What condition is associated with DYSF p.Ile1354= (c.4062C>A)?

DYSF p.Ile1354= (c.4062C>A) is associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin, autosomal recessive limb-girdle muscular dystrophy type 2B, distal myopathy with anterior tibial onset (ClinVar).

DYSF p.Ile1354=

Q: Is DYSF p.Ile1354= (c.4062C>A) pathogenic?

DYSF p.Ile1354= (c.4062C>A) is classified Benign in DYSF (ClinVar, Multiple submitters, 17 submitters; last evaluated 2026-06-12). Common (popmax 53.1%, amr) — too common for a highly-penetrant pathogenic allele; Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

Q: How common is DYSF p.Ile1354= (c.4062C>A) in the general population?

DYSF p.Ile1354= (c.4062C>A) is common (popmax 53.1%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.4062C>A · rs2303606 · VCV94316

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 17 submitters

gnomAD v4.1

Common

common (popmax 53.1%, amr) — too common for a highly-penetrant pathogenic allele

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.38	GERP -3, phastCons 0.99
Overall
CADD	6.799	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 53.1% Admixed American · 31,869/60,016 alleles

Filtering AF 52.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 52.4%

Overall 50.1% 808,434/1,613,814 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	59.8%	2
Finnishnot grpmax-eligible	53.6%	2
Admixed Americangrpmax	53.1%	2
Amishnot grpmax-eligible	51.1%	2
European (non-Finnish)	50.9%	2
Remaining individualsnot grpmax-eligible	50%	2
Middle Eastern	48.6%	2
East Asian	47%	2
South Asian	43%	2
African / African-American	39.6%	3

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile1354=
Coding: c.4062C>A
MANE Select: NM_001130987
dbSNP: rs2303606
Type: single nucleotide variant
Location: chr2:71611467 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1354: the c2 5 domain

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

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2B distal myopathy with anterior tibial onset Miyoshi muscular dystrophy 1

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+1G>C 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

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-ile1354 (accessed [today's date]).

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