Is DYSF p.Ser1726Pro (c.5176T>C) pathogenic?

DYSF p.Ser1726Pro (c.5176T>C) is classified Likely pathogenic in DYSF (ClinVar, Expert panel, 2 submitters; last evaluated 2025-01-28). AlphaMissense: likely pathogenic (0.9219); Absent from gnomAD v4.1; Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with DYSF p.Ser1726Pro (c.5176T>C)?

DYSF p.Ser1726Pro (c.5176T>C) is associated with autosomal recessive limb-girdle muscular dystrophy, neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

How common is DYSF p.Ser1726Pro (c.5176T>C) in the general population?

DYSF p.Ser1726Pro (c.5176T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DYSF p.Ser1726Pro (c.5176T>C)?

AlphaMissense predicts likely pathogenic (score 0.9219) — an in-silico prediction, not a clinical call.

DYSF p.Ser1726Pro

c.5176T>C · rs1573060017 · VCV665724

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9219 · 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):

PM2_Supporting PP4_Strong PP3 PM3

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.5059T>C variant in DYSF, which is also known as NM_001130987.2: c.5176T>C p.(Ser1726Pro), is a missense variant predicted to cause substitution of serine by proline at amino acid 1687, p.(Ser1687Pro). This variant has been identified in one individual with a diagnosis of LGMD, where it it was confirmed in trans with a variant classified as pathogenic by the LGMD VCEP (c.2643+1G>A, 1.0 pt, PMID: 36983702) (PM3). This patient displayed progressive limb girdle muscle weakness and significantly reduced or absent dysferlin protein expression in skeletal muscle and blood monocytes, which is highly specific for DYSF-related LGMD (PMID: 36983702; PP4_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.8, which exceeds the threshold of ≥0.70, evidence that correlates with impact to DYSF function (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; 01/28/2025): PM3, PP4_Strong, PM2_Supporting, PP3.

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

Computational evidence

Protein change
AlphaMissense	0.9219	likely pathogenic ✓ concordant with ClinVar
REVEL	0.795	moderately pathogenic-leaning
SaProt	LLR -12.18	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 2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	25.2	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 S1687P vs ClinVar S1726P) — 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.Ser1726Pro
Coding: c.5176T>C
MANE Select: NM_001130987
dbSNP: rs1573060017
Type: single nucleotide variant
Location: chr2:71665163 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1726: 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: neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Similar variants

DYSF p.Ser1726= 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-ser1726pro (accessed [today's date]).

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