Is DYSF p.Pro2052Arg (c.6155C>G) pathogenic?

DYSF p.Pro2052Arg (c.6155C>G) is classified Likely pathogenic in DYSF (ClinVar, Expert panel, 3 submitters; last evaluated 2025-06-10). AlphaMissense: likely pathogenic (0.9309); Absent from gnomAD v4.1; Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with DYSF p.Pro2052Arg (c.6155C>G)?

DYSF p.Pro2052Arg (c.6155C>G) is associated with autosomal recessive limb-girdle muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2B (ClinVar).

How common is DYSF p.Pro2052Arg (c.6155C>G) in the general population?

DYSF p.Pro2052Arg (c.6155C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DYSF p.Pro2052Arg (c.6155C>G)?

AlphaMissense predicts likely pathogenic (score 0.9309) — an in-silico prediction, not a clinical call.

DYSF p.Pro2052Arg

c.6155C>G · rs886044643 · VCV291078

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9309 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy

ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP

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

PM3_Supporting PM2_Supporting PP4_Strong PP3

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.6038C>G variant in DYSF, which is also known as NM_001130987.2: c.6155C>G p.(Pro2052Arg), is a missense variant predicted to cause substitution of proline by arginine at amino acid 2013, p.(Pro2013Arg). This variant has been reported in unknown phase with a pathogenic variant in at least one individual with LGMD (NM_003494.4: c.3137G>A p.(Arg1064His), 0.5 pts, PMID: 36983702, 30564623; LOVD Individual #00221252) (PM3_Supporting). This individual displayed progressive limb girdle muscle weakness and disease range dysferlin expression by blood monocyte assay, which is highly specific for DYSF-related LGMD (PP4_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.83, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function. In addition, SpliceAI gives a score of 0.31 for donor gain. (PP3). In summary, this variant meets the criteria to be classified as Likely 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 1.0.0; 06/10/2025): PM3_Supporting, PP4_Strong, PM2_Supporting, PP3.

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

Computational evidence

Protein change
AlphaMissense	0.9309	likely pathogenic ✓ concordant with ClinVar
REVEL	0.834	moderately pathogenic-leaning
SaProt	LLR -14.75	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.31	donor gain, 1 bp away · masked 0 · deltas
Pangolin	Δ0.20	gain · loss 0.05 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	27.8	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 P2013R vs ClinVar P2052R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DYSF
Protein: p.Pro2052Arg
Coding: c.6155C>G
MANE Select: NM_001130987
dbSNP: rs886044643
Type: single nucleotide variant
Location: chr2:71681092 (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

Similar variants

DYSF p.Pro2052Ala Uncertain significance ★ ⚠ same residue
DYSF p.Pro2052Leu Uncertain significance ★ ⚠ same residue
DYSF p.Pro2052= 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

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-pro2052arg (accessed [today's date]).

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