphaMissense predicts likely pathogenic (score 0.991) — an in-silico prediction, not a clinical call.

DYSF p.Leu354Pro

Q: What condition is associated with DYSF p.Leu354Pro (c.1061T>C)?

DYSF p.Leu354Pro (c.1061T>C) is associated with autosomal recessive limb-girdle muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2B, neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

c.1061T>C · rs768546511 · VCV551237

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.991 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy

ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP

Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):

PS3_Moderate PP4_Strong PM3_Strong PP3

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.965T>C variant in DYSF, which is also known as NM_001130987.2: c.1061T>C p.(Leu354Pro), is a missense variant predicted to cause substitution of leucine to proline at amino acid 322, p.(Leu322Pro). This variant has been detected in at least 15 unrelated individuals with LGMD (PMID: 29138090, 25591676, 34559919, 27647186, 32576226, 32400077), including in unconfirmed phase with a pathogenic variant in at least 4 patients (NM_003494.3: c.3137G>A p.(Arg1046His), 0.5 pts, PMID: 32400077; c.5077C>T p.(Arg1693Trp), 0.5 pts, PMID: 32400077; c.1852G>A p.(Gly618Arg), 0.5 pts, PMID: 32400077; c.610C>T p.(Arg204Ter), 0.5 pts, PMID: 29138090) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic DYSF variant had a clinical diagnosis of LGMD and absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-associated LGMD (PMID: 25591676; PP4_Strong). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.0 is 0.0003216 (8/44884 East Asian chromosomes), which is greater than the LGMD VCEP threshold (0.0001), not meeting this criterion (PM2_Supporting not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu322Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). The computational predictor REVEL gives a score of 0.94, which is above the VCEP threshold (PP3). In summary, this variant meets the criteria to be classified as Pathogenic 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; 11/17/2025): PM3_Strong, PP4_Strong, PS3_Moderate, PP3.

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

Computational evidence

Protein change
AlphaMissense	0.991	likely pathogenic ✓ concordant with ClinVar · top 3% in DYSF
REVEL	0.943	strongly pathogenic-leaning
SaProt	LLR -13.66	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 7.8	GERP 2.2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic
Overall
CADD	25.0	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 L322P vs ClinVar L354P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0178% East Asian · 8/44,884 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.000496% 8/1,613,974 alleles · ultra-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.Leu354Pro
Coding: c.1061T>C
MANE Select: NM_001130987
dbSNP: rs768546511
Type: single nucleotide variant
Location: chr2:71520816 (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

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

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2B neuromuscular disease caused by qualitative or quantitative defects of dysferlin Miyoshi muscular dystrophy 1

Similar variants

DYSF p.Leu354= 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.1033+5G>A 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

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-leu354pro (accessed [today's date]).

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