Is LRP5 p.Pro1296= (c.3888C>T) pathogenic?

LRP5 p.Pro1296= (c.3888C>T) is classified Likely benign in LRP5 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-29). Rare (popmax 0.156%, eas); Associated with Bone mineral density quantitative trait locus 1.

What condition is associated with LRP5 p.Pro1296= (c.3888C>T)?

LRP5 p.Pro1296= (c.3888C>T) is associated with Bone mineral density quantitative trait locus 1, osteoporosis, exudative vitreoretinopathy 1 (ClinVar).

How common is LRP5 p.Pro1296= (c.3888C>T) in the general population?

LRP5 p.Pro1296= (c.3888C>T) is rare (popmax 0.156%, eas) (gnomAD).

LRP5 p.Pro1296=

c.3888C>T · rs752439831 · VCV735098

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.156%, eas)

Conditions

Bone mineral density quantitative trait locus 1

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	GERP -5.3
Overall
CADD	0.349	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.156% East Asian · 70/44,880 alleles

Filtering AF 0.127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.116%

Overall 0.00682% 110/1,612,934 alleles · rare exomes 91/1,460,572 · genomes 19/152,362 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.156%	641
African / African-American	0.0333%	3,002
Middle Eastern	0.0165%	6,062
South Asian	0.00769%	13,011
Remaining individualsnot grpmax-eligible	0.0032%	31,243
Admixed American	0.00167%	60,022
European (non-Finnish)	0.000339%	294,981

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.Pro1296=
Coding: c.3888C>T
MANE Select: NM_002335
dbSNP: rs752439831
Type: single nucleotide variant
Location: chr11:68433726 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.94 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 78.65
Residue 1296: the ldl-receptor class a 1 domain

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

Disease context

Bone mineral density quantitative trait locus 1 — 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 exudative vitreoretinopathy 4 autosomal dominant osteopetrosis 1 polycystic liver disease 4 with or without kidney cysts

Similar variants

LRP5 p.Pro1296Arg Uncertain significance ★★ ⚠ same residue
LRP5 p.Pro1296Ser Uncertain significance ★★ ⚠ same residue
LRP5 p.Pro1296Ala Uncertain significance ★ ⚠ same residue
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

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-pro1296 (accessed [today's date]).

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