Is LDB3 p.Pro515Ser (c.1543C>T) pathogenic?

LDB3 p.Pro515Ser (c.1543C>T) is classified Uncertain significance in LDB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-16). AlphaMissense: likely benign (0.0905); Very rare (popmax 0.00134%, afr); Associated with myofibrillar myopathy 4.

What condition is associated with LDB3 p.Pro515Ser (c.1543C>T)?

LDB3 p.Pro515Ser (c.1543C>T) is associated with myofibrillar myopathy 4 (ClinVar).

How common is LDB3 p.Pro515Ser (c.1543C>T) in the general population?

LDB3 p.Pro515Ser (c.1543C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about LDB3 p.Pro515Ser (c.1543C>T)?

AlphaMissense predicts likely benign (score 0.0905) — an in-silico prediction, not a clinical call.

LDB3 p.Pro515Ser

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.1543C>T · rs1413862843 · VCV2176676

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0905 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

myofibrillar myopathy 4

Computational evidence

Protein change
AlphaMissense	0.0905	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -6.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -1, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 64 kb · p 0.14 · regional, not allelic
Overall
CADD	17.59	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,864 alleles

Overall 0.000124% 2/1,613,876 alleles · very rare exomes 1/1,461,830 · genomes 1/152,046 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,864
South Asian	0.0011%	91,066

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.Pro515Ser
Coding: c.1543C>T
MANE Select: NM_007078
dbSNP: rs1413862843
Type: single nucleotide variant
Location: chr10:86716638 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.98 · 2 PDB
Residue 515: 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.Pro515Thr Uncertain significance ★ ⚠ same residue
LDB3 p.Pro515Leu 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

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-pro515ser (accessed [today's date]).

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