Is LDB3 p.Pro549Ser (c.1645C>T) pathogenic?

LDB3 p.Pro549Ser (c.1645C>T) is classified Uncertain significance in LDB3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-07). AlphaMissense: likely pathogenic (0.9863); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with LDB3 p.Pro549Ser (c.1645C>T)?

LDB3 p.Pro549Ser (c.1645C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is LDB3 p.Pro549Ser (c.1645C>T) in the general population?

LDB3 p.Pro549Ser (c.1645C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LDB3 p.Pro549Ser (c.1645C>T)?

AlphaMissense predicts likely pathogenic (score 0.9863) — an in-silico prediction, not a clinical call.

LDB3 p.Pro549Ser

c.1645C>T · rs1238404909 · VCV2574524

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9863 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9863	likely pathogenic
REVEL	0.267	benign-leaning
SaProt	LLR -15.34	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 64 kb · p 0.14 · regional, not allelic
Overall
CADD	28.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: LDB3
Protein: p.Pro549Ser
Coding: c.1645C>T
MANE Select: NM_007078
dbSNP: rs1238404909
Type: single nucleotide variant
Location: chr10:86716740 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.98 · 2 PDB
Residue 549: the lim zinc-binding 1 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

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

Similar variants

LDB3 p.Pro549Ala Uncertain significance ★ ⚠ same residue
LDB3 p.Pro549Leu Uncertain significance ★ ⚠ same residue
LDB3 p.Pro549= Uncertain significance ★ same residue
LDB3 c.246-3C>T Uncertain significance ★★ same condition
LDB3 c.860-3C>T Uncertain significance ★★ same condition
LDB3 p.Ala119Val Uncertain significance ★★ ⚠ same condition
LDB3 p.Ala126Val Uncertain significance ★★ ⚠ same condition
LDB3 p.Ala248Thr 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-pro549ser (accessed [today's date]).

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