Is DYSF p.Val70Gly (c.209T>G) pathogenic?

DYSF p.Val70Gly (c.209T>G) is classified Pathogenic in DYSF (ClinVar, Expert panel, 6 submitters; last evaluated 2025-07-29). AlphaMissense: likely pathogenic (0.9733); Absent from gnomAD v4.1; Associated with autosomal recessive limb-girdle muscular dystrophy.

How common is DYSF p.Val70Gly (c.209T>G) in the general population?

DYSF p.Val70Gly (c.209T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DYSF p.Val70Gly (c.209T>G)?

AlphaMissense predicts likely pathogenic (score 0.9733) — an in-silico prediction, not a clinical call.

DYSF p.Val70Gly

Q: What condition is associated with DYSF p.Val70Gly (c.209T>G)?

DYSF p.Val70Gly (c.209T>G) 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.209T>G · rs886042878 · VCV284469

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9733 · 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 PS3_Moderate PP4_Strong PP3 PM3

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.206T>G variant in DYSF, which is also known as NM_001130987.2: c.209T>G p.(Val70Gly), is a missense variant predicted to cause substitution of valine to glycine at amino acid 69, p.(Val69Gly). This variant has been reported in at least four patients with suspected LGMD (PMID: 33250842, 35723113, 39925440), including in a homozygous state in two individuals without known familial consanguinity (1 pt; PMID: 33250842, 35723113) and in unknown phase with a pathogenic variant in one individual (NM_003494.4: c.5668-824C>T, 0.5 pts, PMID: 39925440) (PM3). At least one of the patients with a second presumed diagnostic DYSF variant displayed progressive muscle weakness and absent dysferlin expression in muscle biopsy, which is highly specific for DYSF-related LGMD (PMID: 33250842) (PP4_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Val69Gly protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). In addition, the computational predictor REVEL gives a score of 0.83, 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 1.0.0; 07/29/2025): PM3, PP4_Strong, PM2_Supporting, PS3_Moderate, PP3.

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

Computational evidence

Protein change
AlphaMissense	0.9733	likely pathogenic ✓ concordant with ClinVar · top 7% in DYSF
REVEL	0.83	moderately pathogenic-leaning
SaProt	LLR -15.13	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 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic
Overall
CADD	26.3	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 V69G vs ClinVar V70G) — 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.Val70Gly
Coding: c.209T>G
MANE Select: NM_001130987
dbSNP: rs886042878
Type: single nucleotide variant
Location: chr2:71481940 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 70: a β-strand; the c2 1 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 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
DYSF c.1149+4A>G Pathogenic ★★★ same condition
DYSF c.1149+5G>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-val70gly (accessed [today's date]).

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