Is LTBP3 p.Pro261Arg (c.782C>G) pathogenic?

LTBP3 p.Pro261Arg (c.782C>G) is classified Uncertain significance in LTBP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-18). AlphaMissense: likely benign (0.1468); Very rare (popmax 0.00269%, afr); Associated with brachyolmia-amelogenesis imperfecta syndrome.

What condition is associated with LTBP3 p.Pro261Arg (c.782C>G)?

LTBP3 p.Pro261Arg (c.782C>G) is associated with brachyolmia-amelogenesis imperfecta syndrome (ClinVar).

How common is LTBP3 p.Pro261Arg (c.782C>G) in the general population?

LTBP3 p.Pro261Arg (c.782C>G) is very rare (popmax 0.00269%, afr) (gnomAD).

What do computational predictors say about LTBP3 p.Pro261Arg (c.782C>G)?

AlphaMissense predicts likely benign (score 0.1468) — an in-silico prediction, not a clinical call.

LTBP3 p.Pro261Arg

c.782C>G · rs765178350 · VCV2863719

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1468 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00269%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

brachyolmia-amelogenesis imperfecta syndrome

Computational evidence

Protein change
AlphaMissense	0.1468	likely benign
REVEL	0.42	indeterminate
SaProt	LLR -7.85	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -2.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 567 bp · p 0.74 · regional, not allelic
Overall
CADD	22.3	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 0.00269% African / African-American · 2/74,310 alleles

Filtering AF 0.000447% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000167%

Overall 0.000191% 3/1,566,854 alleles · very rare exomes 1/1,414,850 · genomes 2/152,004 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00269%	37,155
Admixed American	0.00182%	54,996

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.Pro261Arg
Coding: c.782C>G
MANE Select: NM_001130144
dbSNP: rs765178350
Type: single nucleotide variant
Location: chr11:65553783 (GRCh38)
Gene constraint: LOEUF 0.824 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.21
Residue 261: the 'disordered' region

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.Pro261Gln Uncertain significance ★ ⚠ same residue
LTBP3 p.Pro261Leu Uncertain significance ★ ⚠ 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-pro261arg (accessed [today's date]).

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