Is LDB3 p.Pro523Ala (c.1567C>G) pathogenic?

LDB3 p.Pro523Ala (c.1567C>G) is classified Conflicting classifications of pathogenicity in LDB3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-02-19). AlphaMissense: likely benign (0.0517); Very rare (popmax 0.00356%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with LDB3 p.Pro523Ala (c.1567C>G)?

LDB3 p.Pro523Ala (c.1567C>G) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1C, myofibrillar myopathy 4 (ClinVar).

How common is LDB3 p.Pro523Ala (c.1567C>G) in the general population?

LDB3 p.Pro523Ala (c.1567C>G) is very rare (popmax 0.00356%, nfe) (gnomAD).

What do computational predictors say about LDB3 p.Pro523Ala (c.1567C>G)?

AlphaMissense predicts likely benign (score 0.0517) — an in-silico prediction, not a clinical call.

LDB3 p.Pro523Ala

c.1567C>G · rs794729062 · VCV201850

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0517 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0517	likely benign
REVEL	0.162	moderately benign-leaning
SaProt	LLR -8.03	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 0.21	GERP -0.65
Regional constraint	o/e 0.95	unconstrained · MANE · 64 kb · p 0.14 · regional, not allelic
Overall
CADD	11.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00356% European (non-Finnish) · 42/1,180,010 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00273% 44/1,613,898 alleles · very rare exomes 43/1,461,796 · genomes 1/152,102 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00356%	28,095
African / African-American	0.00267%	37,451

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.Pro523Ala
Coding: c.1567C>G
MANE Select: NM_007078
dbSNP: rs794729062
Type: single nucleotide variant
Location: chr10:86716662 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.98 · 2 PDB
Residue 523: the 'disordered' region

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy 1C myofibrillar myopathy 4

Similar variants

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
LDB3 c.859+5G>C 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-pro523ala (accessed [today's date]).

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