Is LDB3 p.Arg559fs (c.1675del) pathogenic?

LDB3 p.Arg559fs (c.1675del) is classified Pathogenic in LDB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-07). Very rare (popmax 8.5e-05%, nfe); Associated with myofibrillar myopathy 4.

What condition is associated with LDB3 p.Arg559fs (c.1675del)?

LDB3 p.Arg559fs (c.1675del) is associated with myofibrillar myopathy 4 (ClinVar).

How common is LDB3 p.Arg559fs (c.1675del) in the general population?

LDB3 p.Arg559fs (c.1675del) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

LDB3 p.Arg559fs

Q: How is Late-onset distal myopathy, Markesbery-Griggs type inherited?

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

c.1675del · VCV3666400

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Conditions

myofibrillar myopathy 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.5e-05% European (non-Finnish) · 1/1,176,322 alleles

Overall 6.23e-05% 1/1,605,128 alleles · very rare exomes 0/1,452,994 · genomes 1/152,134 · joint denominator

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: LDB3
Protein: p.Arg559fs
Coding: c.1675del
MANE Select: NM_007078
Type: Deletion
Location: chr10:86716769 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.98 · 2 PDB
Residue 559: the lim zinc-binding 1 domain; a UniProt-annotated variant site (in cmd2l; likely pathogenic)

Full LDB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

myofibrillar myopathy 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Late-onset distal myopathy, Markesbery-Griggs type (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

LDB3 p.Arg559Gln Uncertain significance ★★ ⚠ same residue
LDB3 p.Arg559= Uncertain significance ★ same residue
LDB3 p.Arg559Leu Uncertain significance ★ ⚠ same residue
LDB3 p.Arg559Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
LDB3 c.860-22_860-12del Uncertain significance ★★ same condition
LDB3 p.Glu483_Ala485del Uncertain significance ★★ same condition
LDB3 p.Val676fs Uncertain significance ★★ same condition
LDB3 c.1086-247_1231+2del 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/ldb3-p-arg559fs (accessed [today's date]).

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