Is LRP6 p.Pro1104Ser (c.3310C>T) pathogenic?

LRP6 p.Pro1104Ser (c.3310C>T) is classified Uncertain significance in LRP6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-10). AlphaMissense: likely pathogenic (0.9879); Very rare (popmax 0.00703%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LRP6 p.Pro1104Ser (c.3310C>T)?

LRP6 p.Pro1104Ser (c.3310C>T) is associated with Inborn genetic diseases (ClinVar).

How common is LRP6 p.Pro1104Ser (c.3310C>T) in the general population?

LRP6 p.Pro1104Ser (c.3310C>T) is very rare (popmax 0.00703%, nfe) (gnomAD).

What do computational predictors say about LRP6 p.Pro1104Ser (c.3310C>T)?

AlphaMissense predicts likely pathogenic (score 0.9879) — an in-silico prediction, not a clinical call.

LRP6 p.Pro1104Ser

c.3310C>T · rs771350940 · VCV2338349

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9879 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00703%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9879	likely pathogenic
REVEL	0.945	strongly pathogenic-leaning
SaProt	LLR -13.99	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 38 kb · p 0.001 · regional, not allelic
Overall
CADD	27.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00703% European (non-Finnish) · 83/1,179,992 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00533%

Overall 0.00527% 85/1,613,930 alleles · very rare exomes 82/1,461,832 · genomes 3/152,098 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00703%	14,217
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00134%	74,896

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.Pro1104Ser
Coding: c.3310C>T
MANE Select: NM_002336
dbSNP: rs771350940
Type: single nucleotide variant
Location: chr12:12147453 (GRCh38)
Gene constraint: LOEUF 0.27 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.87 · 30 PDB
Residue 1104: a β-strand; the 'beta-propeller 4' region; 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 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
LRP6 p.Arg1124Trp 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-pro1104ser (accessed [today's date]).

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