Is LRP2 p.Ser2132Pro (c.6394T>C) pathogenic?

LRP2 p.Ser2132Pro (c.6394T>C) is classified Uncertain significance in LRP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-15). AlphaMissense: likely pathogenic (0.6166); Very rare (popmax 0.000124%).

How common is LRP2 p.Ser2132Pro (c.6394T>C) in the general population?

LRP2 p.Ser2132Pro (c.6394T>C) is very rare (popmax 0.000124%) (gnomAD).

What do computational predictors say about LRP2 p.Ser2132Pro (c.6394T>C)?

AlphaMissense predicts likely pathogenic (score 0.6166) — an in-silico prediction, not a clinical call.

LRP2 p.Ser2132Pro

c.6394T>C · rs2105337080 · VCV1419061

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6166 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000124%)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.6166	likely pathogenic
REVEL	0.843	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 156 kb · p 7.9e-06 · regional, not allelic
Overall
CADD	24.3	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000124%

Overall 0.000124% 2/1,614,136 alleles · very rare exomes 2/1,461,834 · genomes 0/152,302 · 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: LRP2
Protein: p.Ser2132Pro
Coding: c.6394T>C
MANE Select: NM_004525
dbSNP: rs2105337080
Type: single nucleotide variant
Location: chr2:169209528 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)

Full LRP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LRP2 p.Ser2132= Likely benign ★★ same residue
LRP2 p.Ser2132Tyr Uncertain significance ★ ⚠ same residue
LRP2 c.12019+1G>A Likely pathogenic ★★ same type
LRP2 c.2639+1G>A Pathogenic/Likely pathogenic ★★ same type
LRP2 c.3667+1G>A Pathogenic/Likely pathogenic ★★ same type
LRP2 c.8452+1G>A Pathogenic ★★ same type
LRP2 p.Arg1953Ter Pathogenic/Likely pathogenic ★★ same type
LRP2 p.Arg2095Ter Pathogenic/Likely 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/lrp2-p-ser2132pro (accessed [today's date]).

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