Is LRP5 p.Ser708= (c.2124G>A) pathogenic?

LRP5 p.Ser708= (c.2124G>A) is classified Conflicting classifications of pathogenicity in LRP5 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-01). Rare (popmax 0.713%, afr); Associated with osteogenesis imperfecta.

What condition is associated with LRP5 p.Ser708= (c.2124G>A)?

LRP5 p.Ser708= (c.2124G>A) is associated with osteogenesis imperfecta (ClinVar).

How common is LRP5 p.Ser708= (c.2124G>A) in the general population?

LRP5 p.Ser708= (c.2124G>A) is rare (popmax 0.713%, afr) (gnomAD).

How is Osteogenesis imperfecta inherited?

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

LRP5 p.Ser708=

c.2124G>A · rs140977837 · VCV287337

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.713%, afr)

Conditions

osteogenesis imperfecta

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 -3.9
Overall
CADD	0.104	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.713% African / African-American · 535/75,002 alleles

Filtering AF 0.663% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.644%

Overall 0.0387% 625/1,614,052 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.713%	140
Admixed American	0.0633%	1,579
Middle Eastern	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.0464%	2,156
South Asian	0.0022%	45,535
European (non-Finnish)	0.00153%	65,557

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.Ser708=
Coding: c.2124G>A
MANE Select: NM_002335
dbSNP: rs140977837
Type: single nucleotide variant
Location: chr11:68409946 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.94 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 78.65
Residue 708: the 'beta-propeller 3' region

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

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.Ser708Leu 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
LRP5 p.Arg398Cys 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-ser708 (accessed [today's date]).

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