Is LTBP3 p.Pro288Arg (c.863C>G) pathogenic?

LTBP3 p.Pro288Arg (c.863C>G) is classified Uncertain significance in LTBP3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-05-15). AlphaMissense: likely benign (0.2618); Very rare (popmax 0.000171%, nfe); Associated with LTBP3-related disorder.

What condition is associated with LTBP3 p.Pro288Arg (c.863C>G)?

LTBP3 p.Pro288Arg (c.863C>G) is associated with LTBP3-related disorder (ClinVar).

How common is LTBP3 p.Pro288Arg (c.863C>G) in the general population?

LTBP3 p.Pro288Arg (c.863C>G) is very rare (popmax 0.000171%, nfe) (gnomAD).

What do computational predictors say about LTBP3 p.Pro288Arg (c.863C>G)?

AlphaMissense predicts likely benign (score 0.2618) — an in-silico prediction, not a clinical call.

LTBP3 p.Pro288Arg

c.863C>G · VCV3344354

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2618 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000171%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

LTBP3-related disorder

Computational evidence

Protein change
AlphaMissense	0.2618	likely benign
REVEL	0.291	indeterminate
SaProt	LLR -6.21	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 2.1	GERP -0.52, phastCons 0.99
Regional constraint	o/e 0.60	unconstrained · MANE · 1,631 bp · p 1.2e-10 · regional, not allelic
Overall
CADD	13.6	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 0.000171% European (non-Finnish) · 2/1,167,962 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000127% 2/1,574,680 alleles · very rare exomes 2/1,422,516 · genomes 0/152,164 · 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.Pro288Arg
Coding: c.863C>G
MANE Select: NM_001130144
Type: single nucleotide variant
Location: chr11:65553702 (GRCh38)
Gene constraint: LOEUF 0.824 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.21
Residue 288: the tb 1 domain

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

Disease context

LTBP3-related disorder

Similar variants

LTBP3 p.Pro288= Conflicting classifications of pathogenicity ★ same residue
LTBP3 c.1063+1G>T Likely pathogenic ★★ same condition
LTBP3 p.Arg138Cys Uncertain significance ★★ ⚠ same condition
LTBP3 p.Pro549Ala Uncertain significance ★★ ⚠ same condition
LTBP3 p.Tyr377Cys Uncertain significance ⚠ same condition
LTBP3 c.3760+7C>G Likely benign same condition
LTBP3 c.-6C>A Likely benign same condition
LTBP3 c.-8G>A Likely benign 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-pro288arg (accessed [today's date]).

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