Is LTBP2 p.Pro1556= (c.4668G>C) pathogenic?

LTBP2 p.Pro1556= (c.4668G>C) is classified Likely benign in LTBP2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-02-27). Ultra-rare (popmax 0.0165%, mid); Associated with OPTN-related open angle glaucoma.

What condition is associated with LTBP2 p.Pro1556= (c.4668G>C)?

LTBP2 p.Pro1556= (c.4668G>C) is associated with OPTN-related open angle glaucoma (ClinVar).

How common is LTBP2 p.Pro1556= (c.4668G>C) in the general population?

LTBP2 p.Pro1556= (c.4668G>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

LTBP2 p.Pro1556=

c.4668G>C · rs137854866 · VCV126957

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

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 -10	GERP -3.8
Overall
CADD	0.102	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00279% 45/1,613,126 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
European (non-Finnish)	0.00356%	28,089
Admixed American	0.00167%	59,960
Remaining individualsnot grpmax-eligible	0.0016%	62,464

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.Pro1556=
Coding: c.4668G>C
MANE Select: NM_000428
dbSNP: rs137854866
Type: single nucleotide variant
Location: chr14:74503521 (GRCh38)
Gene constraint: LOEUF 0.595 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.33
Residue 1556: the egf-like 18; calcium-binding 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.Pro1556Ser 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.Pro1452= 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-pro1556 (accessed [today's date]).

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