Is DYSF p.Arg419Pro (c.1256G>C) pathogenic?

DYSF p.Arg419Pro (c.1256G>C) is classified Uncertain significance in DYSF (ClinVar, Expert panel, 2 submitters; last evaluated 2025-06-24). AlphaMissense: likely pathogenic (0.9868); Very rare (popmax 0.00223%, eas); Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with DYSF p.Arg419Pro (c.1256G>C)?

DYSF p.Arg419Pro (c.1256G>C) is associated with autosomal recessive limb-girdle muscular dystrophy (ClinVar).

How common is DYSF p.Arg419Pro (c.1256G>C) in the general population?

DYSF p.Arg419Pro (c.1256G>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about DYSF p.Arg419Pro (c.1256G>C)?

AlphaMissense predicts likely pathogenic (score 0.9868) — an in-silico prediction, not a clinical call.

DYSF p.Arg419Pro

c.1256G>C · rs776036392 · VCV498211

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9868 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy

ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP

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

PM2_Supporting PP3 PP4 PM3

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.1160G>C variant in DYSF, which is also known as NM_001130987.2: c.1256G>C p.(Arg419Pro), is a missense variant predicted to cause substitution of arginine to proline at amino acid 387, p.(Arg387Pro). This variant has been reported in three patients with LGMD (PMID: 30564623, 39548682), including in an unknown phase with a pathogenic variant (c.2163-2A>G, 0.5 pts, PMID: 30564623, LOVD Individual #00222090) and in a homozygous state in two individuals, both with known consanguinity (0.25 pts for each patient; PMID: 39548682, LOVD Individuals #00392018, #00391975) (PM3; PP4). The highest minor allele frequency for this variant is 0.00002519 (1/39700 exome chromosomes) in the East Asian population in gnomAD v4.1.0, which is less than the VCEP threshold of 0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.86, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, due to insufficient evidence, this variant is classified as a variant of uncertain significance 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; 06/24/2025): PM2_Supporting, PM3, PP4, PP3.

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

Computational evidence

Protein change
AlphaMissense	0.9868	likely pathogenic · top 4% in DYSF
REVEL	0.861	moderately pathogenic-leaning
SaProt	LLR -14.15	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 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R387P vs ClinVar R419P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,868 alleles

Overall 0.000137% 2/1,461,812 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,868
European (non-Finnish)	8.47e-05%	1,179,981

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.Arg419Pro
Coding: c.1256G>C
MANE Select: NM_001130987
dbSNP: rs776036392
Type: single nucleotide variant
Location: chr2:71526326 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 419: a β-strand; the c2 3 domain

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

Similar variants

DYSF p.Arg419Leu Uncertain significance ★★ ⚠ same residue
DYSF p.Arg419Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
DYSF p.Arg419Trp Conflicting classifications of pathogenicity ★ ⚠ 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-arg419pro (accessed [today's date]).

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