Is LDB3 p.Glu658Lys (c.1972G>A) pathogenic?

LDB3 p.Glu658Lys (c.1972G>A) is classified Uncertain significance in LDB3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-01). AlphaMissense: likely pathogenic (0.9612); Very rare (popmax 0.00769%, sas); Associated with myofibrillar myopathy 4.

What condition is associated with LDB3 p.Glu658Lys (c.1972G>A)?

LDB3 p.Glu658Lys (c.1972G>A) is associated with myofibrillar myopathy 4 (ClinVar).

How common is LDB3 p.Glu658Lys (c.1972G>A) in the general population?

LDB3 p.Glu658Lys (c.1972G>A) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about LDB3 p.Glu658Lys (c.1972G>A)?

AlphaMissense predicts likely pathogenic (score 0.9612) — an in-silico prediction, not a clinical call.

LDB3 p.Glu658Lys

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.1972G>A · rs760563152 · VCV582501

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9612 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

myofibrillar myopathy 4

Computational evidence

Protein change
AlphaMissense	0.9612	likely pathogenic
REVEL	0.632	indeterminate
SaProt	LLR -14.12	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 64 kb · p 0.14 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00769% South Asian · 7/91,084 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00533%

Overall 0.00595% 96/1,613,958 alleles · very rare exomes 88/1,461,768 · genomes 8/152,190 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0096%	10,414
South Asiangrpmax	0.00769%	13,012
European (non-Finnish)	0.00703%	14,217

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Glu658Lys
Coding: c.1972G>A
MANE Select: NM_007078
dbSNP: rs760563152
Type: single nucleotide variant
Location: chr10:86718841 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.98 · 2 PDB
Residue 658: the lim zinc-binding 2 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.Glu658Gly 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-glu658lys (accessed [today's date]).

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