Is LRP5 p.Val1245= (c.3735G>T) pathogenic?

LRP5 p.Val1245= (c.3735G>T) is classified Conflicting classifications of pathogenicity in LRP5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-06). Very rare (popmax 0.00167%, amr); Associated with Bone mineral density quantitative trait locus 1.

What condition is associated with LRP5 p.Val1245= (c.3735G>T)?

LRP5 p.Val1245= (c.3735G>T) is associated with Bone mineral density quantitative trait locus 1, autosomal dominant osteosclerosis, Worth type, osteoporosis-pseudoglioma syndrome (ClinVar).

How common is LRP5 p.Val1245= (c.3735G>T) in the general population?

LRP5 p.Val1245= (c.3735G>T) is very rare (popmax 0.00167%, amr) (gnomAD).

LRP5 p.Val1245=

c.3735G>T · rs1251382942 · VCV1658071

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

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 0.81	GERP -5.1, phastCons 1
Overall
CADD	5.035	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,024 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,461,840 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,024
European (non-Finnish)	0.000254%	393,351

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.Val1245=
Coding: c.3735G>T
MANE Select: NM_002335
dbSNP: rs1251382942
Type: single nucleotide variant
Location: chr11:68429672 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.94 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 78.65
Residue 1245: the egf-like 4 domain; a disulfide bond

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: 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.Val1245Met Conflicting classifications of pathogenicity ★ ⚠ same residue
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.Arg353Gln Pathogenic/Likely pathogenic ★★ same condition
LRP5 p.Arg428Ter 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-val1245 (accessed [today's date]).

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