Is LTBP2 p.Pro1452= (c.4356G>A) pathogenic?

LTBP2 p.Pro1452= (c.4356G>A) is classified Benign in LTBP2 (ClinVar, Single submitter, 2 submitters; last evaluated 2026-01-27). Ultra-rare (popmax 0.06%, afr); Associated with OPTN-related open angle glaucoma.

What condition is associated with LTBP2 p.Pro1452= (c.4356G>A)?

LTBP2 p.Pro1452= (c.4356G>A) is associated with OPTN-related open angle glaucoma (ClinVar).

How common is LTBP2 p.Pro1452= (c.4356G>A) in the general population?

LTBP2 p.Pro1452= (c.4356G>A) is ultra-rare (popmax 0.06%, afr) (gnomAD).

LTBP2 p.Pro1452=

c.4356G>A · rs137854865 · VCV126956

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.06%, afr)

Conditions

OPTN-related open angle glaucoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.6	GERP -2.2
Overall
CADD	3.923	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.06% African / African-American · 45/75,044 alleles

Filtering AF 0.046% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0411%

Overall 0.0574% 926/1,614,190 alleles · ultra-rare exomes 741/1,461,880 · genomes 185/152,310 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.15%	87
African / African-Americangrpmax	0.06%	1,668
Remaining individualsnot grpmax-eligible	0.024%	4,167
South Asian	0.011%	9,109
Admixed American	0.00999%	10,005
European (non-Finnish)	0.00924%	10,826
East Asian	0.00446%	22,433
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

Finnish 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.Pro1452=
Coding: c.4356G>A
MANE Select: NM_000428
dbSNP: rs137854865
Type: single nucleotide variant
Location: chr14:74504996 (GRCh38)
Gene constraint: LOEUF 0.595 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.33
Residue 1452: the tb 3 domain

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

Disease context

OPTN-related open angle glaucoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LTBP2 p.Pro1452Leu Uncertain significance ★★ ⚠ same residue
LTBP2 p.Glu1191Lys Uncertain significance ★★ ⚠ same condition
LTBP2 p.Val1638Met Uncertain significance ★★ ⚠ same condition
LTBP2 p.Gln1417Arg Conflicting classifications of pathogenicity ★ ⚠ same condition
LTBP2 p.Pro1556= Likely benign ★ same condition
LTBP2 p.Arg495Gln Likely pathogenic ⚠ same condition
LTBP2 c.2389-2A>G Likely pathogenic ★★ same type
LTBP2 c.2659+2T>C Likely pathogenic ★★ same type

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-pro1452 (accessed [today's date]).

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