Is LRP5 p.Pro1389= (c.4167C>T) pathogenic?

LRP5 p.Pro1389= (c.4167C>T) is classified Likely benign in LRP5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-05). Ultra-rare (popmax 0.0164%, mid); Associated with exudative vitreoretinopathy 4.

What condition is associated with LRP5 p.Pro1389= (c.4167C>T)?

LRP5 p.Pro1389= (c.4167C>T) is associated with exudative vitreoretinopathy 4, osteoporosis, exudative vitreoretinopathy 1 (ClinVar).

How common is LRP5 p.Pro1389= (c.4167C>T) in the general population?

LRP5 p.Pro1389= (c.4167C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

LRP5 p.Pro1389=

c.4167C>T · rs780535389 · VCV1639802

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

exudative vitreoretinopathy 4

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 -20
Overall
CADD	0.022	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00124% 20/1,614,118 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
South Asian	0.0154%	6,507
Remaining individualsnot grpmax-eligible	0.0048%	20,829
East Asian	0.00223%	44,902
African / African-American	0.00133%	74,952

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: LRP5
Protein: p.Pro1389=
Coding: c.4167C>T
MANE Select: NM_002335
dbSNP: rs780535389
Type: single nucleotide variant
Location: chr11:68438501 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.94 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 78.65

Full LRP5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

exudative vitreoretinopathy 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: osteoporosis exudative vitreoretinopathy 1 autosomal dominant osteosclerosis, Worth type osteoporosis-pseudoglioma syndrome autosomal dominant osteopetrosis 1 polycystic liver disease 4 with or without kidney cysts

Similar variants

LRP5 c.1412+1G>A Pathogenic ★★ same condition
LRP5 c.3236+2T>G Pathogenic/Likely pathogenic ★★ same condition
LRP5 c.4488+2T>G Pathogenic/Likely pathogenic ★★ same condition
LRP5 p.Ala214Thr Pathogenic ★★ same condition
LRP5 p.Ala242Thr Pathogenic/Likely pathogenic ★★ same condition
LRP5 p.Ala422Thr Likely pathogenic ★★ same condition
LRP5 p.Arg1078Ter Pathogenic ★★ same condition
LRP5 p.Arg353Gln Pathogenic/Likely pathogenic ★★ 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/lrp5-p-pro1389 (accessed [today's date]).

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