Is LTBP3 p.Pro399Gln (c.1196C>A) pathogenic?

LTBP3 p.Pro399Gln (c.1196C>A) is classified Uncertain significance in LTBP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-28). AlphaMissense: likely benign (0.0991); Absent from gnomAD v4.1; Associated with brachyolmia-amelogenesis imperfecta syndrome.

What condition is associated with LTBP3 p.Pro399Gln (c.1196C>A)?

LTBP3 p.Pro399Gln (c.1196C>A) is associated with brachyolmia-amelogenesis imperfecta syndrome (ClinVar).

How common is LTBP3 p.Pro399Gln (c.1196C>A) in the general population?

LTBP3 p.Pro399Gln (c.1196C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LTBP3 p.Pro399Gln (c.1196C>A)?

AlphaMissense predicts likely benign (score 0.0991) — an in-silico prediction, not a clinical call.

LTBP3 p.Pro399Gln

c.1196C>A · rs764981765 · VCV2024374

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0991 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

brachyolmia-amelogenesis imperfecta syndrome

Computational evidence

Protein change
AlphaMissense	0.0991	likely benign
REVEL	0.496	indeterminate
SaProt	LLR -6.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 0.64, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 1,631 bp · p 1.2e-10 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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: LTBP3
Protein: p.Pro399Gln
Coding: c.1196C>A
MANE Select: NM_001130144
dbSNP: rs764981765
Type: single nucleotide variant
Location: chr11:65552397 (GRCh38)
Gene constraint: LOEUF 0.824 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.21

Full LTBP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

brachyolmia-amelogenesis imperfecta syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LTBP3 p.Pro399Leu Uncertain significance ★★ ⚠ same residue
LTBP3 p.Pro399= Likely benign ★★ same residue
LTBP3 c.1063+1G>T Likely pathogenic ★★ same condition
LTBP3 c.3629-3C>T Uncertain significance ★★ same condition
LTBP3 c.3761-2A>G Uncertain significance ★★ same condition
LTBP3 p.Ala1149Thr Uncertain significance ★★ ⚠ same condition
LTBP3 p.Ala1153Val Uncertain significance ★★ ⚠ same condition
LTBP3 p.Ala1182Val 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/ltbp3-p-pro399gln (accessed [today's date]).

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