Is LTBP2 p.Arg847= (c.2541A>G) pathogenic?

LTBP2 p.Arg847= (c.2541A>G) is classified Conflicting classifications of pathogenicity in LTBP2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-01). Ultra-rare (popmax 0.0779%, nfe); Associated with glaucoma 3, primary congenital, D.

What condition is associated with LTBP2 p.Arg847= (c.2541A>G)?

LTBP2 p.Arg847= (c.2541A>G) is associated with glaucoma 3, primary congenital, D, Weill-Marchesani syndrome (ClinVar).

How common is LTBP2 p.Arg847= (c.2541A>G) in the general population?

LTBP2 p.Arg847= (c.2541A>G) is ultra-rare (popmax 0.0779%, nfe) (gnomAD).

LTBP2 p.Arg847=

c.2541A>G · rs140719298 · VCV314299

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0779%, nfe)

Conditions

glaucoma 3, primary congenital, D

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1	GERP -2.7, phastCons 0.001
Overall
CADD	2.547	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0779% European (non-Finnish) · 919/1,179,474 alleles

Filtering AF 0.0737% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.072%

Overall 0.0653% 1,052/1,612,060 alleles · ultra-rare exomes 969/1,459,772 · genomes 83/152,288 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0779%	1,283
Finnishnot grpmax-eligible	0.0551%	1,816
Admixed American	0.0502%	1,992
Remaining individualsnot grpmax-eligible	0.0448%	2,230
South Asian	0.0353%	2,829
Middle Eastern	0.0165%	6,054
African / African-American	0.00933%	10,717

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.Arg847=
Coding: c.2541A>G
MANE Select: NM_000428
dbSNP: rs140719298
Type: single nucleotide variant
Location: chr14:74522908 (GRCh38)
Gene constraint: LOEUF 0.595 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.33
Residue 847: the egf-like 4 domain

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

Disease context

glaucoma 3, primary congenital, D — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Weill-Marchesani syndrome

Similar variants

LTBP3 p.Ser847Pro 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
LTBP2 p.Ala1359Thr 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-arg847 (accessed [today's date]).

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