Is LDB3 p.Pro99Ser (c.295C>T) pathogenic?

LDB3 p.Pro99Ser (c.295C>T) is classified Benign/Likely benign in LDB3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.087); Very rare (popmax 0.00881%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with LDB3 p.Pro99Ser (c.295C>T)?

LDB3 p.Pro99Ser (c.295C>T) is associated with Cardiovascular phenotype, myofibrillar myopathy 4 (ClinVar).

How common is LDB3 p.Pro99Ser (c.295C>T) in the general population?

LDB3 p.Pro99Ser (c.295C>T) is very rare (popmax 0.00881%, nfe) (gnomAD).

What do computational predictors say about LDB3 p.Pro99Ser (c.295C>T)?

AlphaMissense predicts likely benign (score 0.087) — an in-silico prediction, not a clinical call.

LDB3 p.Pro99Ser

c.295C>T · rs201693259 · VCV178059

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.087 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00881%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.087	likely benign
REVEL	0.157	moderately benign-leaning
SaProt	LLR -7.10	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 3.3	GERP 2.1, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 64 kb · p 0.14 · regional, not allelic
Overall
CADD	21.5	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 0.00881% European (non-Finnish) · 104/1,180,008 alleles

Filtering AF 0.00741% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00692%

Overall 0.043% 694/1,614,212 alleles · very rare exomes 572/1,461,852 · genomes 122/152,360 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.884%	113
Remaining individualsnot grpmax-eligible	0.0384%	2,605
European (non-Finnish)grpmax	0.00881%	11,346

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro99Ser
Coding: c.295C>T
MANE Select: NM_007078
dbSNP: rs201693259
Type: single nucleotide variant
Location: chr10:86680131 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.98 · 2 PDB
Residue 99: 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: myofibrillar myopathy 4

Similar variants

LDB3 p.Pro99Leu 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
LDB3 c.859+3G>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-pro99ser (accessed [today's date]).

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