Is LDB3 p.Ser440Pro (c.1318T>C) pathogenic?

LDB3 p.Ser440Pro (c.1318T>C) is classified Likely benign in LDB3 (ClinVar, Single submitter, 5 submitters; last evaluated 2018-02-13). AlphaMissense: likely benign (0.1061); Low-frequency (popmax 1.02%, afr); Associated with hypertrophic cardiomyopathy 2.

What condition is associated with LDB3 p.Ser440Pro (c.1318T>C)?

LDB3 p.Ser440Pro (c.1318T>C) is associated with hypertrophic cardiomyopathy 2 (ClinVar).

How common is LDB3 p.Ser440Pro (c.1318T>C) in the general population?

LDB3 p.Ser440Pro (c.1318T>C) is low-frequency (popmax 1.02%, afr) (gnomAD).

What do computational predictors say about LDB3 p.Ser440Pro (c.1318T>C)?

AlphaMissense predicts likely benign (score 0.1061) — an in-silico prediction, not a clinical call.

LDB3 p.Ser440Pro

c.1318T>C · rs868594949 · VCV1299814

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1061 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.02%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypertrophic cardiomyopathy 2

Computational evidence

Protein change
AlphaMissense	0.1061	likely benign
REVEL	0.112	moderately benign-leaning
SaProt	LLR -11.53	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 2.9	GERP 1.5, phastCons 0.97
Regional constraint	o/e 0.95	unconstrained · MANE · 64 kb · p 0.14 · regional, not allelic
Overall
CADD	15.04	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 1.02% African / African-American · 159/15,614 alleles

Filtering AF 0.889% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.84%

Overall 0.17% 1,017/598,982 alleles · low-frequency exomes 612/588,666 · genomes 405/10,316 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.02%	98
Admixed American	0.844%	118
Finnishnot grpmax-eligible	0.499%	200
East Asian	0.479%	209
South Asian	0.394%	254
Middle Eastern	0.276%	362
Remaining individualsnot grpmax-eligible	0.179%	560
Ashkenazi Jewishnot grpmax-eligible	0.153%	654
European (non-Finnish)	0.0881%	1,135

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.Ser440Pro
Coding: c.1318T>C
MANE Select: NM_007078
dbSNP: rs868594949
Type: single nucleotide variant
Location: chr10:86716413 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.98 · 2 PDB
Residue 440: the 'disordered' region

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

Disease context

hypertrophic cardiomyopathy 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LDB3 p.Ser440= Likely benign ★★ same residue
LDB3 p.Ala434Pro Benign/Likely benign ★★ ⚠ same condition
LDB3 p.Pro435= Benign ★ same condition
LDB3 p.Ser440fs Likely benign ★ same residue
LDB3 p.Ala147Thr Pathogenic/Likely pathogenic ★★ same type
LDB3 p.Ala165Val Pathogenic/Likely pathogenic ★★ same type
LDB3 c.1231+4A>C Uncertain significance ★★ same type
LDB3 c.1858-11C>A Uncertain significance ★★ same type

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-ser440pro (accessed [today's date]).

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