Is DYSF p.Leu730Val (c.2188C>G) pathogenic?

DYSF p.Leu730Val (c.2188C>G) is classified Uncertain significance in DYSF (ClinVar, Single submitter, 2 submitters; last evaluated 2026-03-25). AlphaMissense: likely benign (0.1353); Very rare (popmax 8.6e-05%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy type 2B.

What condition is associated with DYSF p.Leu730Val (c.2188C>G)?

DYSF p.Leu730Val (c.2188C>G) is associated with autosomal recessive limb-girdle muscular dystrophy type 2B (ClinVar).

How common is DYSF p.Leu730Val (c.2188C>G) in the general population?

DYSF p.Leu730Val (c.2188C>G) is very rare (popmax 8.6e-05%, nfe) (gnomAD).

What do computational predictors say about DYSF p.Leu730Val (c.2188C>G)?

AlphaMissense predicts likely benign (score 0.1353) — an in-silico prediction, not a clinical call.

DYSF p.Leu730Val

Q: How is Dysferlin-related limb-girdle muscular dystrophy R2 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.2188C>G · VCV4067084

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1353 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.6e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2B

Computational evidence

Protein change
AlphaMissense	0.1353	likely benign
REVEL	0.165	moderately benign-leaning
SaProt	LLR -6.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.24	donor gain, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.9	GERP -0.72, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 18 kb · p 4.1e-05 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L712V vs ClinVar L730V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.6e-05% European (non-Finnish) · 1/1,162,302 alleles

Overall 7.02e-05% 1/1,424,986 alleles · very rare

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.Leu730Val
Coding: c.2188C>G
MANE Select: NM_001130987
Type: single nucleotide variant
Location: chr2:71556043 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB

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

Disease context

autosomal recessive limb-girdle muscular dystrophy type 2B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Dysferlin-related limb-girdle muscular dystrophy R2 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult
Prevalence: 1-9 / 1 000 000 (United Kingdom)

Similar variants

DYSF c.1033+1G>A 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
DYSF c.1481-1G>A Pathogenic ★★★ same condition
DYSF c.1693-6T>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-leu730val (accessed [today's date]).

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