Is LRP6 p.Ser901Pro (c.2701T>C) pathogenic?

LRP6 p.Ser901Pro (c.2701T>C) is classified Uncertain significance in LRP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-30). AlphaMissense: ambiguous (0.5513); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LRP6 p.Ser901Pro (c.2701T>C)?

LRP6 p.Ser901Pro (c.2701T>C) is associated with Inborn genetic diseases (ClinVar).

How common is LRP6 p.Ser901Pro (c.2701T>C) in the general population?

LRP6 p.Ser901Pro (c.2701T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about LRP6 p.Ser901Pro (c.2701T>C)?

AlphaMissense predicts ambiguous (score 0.5513) — an in-silico prediction, not a clinical call.

LRP6 p.Ser901Pro

c.2701T>C · rs1862667990 · VCV3120320

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5513 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5513	ambiguous
REVEL	0.827	moderately pathogenic-leaning
SaProt	LLR -15.92	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	GERP -0.98, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 3,455 bp · p 4.2e-10 · regional, not allelic
Overall
CADD	25.9	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 0.000339% European (non-Finnish) · 4/1,180,050 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,122 alleles · very rare exomes 3/1,461,890 · genomes 1/152,232 · 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.Ser901Pro
Coding: c.2701T>C
MANE Select: NM_002336
dbSNP: rs1862667990
Type: single nucleotide variant
Location: chr12:12158919 (GRCh38)
Gene constraint: LOEUF 0.27 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.87 · 30 PDB
Residue 901: the egf-like 3 domain; a β-strand; 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

Disease context

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

Similar variants

LRP6 p.Ser901= Likely benign ★ same residue
LRP6 c.3207-2A>G Likely pathogenic ★★ same condition
LRP6 p.Arg335Ter Pathogenic/Likely pathogenic ★★ same condition
LRP6 p.Arg990Ter Pathogenic ★★ same condition
LRP6 p.Ala1304Thr Uncertain significance ★★ ⚠ same condition
LRP6 p.Ala74Thr Uncertain significance ★★ ⚠ same condition
LRP6 p.Ala992Glu Uncertain significance ★★ ⚠ same condition
LRP6 p.Arg1085Trp 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/lrp6-p-ser901pro (accessed [today's date]).

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