Is DYSF p.Asp320Val (c.959A>T) pathogenic?

DYSF p.Asp320Val (c.959A>T) is classified Pathogenic in DYSF (ClinVar, Expert panel, 5 submitters; last evaluated 2025-10-29). AlphaMissense: likely pathogenic (0.8345); Absent from gnomAD v4.1; Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with DYSF p.Asp320Val (c.959A>T)?

DYSF p.Asp320Val (c.959A>T) is associated with autosomal recessive limb-girdle muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2B, distal myopathy with anterior tibial onset (ClinVar).

How common is DYSF p.Asp320Val (c.959A>T) in the general population?

DYSF p.Asp320Val (c.959A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DYSF p.Asp320Val (c.959A>T)?

AlphaMissense predicts likely pathogenic (score 0.8345) — an in-silico prediction, not a clinical call.

DYSF p.Asp320Val

c.959A>T · rs1553522751 · VCV555770

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.8345 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy

ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP

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

PM2_Supporting PP4_Strong PM3_Strong PP3

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.863A>T variant in DYSF, which is also known as NM_001130987.2: c.959A>T p.(Asp320Val), is a missense variant predicted to cause the substitution of valine for aspartic acid at codon 288. This variant has been reported in at least 11 individuals with features consistent with limb-girdle muscular dystrophy (PMID: 34559919, 28403181, 27647186, 25591676), including in a homozygous state in two individuals without reported consanguinity (0.5 pts x2 = 1.0 pt; PMID 28403181, 27647186), confirmed in trans with a pathogenic variant in one case (NM_003494.4: c.5077C>T p.(Arg1693Trp), 1.0 pt, PMID: 28403181), and in unconfirmed phase with a pathogenic variant in three unrelated individuals (NM_003494.4: c.3137G>A p.(Arg1046His), 0.5 pts, PMID: 25591676; NM_003494.4: c.5077C>T p.(Arg1693Trp), 0.5 pts, PMID: 27647186; NM_003494.4: c.1667T>C p.(Leu556Pro), 0.5 pts, PMID: 27647186) (PM3_Strong). All of these patients were of Chinese ancestry. At least one of the patients with this variant had a second presumed diagnostic DYSF variant, a clinical diagnosis of LGMD, and absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-associated LGMD (PMID 27647186; PP4_Strong). This variant is absent from gnomAD v.4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.971, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic 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): PM3_Strong, PP4_Strong, PP3, PM2_Supporting.

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

Computational evidence

Protein change
AlphaMissense	0.8345	likely pathogenic ✓ concordant with ClinVar
REVEL	0.971	strongly pathogenic-leaning
SaProt	LLR -11.36	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic
Overall
CADD	23.1	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 D288V vs ClinVar D320V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DYSF
Protein: p.Asp320Val
Coding: c.959A>T
MANE Select: NM_001130987
dbSNP: rs1553522751
Type: single nucleotide variant
Location: chr2:71516996 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 320: a β-strand; the c2 2 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 distal myopathy with anterior tibial onset neuromuscular disease caused by qualitative or quantitative defects of dysferlin Miyoshi muscular dystrophy 1

Similar variants

DYSF p.Asp320= Likely benign ★ same residue
DYSF p.Asp320fs Pathogenic ★★★ 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-asp320val (accessed [today's date]).

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