Is LTBP2 p.Pro1269= (c.3807G>A) pathogenic?

LTBP2 p.Pro1269= (c.3807G>A) is classified Conflicting classifications of pathogenicity in LTBP2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-02). Rare (popmax 0.362%, sas); Associated with Weill-Marchesani syndrome.

What condition is associated with LTBP2 p.Pro1269= (c.3807G>A)?

LTBP2 p.Pro1269= (c.3807G>A) is associated with Weill-Marchesani syndrome, glaucoma 3, primary congenital, D (ClinVar).

How common is LTBP2 p.Pro1269= (c.3807G>A) in the general population?

LTBP2 p.Pro1269= (c.3807G>A) is rare (popmax 0.362%, sas) (gnomAD).

LTBP2 p.Pro1269=

c.3807G>A · rs149953380 · VCV732472

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.362%, sas)

Conditions

Weill-Marchesani syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.007	strongly benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -16	GERP -3.8
Overall
CADD	0.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.362% South Asian · 330/91,078 alleles

Filtering AF 0.33% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.318%

Overall 0.205% 3,314/1,614,156 alleles · rare exomes 3,021/1,461,858 · genomes 293/152,298 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.37%	73
Amishnot grpmax-eligible	0.439%	228
Finnishnot grpmax-eligible	0.419%	239
South Asiangrpmax	0.362%	276
Middle Eastern	0.346%	289
Remaining individualsnot grpmax-eligible	0.267%	374
European (non-Finnish)	0.174%	575
Admixed American	0.07%	1,429
African / African-American	0.0307%	3,262
East Asian	0.00446%	22,442

Ashkenazi Jewish 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: LTBP2
Protein: p.Pro1269=
Coding: c.3807G>A
MANE Select: NM_000428
dbSNP: rs149953380
Type: single nucleotide variant
Location: chr14:74507279 (GRCh38)
Gene constraint: LOEUF 0.595 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.33
Residue 1269: the egf-like 14; calcium-binding domain

Full LTBP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Weill-Marchesani syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: glaucoma 3, primary congenital, D

Similar variants

LTBP2 p.Pro1269Leu Uncertain significance ★ ⚠ same residue
LTBP3 p.Lys1269Asn Uncertain significance ★ ⚠ same residue
LTBP2 c.2389-2A>G Likely pathogenic ★★ same condition
LTBP2 p.Arg299Ter Pathogenic ★★ same condition
LTBP2 p.Cys1438Tyr Likely pathogenic ★★ same condition
LTBP2 c.-55G>A Uncertain significance ★★ same condition
LTBP2 c.-93C>T Uncertain significance ★★ same condition
LTBP2 c.*229C>T 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/ltbp2-p-pro1269 (accessed [today's date]).

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