Is DYSF p.Leu574Pro (c.1721T>C) pathogenic?

DYSF p.Leu574Pro (c.1721T>C) is classified Pathogenic in DYSF (ClinVar, Expert panel, 8 submitters; last evaluated 2026-01-23). AlphaMissense: likely pathogenic (0.9806); Ultra-rare (popmax 0.0179%, eas); Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with DYSF p.Leu574Pro (c.1721T>C)?

DYSF p.Leu574Pro (c.1721T>C) is associated with autosomal recessive limb-girdle muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2B, distal myopathy with anterior tibial onset (ClinVar).

How common is DYSF p.Leu574Pro (c.1721T>C) in the general population?

DYSF p.Leu574Pro (c.1721T>C) is ultra-rare (popmax 0.0179%, eas) (gnomAD).

What do computational predictors say about DYSF p.Leu574Pro (c.1721T>C)?

AlphaMissense predicts likely pathogenic (score 0.9806) — an in-silico prediction, not a clinical call.

DYSF p.Leu574Pro

c.1721T>C · rs200916654 · VCV545009

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9806 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0179%, 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 PP1 PP3

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.1667T>C variant in DYSF, which is also known as NM_001130987.2: c.1721T>C p.(Leu574Pro), is a missense variant predicted to cause substitution of leucine by proline at amino acid 556, p.(Leu556Pro). This variant has been reported in at least 18 individuals with features of LGMD (PMID: 27647186, 3560664 34559919). At least 11 individuals were homozygous, including three siblings with known consanguinity (1.0 pt, PMID: 27647186, 3560664 34559919; PP1). It was also identified in trans phase with a pathogenic variant in one individual (NM_003494.4: c.6124C>T p.(Arg2042Cys), 1.0 pt, PMID: 33560664) (PM3_Strong). At least one of these patients with two presumed diagnostic variants and clinical features of LGMD had absent dysferlin expression in muscle, which is highly specific for DYSF-related LGMD (PMID: 27647186, 33560664; PP4_Strong). The Grpmax variant allele frequency in gnomAD v4.1.0 is 0.0003332 (8/44628 East Asian chromosomes), which is greater than the LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu556Pro 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 0.72, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (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; 01/23/2026): PM3_Strong, PP4_Strong, PS3_Moderate, PP1, PP3.

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

Computational evidence

Protein change
AlphaMissense	0.9806	likely pathogenic ✓ concordant with ClinVar · top 6% in DYSF
REVEL	0.718	pathogenic-leaning
SaProt	LLR -15.31	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 6.2	GERP 0.76, phastCons 0.98
Regional constraint	o/e 1.02	unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic
Overall
CADD	24.4	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 L556P vs ClinVar L574P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0179% East Asian · 8/44,628 alleles

Filtering AF 0.00888% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00644%

Overall 0.000497% 8/1,609,460 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.Leu574Pro
Coding: c.1721T>C
MANE Select: NM_001130987
dbSNP: rs200916654
Type: single nucleotide variant
Location: chr2:71551635 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 574: a β-strand

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 distal myopathy with anterior tibial onset neuromuscular disease caused by qualitative or quantitative defects of dysferlin Miyoshi muscular dystrophy 1

Similar variants

DYSF p.Leu574_Leu575insVal 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.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-leu574pro (accessed [today's date]).

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