Is LTBP3 p.Ala20Ser (c.58G>T) pathogenic?

LTBP3 p.Ala20Ser (c.58G>T) is classified Uncertain significance in LTBP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-20). AlphaMissense: likely benign (0.1647); Very rare (popmax 0.0001%, nfe); Associated with brachyolmia-amelogenesis imperfecta syndrome.

What condition is associated with LTBP3 p.Ala20Ser (c.58G>T)?

LTBP3 p.Ala20Ser (c.58G>T) is associated with brachyolmia-amelogenesis imperfecta syndrome (ClinVar).

How common is LTBP3 p.Ala20Ser (c.58G>T) in the general population?

LTBP3 p.Ala20Ser (c.58G>T) is very rare (popmax 0.0001%, nfe) (gnomAD).

What do computational predictors say about LTBP3 p.Ala20Ser (c.58G>T)?

AlphaMissense predicts likely benign (score 0.1647) — an in-silico prediction, not a clinical call.

LTBP3 p.Ala20Ser

c.58G>T · VCV3690814

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1647 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0001%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

brachyolmia-amelogenesis imperfecta syndrome

Computational evidence

Protein change
AlphaMissense	0.1647	likely benign
REVEL	0.222	benign-leaning
SaProt	LLR -7.53	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 0.67	GERP 0.92, phastCons 0.97
Regional constraint	o/e 1.22	unconstrained · MANE · 146 bp · p 0.075 · regional, not allelic
Overall
CADD	18.31	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

Grpmax group 0.0001% European (non-Finnish) · 1/998,962 alleles

Overall 7.86e-05% 1/1,271,932 alleles · very rare exomes 1/1,121,376 · genomes 0/150,556 · 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: LTBP3
Protein: p.Ala20Ser
Coding: c.58G>T
MANE Select: NM_001130144
Type: single nucleotide variant
Location: chr11:65557902 (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.Ala20Thr Uncertain significance ★★ ⚠ same residue
LTBP3 p.Ala20Val Uncertain significance ★ ⚠ same residue
LTBP3 p.Ala20= 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

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-ala20ser (accessed [today's date]).

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