Is DYSF p.Pro1737Arg (c.5210C>G) pathogenic?

DYSF p.Pro1737Arg (c.5210C>G) is classified Likely pathogenic in DYSF (ClinVar, Expert panel, 3 submitters; last evaluated 2026-01-23). AlphaMissense: likely pathogenic (0.9865); Very rare (popmax 0.0011%, sas); Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with DYSF p.Pro1737Arg (c.5210C>G)?

DYSF p.Pro1737Arg (c.5210C>G) 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.Pro1737Arg (c.5210C>G) in the general population?

DYSF p.Pro1737Arg (c.5210C>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about DYSF p.Pro1737Arg (c.5210C>G)?

AlphaMissense predicts likely pathogenic (score 0.9865) — an in-silico prediction, not a clinical call.

DYSF p.Pro1737Arg

c.5210C>G · rs776452710 · VCV567124

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9865 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

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 PM5_Supporting PP1 PP3 PP4

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.5093C>G variant in DYSF, which is also known as NM_001130987.2: c.5210C>G p.(Pro1737Arg), is a missense variant predicted to cause substitution of proline to arginine at amino acid 1698, p.(Pro1698Arg). This variant has been observed in three individuals with LGMD, including two siblings in a homozygous state with reported consanguinity (0.25 pts, ClinVar SCV000814671.7 internal data communication; PP1) and one with a pathogenic variant in unknown phase (NM_003494.4: c.265C>T p.(Arg89Ter), 0.5 pts, PMID: 38582400) (PM3_Supporting; PP4). The highest allele frequency for this variant in gnomAD v4.1.0 is 0.00001098 (1/91080 South Asian chromosomes), which is less than the ClinGen LGMD VCEP threshold (<0.0001) (PM2_Supporting). The computational predictor REVEL gives a score of 0.91, which is above the LGMD VCEP threshold of ≥0.70 (PP3). In addition, another missense variant at the same codon, NM_003494.4: c.5093C>T p.(Pro1698Leu), has been classified as likely pathogenic by the ClinGen LGMD VCEP (PM5_Supporting). In summary, this variant is 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 (specifications v2.0.0; 01/23/2026): PM3_Supporting, PP4, PP3, PM2_Supporting, PM5_Supporting, PP1.

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

Computational evidence

Protein change
AlphaMissense	0.9865	likely pathogenic ✓ concordant with ClinVar · top 4% in DYSF
REVEL	0.908	moderately pathogenic-leaning
SaProt	LLR -17.23	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, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	24.8	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 P1698R vs ClinVar P1737R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,080 alleles

Overall 6.84e-05% 1/1,461,694 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.Pro1737Arg
Coding: c.5210C>G
MANE Select: NM_001130987
dbSNP: rs776452710
Type: single nucleotide variant
Location: chr2:71665197 (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: neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Similar variants

DYSF p.Pro1737Leu Likely pathogenic ★★★ same residue
DYSF p.Pro1737= Likely benign ★ same residue
DYSF p.Pro1737Ser Uncertain significance ★ ⚠ 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-pro1737arg (accessed [today's date]).

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