Is LDB3 p.Pro463His (c.1388C>A) pathogenic?

LDB3 p.Pro463His (c.1388C>A) is classified Uncertain significance in LDB3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-22). AlphaMissense: likely benign (0.1276); Very rare (popmax 0.00541%, afr); Associated with Cardiovascular phenotype.

What condition is associated with LDB3 p.Pro463His (c.1388C>A)?

LDB3 p.Pro463His (c.1388C>A) is associated with Cardiovascular phenotype, myofibrillar myopathy 4 (ClinVar).

How common is LDB3 p.Pro463His (c.1388C>A) in the general population?

LDB3 p.Pro463His (c.1388C>A) is very rare (popmax 0.00541%, afr) (gnomAD).

What do computational predictors say about LDB3 p.Pro463His (c.1388C>A)?

AlphaMissense predicts likely benign (score 0.1276) — an in-silico prediction, not a clinical call.

LDB3 p.Pro463His

c.1388C>A · rs962833066 · VCV1771452

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1276 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00541%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1276	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -11.67	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 0.58, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 64 kb · p 0.14 · regional, not allelic
Overall
CADD	20.3	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 0.00541% African / African-American · 4/73,942 alleles

Filtering AF 0.00176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00105%

Overall 0.000248% 4/1,610,948 alleles · very rare exomes 1/1,461,350 · genomes 3/149,598 · 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.Pro463His
Coding: c.1388C>A
MANE Select: NM_007078
dbSNP: rs962833066
Type: single nucleotide variant
Location: chr10:86716483 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.98 · 2 PDB

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: myofibrillar myopathy 4

Similar variants

LDB3 p.Pro463Leu Uncertain significance ★★ ⚠ same residue
LDB3 p.Pro463Ser 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-pro463his (accessed [today's date]).

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