Is LRP6 p.Pro955= (c.2865C>T) pathogenic?

LRP6 p.Pro955= (c.2865C>T) is classified Benign in LRP6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). Low-frequency (popmax 1.63%, mid).

How common is LRP6 p.Pro955= (c.2865C>T) in the general population?

LRP6 p.Pro955= (c.2865C>T) is low-frequency (popmax 1.63%, mid) (gnomAD).

LRP6 p.Pro955=

c.2865C>T · rs34143723 · VCV1575990

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.63%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.44	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 1.3	GERP -3, phastCons 0.99
Overall
CADD	19.25	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.63% Middle Eastern · 99/6,056 alleles

Filtering AF 1.43% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.42%

Overall 1.25% 20,171/1,614,094 alleles · low-frequency exomes 18,703/1,461,836 · genomes 1,468/152,258 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	4.82%	21
Ashkenazi Jewishnot grpmax-eligible	1.67%	60
Middle Easterngrpmax	1.63%	61
European (non-Finnish)	1.45%	69
Remaining individualsnot grpmax-eligible	1.18%	85
Admixed American	0.858%	117
South Asian	0.694%	144
Finnishnot grpmax-eligible	0.642%	156
African / African-American	0.212%	472
East Asian	0.00223%	44,876

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro955=
Coding: c.2865C>T
MANE Select: NM_002336
dbSNP: rs34143723
Type: single nucleotide variant
Location: chr12:12150965 (GRCh38)
Gene constraint: LOEUF 0.27 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.87 · 30 PDB
Residue 955: an α-helix; 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

Similar variants

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
LRP6 p.Arg990Ter Pathogenic ★★ same type
LRP6 p.Ala1304Thr Uncertain significance ★★ ⚠ 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-pro955 (accessed [today's date]).

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