Is LRP5 p.Val232Ala (c.695T>C) pathogenic?

LRP5 p.Val232Ala (c.695T>C) is classified Uncertain significance in LRP5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-19). AlphaMissense: likely pathogenic (0.7754); Very rare (popmax 0.00399%, nfe); Associated with Bone mineral density quantitative trait locus 1.

What condition is associated with LRP5 p.Val232Ala (c.695T>C)?

LRP5 p.Val232Ala (c.695T>C) is associated with Bone mineral density quantitative trait locus 1, autosomal dominant osteosclerosis, Worth type, osteoporosis-pseudoglioma syndrome (ClinVar).

How common is LRP5 p.Val232Ala (c.695T>C) in the general population?

LRP5 p.Val232Ala (c.695T>C) is very rare (popmax 0.00399%, nfe) (gnomAD).

What do computational predictors say about LRP5 p.Val232Ala (c.695T>C)?

AlphaMissense predicts likely pathogenic (score 0.7754) — an in-silico prediction, not a clinical call.

LRP5 p.Val232Ala

c.695T>C · rs1472661046 · VCV839620

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7754 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00399%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bone mineral density quantitative trait locus 1

Computational evidence

Protein change
AlphaMissense	0.7754	likely pathogenic
REVEL	0.895	moderately pathogenic-leaning
SaProt	LLR -9.15	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 99 kb · p 4.9e-23 · regional, not allelic
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00399% European (non-Finnish) · 47/1,178,470 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00275%

Overall 0.00322% 47/1,459,212 alleles · very rare

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.Val232Ala
Coding: c.695T>C
MANE Select: NM_002335
dbSNP: rs1472661046
Type: single nucleotide variant
Location: chr11:68363755 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.94 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 78.65
Residue 232: the 'beta-propeller 1' region

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.Val232= Likely benign ★ 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-val232ala (accessed [today's date]).

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