Is LRP5 p.Ile464= (c.1392C>T) pathogenic?

LRP5 p.Ile464= (c.1392C>T) is classified Benign/Likely benign in LRP5 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-27). Rare (popmax 0.979%, sas); Associated with polycystic liver disease 4 with or without kidney cysts.

What condition is associated with LRP5 p.Ile464= (c.1392C>T)?

LRP5 p.Ile464= (c.1392C>T) is associated with polycystic liver disease 4 with or without kidney cysts, osteoporosis, exudative vitreoretinopathy 1 (ClinVar).

How common is LRP5 p.Ile464= (c.1392C>T) in the general population?

LRP5 p.Ile464= (c.1392C>T) is rare (popmax 0.979%, sas) (gnomAD).

LRP5 p.Ile464=

c.1392C>T · rs569443429 · VCV284533

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.979%, sas)

Conditions

polycystic liver disease 4 with or without kidney cysts

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 -11	GERP -3.9
Overall
CADD	1.491	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.979% South Asian · 892/91,076 alleles

Filtering AF 0.926% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.905%

Overall 0.0593% 956/1,613,236 alleles · rare exomes 908/1,460,880 · genomes 48/152,356 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.979%	102
Remaining individualsnot grpmax-eligible	0.0672%	1,488
Middle Eastern	0.066%	1,516
African / African-American	0.004%	25,019
East Asian	0.00223%	44,878
Admixed American	0.00167%	60,010
European (non-Finnish)	0.0011%	90,761

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.Ile464=
Coding: c.1392C>T
MANE Select: NM_002335
dbSNP: rs569443429
Type: single nucleotide variant
Location: chr11:68386692 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.94 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 78.65
Residue 464: the 'beta-propeller 2' region

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

Disease context

polycystic liver disease 4 with or without kidney cysts — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: osteoporosis exudative vitreoretinopathy 1 autosomal dominant osteosclerosis, Worth type osteoporosis-pseudoglioma syndrome exudative vitreoretinopathy 4 autosomal dominant osteopetrosis 1 osteogenesis imperfecta

Similar variants

LRP5 c.1412+1G>A Pathogenic ★★ same condition
LRP5 c.3236+2T>G Pathogenic/Likely pathogenic ★★ same condition
LRP5 c.4488+2T>G Pathogenic/Likely pathogenic ★★ same condition
LRP5 c.884-2A>G 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.Arg1078Ter 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-ile464 (accessed [today's date]).

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