Is LDB3 p.Ala126= (c.378G>A) pathogenic?

LDB3 p.Ala126= (c.378G>A) is classified Benign/Likely benign in LDB3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-09). Rare (popmax 0.12%, sas); Associated with myofibrillar myopathy 4.

What condition is associated with LDB3 p.Ala126= (c.378G>A)?

LDB3 p.Ala126= (c.378G>A) is associated with myofibrillar myopathy 4 (ClinVar).

How common is LDB3 p.Ala126= (c.378G>A) in the general population?

LDB3 p.Ala126= (c.378G>A) is rare (popmax 0.12%, sas) (gnomAD).

LDB3 p.Ala126=

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.378G>A · rs149872184 · VCV464272

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.12%, sas)

Conditions

myofibrillar myopathy 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.6	GERP -4
Overall
CADD	3.206	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.12% South Asian · 109/91,042 alleles

Filtering AF 0.102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0946%

Overall 0.0101% 162/1,609,794 alleles · rare exomes 151/1,457,532 · genomes 11/152,262 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.12%	835
Remaining individualsnot grpmax-eligible	0.0128%	7,807
European (non-Finnish)	0.00381%	26,217

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.Ala126=
Coding: c.378G>A
MANE Select: NM_007078
dbSNP: rs149872184
Type: single nucleotide variant
Location: chr10:86681492 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.98 · 2 PDB
Residue 126: the 'disordered' region

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.Ala126Val Uncertain significance ★★ ⚠ same residue
LDB3 p.Ala147Thr Pathogenic/Likely pathogenic ★★ same condition
LDB3 p.Ala165Val Pathogenic/Likely pathogenic ★★ same condition
LDB3 c.1231+4A>C Uncertain significance ★★ same condition
LDB3 c.1858-11C>A Uncertain significance ★★ same condition
LDB3 c.246-3C>T Uncertain significance ★★ same condition
LDB3 c.322-1G>A Uncertain significance ★★ same condition
LDB3 c.859+3G>A Uncertain significance ★★ 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-ala126 (accessed [today's date]).

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