Is DYSF p.Tyr1252= (c.3756T>C) pathogenic?

DYSF p.Tyr1252= (c.3756T>C) is classified Likely benign in DYSF (ClinVar, Expert panel, 7 submitters; last evaluated 2025-10-29). Ultra-rare (popmax 0.0583%, amr); Associated with autosomal recessive limb-girdle muscular dystrophy.

How common is DYSF p.Tyr1252= (c.3756T>C) in the general population?

DYSF p.Tyr1252= (c.3756T>C) is ultra-rare (popmax 0.0583%, amr) (gnomAD).

DYSF p.Tyr1252=

Q: What condition is associated with DYSF p.Tyr1252= (c.3756T>C)?

DYSF p.Tyr1252= (c.3756T>C) is associated with autosomal recessive limb-girdle muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2B, neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

c.3756T>C · rs141720146 · VCV167024

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0583%, amr)

Conditions

autosomal recessive limb-girdle muscular dystrophy

ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP

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

BP7_Strong BP4

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.3702T>C p.(Tyr1234=) variant in DYSF, which is also known as NM_001130987.2: c.3756T>C (p.Tyr1252=), is a synonymous (silent) variant that affects the last nucleotide of exon 33. The SpliceAI prediction score for this variant is 0.00 (BP4), and RNASeq data showed this variant does not affect splicing (PMID: 36983702; BP7_Strong_RNA). This variant has been identified in three individuals with suspected LGMD, all with at least two additional DYSF variants including those classified as pathogenic. However, phase was not known in any of these individuals (PMID: 18853459, 36983702; PM3 and BP2 not met). The Grpmax variant allele frequency for this variant in gnomAD v4.1.0 is 0.0005834 (35/59994 Admixed American chromosomes), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). This population also includes one homozygous individual. In summary, this variant meets the criteria to be classified as Likely Benign 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 2.0.0; 10/29/2025): BP4, BP7_Strong_RNA.

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

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 -20	GERP -4
Overall
CADD	0.01	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0583% Admixed American · 35/59,994 alleles

Filtering AF 0.0431% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0378%

Overall 0.0162% 261/1,611,652 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0583%	1,714
Remaining individualsnot grpmax-eligible	0.0208%	4,805
European (non-Finnish)	0.0175%	5,701
African / African-American	0.00534%	18,731
East Asian	0.00446%	22,445

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.Tyr1252=
Coding: c.3756T>C
MANE Select: NM_001130987
dbSNP: rs141720146
Type: single nucleotide variant
Location: chr2:71598745 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1252: the c2 4 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

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2B neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Similar variants

DYSF p.Tyr1252Ter Pathogenic ★ same residue
DYSF p.Tyr1252Cys 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
DYSF c.1149+1G>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-tyr1252 (accessed [today's date]).

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