Is LRP5 p.Ile641Phe (c.1921A>T) pathogenic?

LRP5 p.Ile641Phe (c.1921A>T) is classified Uncertain significance in LRP5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-12). AlphaMissense: likely benign (0.2429); Absent from gnomAD v4.1; Associated with polycystic liver disease 4 with or without kidney cysts.

What condition is associated with LRP5 p.Ile641Phe (c.1921A>T)?

LRP5 p.Ile641Phe (c.1921A>T) is associated with polycystic liver disease 4 with or without kidney cysts, autosomal dominant osteosclerosis, Worth type, osteoporosis-pseudoglioma syndrome (ClinVar).

How common is LRP5 p.Ile641Phe (c.1921A>T) in the general population?

LRP5 p.Ile641Phe (c.1921A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LRP5 p.Ile641Phe (c.1921A>T)?

AlphaMissense predicts likely benign (score 0.2429) — an in-silico prediction, not a clinical call.

LRP5 p.Ile641Phe

c.1921A>T · VCV3600204

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2429 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

polycystic liver disease 4 with or without kidney cysts

Computational evidence

Protein change
AlphaMissense	0.2429	likely benign
REVEL	0.753	pathogenic-leaning
SaProt	LLR -7.23	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.8, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 99 kb · p 4.9e-23 · regional, not allelic
Overall
CADD	23.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: LRP5
Protein: p.Ile641Phe
Coding: c.1921A>T
MANE Select: NM_002335
Type: single nucleotide variant
Location: chr11:68406643 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.94 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 78.65
Residue 641: the egf-like 2 domain

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

Similar variants

LRP5 p.Ile641= 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-ile641phe (accessed [today's date]).

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