Is LRP5 p.Arg1237Gln (c.3710G>A) pathogenic?

LRP5 p.Arg1237Gln (c.3710G>A) is classified Uncertain significance in LRP5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-23). AlphaMissense: ambiguous (0.5278); Very rare (popmax 0.00833%, amr); Associated with autosomal dominant osteopetrosis 1.

What condition is associated with LRP5 p.Arg1237Gln (c.3710G>A)?

LRP5 p.Arg1237Gln (c.3710G>A) is associated with autosomal dominant osteopetrosis 1, autosomal dominant osteosclerosis, Worth type, osteoporosis-pseudoglioma syndrome (ClinVar).

How common is LRP5 p.Arg1237Gln (c.3710G>A) in the general population?

LRP5 p.Arg1237Gln (c.3710G>A) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about LRP5 p.Arg1237Gln (c.3710G>A)?

AlphaMissense predicts ambiguous (score 0.5278) — an in-silico prediction, not a clinical call.

LRP5 p.Arg1237Gln

c.3710G>A · rs765434644 · VCV1492779

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5278 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

autosomal dominant osteopetrosis 1

Computational evidence

Protein change
AlphaMissense	0.5278	ambiguous
REVEL	0.769	pathogenic-leaning
SaProt	LLR -5.05	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 38 kb · p 0.00085 · regional, not allelic
Overall
CADD	29.9	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 0.00833% Admixed American · 5/60,000 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00112% 18/1,614,060 alleles · very rare exomes 14/1,461,852 · genomes 4/152,208 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,000
Remaining individualsnot grpmax-eligible	0.0016%	62,484
Finnishnot grpmax-eligible	0.00156%	64,014
South Asian	0.0011%	91,090
European (non-Finnish)	0.000847%	118,004

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.Arg1237Gln
Coding: c.3710G>A
MANE Select: NM_002335
dbSNP: rs765434644
Type: single nucleotide variant
Location: chr11:68429647 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.94 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 78.65
Residue 1237: the egf-like 4 domain

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

Disease context

autosomal dominant osteopetrosis 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 polycystic liver disease 4 with or without kidney cysts

Similar variants

LRP5 p.Arg1237Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
LRP5 p.Arg1237Gly Uncertain significance ★ ⚠ same residue
LRP5 p.Arg1237= 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

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-arg1237gln (accessed [today's date]).

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