Is LRP5 p.Phe617Val (c.1849T>G) pathogenic?

LRP5 p.Phe617Val (c.1849T>G) is classified Uncertain significance in LRP5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-01). AlphaMissense: ambiguous (0.4469); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with LRP5 p.Phe617Val (c.1849T>G)?

LRP5 p.Phe617Val (c.1849T>G) is associated with Inborn genetic diseases (ClinVar).

How common is LRP5 p.Phe617Val (c.1849T>G) in the general population?

LRP5 p.Phe617Val (c.1849T>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about LRP5 p.Phe617Val (c.1849T>G)?

AlphaMissense predicts ambiguous (score 0.4469) — an in-silico prediction, not a clinical call.

LRP5 p.Phe617Val

c.1849T>G · rs367619965 · VCV1900852

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4469 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4469	ambiguous
REVEL	0.608	indeterminate
SaProt	LLR -9.24	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP 0.81, phastCons 0.84
Regional constraint	o/e 0.70	unconstrained · MANE · 99 kb · p 4.9e-23 · regional, not allelic
Overall
CADD	21.1	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 0.00133% African / African-American · 1/74,930 alleles

Overall 6.2e-05% 1/1,614,078 alleles · very rare exomes 0/1,461,870 · genomes 1/152,208 · joint denominator

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.Phe617Val
Coding: c.1849T>G
MANE Select: NM_002335
dbSNP: rs367619965
Type: single nucleotide variant
Location: chr11:68406571 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.94 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 78.65
Residue 617: a UniProt-annotated variant site (in evr4; autosomal recessive); the egf-like 2 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LRP5 p.Phe617Cys Uncertain significance ★ ⚠ same residue
LRP5 p.Arg1078Ter Pathogenic ★★ same condition
LRP5 p.Arg570Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
LRP5 p.Ala1214Val Uncertain significance ★★ ⚠ same condition
LRP5 p.Ala1265Pro Uncertain significance ★★ ⚠ same condition
LRP5 p.Ala1306Thr Uncertain significance ★★ ⚠ same condition
LRP5 p.Ala1491Pro Uncertain significance ★★ ⚠ same condition
LRP5 p.Ala179Val 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-phe617val (accessed [today's date]).

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