Is LRP5 p.Pro943= (c.2829G>A) pathogenic?

LRP5 p.Pro943= (c.2829G>A) is classified Conflicting classifications of pathogenicity in LRP5 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-16). Ultra-rare (popmax 0.067%, sas); Associated with osteogenesis imperfecta.

What condition is associated with LRP5 p.Pro943= (c.2829G>A)?

LRP5 p.Pro943= (c.2829G>A) is associated with osteogenesis imperfecta, severe early-childhood-onset retinal dystrophy (ClinVar).

How common is LRP5 p.Pro943= (c.2829G>A) in the general population?

LRP5 p.Pro943= (c.2829G>A) is ultra-rare (popmax 0.067%, sas) (gnomAD).

How is Osteogenesis imperfecta inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

LRP5 p.Pro943=

c.2829G>A · rs201018263 · VCV1106293

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.067%, sas)

Conditions

osteogenesis imperfecta

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -5.8	GERP -3.3
Overall
CADD	3.134	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.067% South Asian · 61/91,052 alleles

Filtering AF 0.0535% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0486%

Overall 0.0338% 546/1,613,852 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0767%	1,304
South Asiangrpmax	0.067%	1,493
Remaining individualsnot grpmax-eligible	0.0384%	2,604
European (non-Finnish)	0.0346%	2,892
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Admixed American	0.00333%	30,006
East Asian	0.00223%	44,878

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro943=
Coding: c.2829G>A
MANE Select: NM_002335
dbSNP: rs201018263
Type: single nucleotide variant
Location: chr11:68416329 (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

osteogenesis imperfecta — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: severe early-childhood-onset retinal dystrophy

For Osteogenesis imperfecta (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Worldwide)

Similar variants

LRP5 p.Pro943Leu Uncertain significance ★★ ⚠ same residue
LRP5 p.Pro943Ser Uncertain significance ★★ ⚠ same residue
LRP5 c.884-2A>G Likely pathogenic ★★ same condition
LRP5 p.Met1Val Pathogenic/Likely pathogenic ★★ same condition
LRP5 p.Trp1278Ter Pathogenic/Likely pathogenic ★★ same condition
LRP5 p.Ala1265Pro Uncertain significance ★★ ⚠ same condition
LRP5 p.Ala465Thr Uncertain significance ★★ ⚠ same condition
LRP5 p.Arg178Leu Uncertain significance ★★ ⚠ 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-pro943 (accessed [today's date]).

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