Is DYSF p.Ile686= (c.2058C>T) pathogenic?

DYSF p.Ile686= (c.2058C>T) is classified Likely benign in DYSF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). Ultra-rare (popmax 0.0134%, eas); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

How common is DYSF p.Ile686= (c.2058C>T) in the general population?

DYSF p.Ile686= (c.2058C>T) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

DYSF p.Ile686=

Q: What condition is associated with DYSF p.Ile686= (c.2058C>T)?

DYSF p.Ile686= (c.2058C>T) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

c.2058C>T · rs938649493 · VCV1122221

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Conditions

neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.2	GERP -2.2, phastCons 1
Overall
CADD	12.17	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,858 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.000496% 8/1,614,048 alleles · ultra-rare exomes 8/1,461,812 · genomes 0/152,236 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,476
Remaining individualsnot grpmax-eligible	0.0016%	62,498
South Asian	0.0011%	91,080

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.Ile686=
Coding: c.2058C>T
MANE Select: NM_001130987
dbSNP: rs938649493
Type: single nucleotide variant
Location: chr2:71553880 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 686: an α-helix

Full DYSF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuromuscular disease caused by qualitative or quantitative defects of dysferlin — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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.1149+1G>A Pathogenic ★★★ same condition
DYSF c.1149+4A>G Pathogenic ★★★ same condition
DYSF c.1276+5G>A Pathogenic ★★★ same condition
DYSF c.1276+5G>C Pathogenic ★★★ same condition
DYSF c.1481-1G>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-ile686 (accessed [today's date]).

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