Is LRP6 p.Pro591Arg (c.1772C>G) pathogenic?

LRP6 p.Pro591Arg (c.1772C>G) is classified Uncertain significance in LRP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-22). AlphaMissense: likely benign (0.1203); Very rare (popmax 0.00212%, nfe).

How common is LRP6 p.Pro591Arg (c.1772C>G) in the general population?

LRP6 p.Pro591Arg (c.1772C>G) is very rare (popmax 0.00212%, nfe) (gnomAD).

What do computational predictors say about LRP6 p.Pro591Arg (c.1772C>G)?

AlphaMissense predicts likely benign (score 0.1203) — an in-silico prediction, not a clinical call.

LRP6 p.Pro591Arg

c.1772C>G · rs747337245 · VCV2080833

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1203 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1203	likely benign
REVEL	0.71	pathogenic-leaning
SaProt	LLR -7.64	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 104 kb · p 3.9e-13 · regional, not allelic
Overall
CADD	24.9	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 0.00212% European (non-Finnish) · 25/1,180,016 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00155% 25/1,613,934 alleles · very rare exomes 22/1,461,850 · genomes 3/152,084 · 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: LRP6
Protein: p.Pro591Arg
Coding: c.1772C>G
MANE Select: NM_002336
dbSNP: rs747337245
Type: single nucleotide variant
Location: chr12:12164553 (GRCh38)
Gene constraint: LOEUF 0.27 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.87 · 30 PDB
Residue 591: the egf-like 2 domain; an α-helix; a UniProt-annotated variant site (in sthag7; pathogenic; loss of function in wnt signaling)

Full LRP6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LRP6 p.Pro591Ala Uncertain significance ★★ ⚠ same residue
LRP6 p.Pro591= Likely benign ★ same residue
LRP6 c.3207-2A>G Likely pathogenic ★★ same type
LRP6 p.Arg335Ter Pathogenic/Likely pathogenic ★★ same type
LRP6 p.Arg415Ter Pathogenic/Likely pathogenic ★★ same type
LRP6 p.Arg585Ter Pathogenic/Likely pathogenic ★★ same type
LRP6 p.Arg644Ter Pathogenic ★★ same type
LRP6 p.Arg728Ter Pathogenic ★★ same type

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/lrp6-p-pro591arg (accessed [today's date]).

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