Is LRP2 p.Pro4378Arg (c.13133C>G) pathogenic?

LRP2 p.Pro4378Arg (c.13133C>G) is classified Uncertain significance in LRP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-27). AlphaMissense: likely benign (0.1485); Very rare (popmax 0.000424%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LRP2 p.Pro4378Arg (c.13133C>G)?

LRP2 p.Pro4378Arg (c.13133C>G) is associated with Inborn genetic diseases (ClinVar).

How common is LRP2 p.Pro4378Arg (c.13133C>G) in the general population?

LRP2 p.Pro4378Arg (c.13133C>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about LRP2 p.Pro4378Arg (c.13133C>G)?

AlphaMissense predicts likely benign (score 0.1485) — an in-silico prediction, not a clinical call.

LRP2 p.Pro4378Arg

c.13133C>G · rs746070288 · VCV2274030

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1485 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1485	likely benign
REVEL	0.695	pathogenic-leaning
SaProt	—	not scored · why
⇒ REVEL calls this damaging; AlphaMissense does not; SaProt makes no call.
Splicing
SpliceAI	Δ0.25	acceptor loss, 13 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 9.8	GERP 2.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 14 kb · p 0.27 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,880 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,958 alleles · very rare exomes 5/1,461,666 · genomes 0/152,292 · 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.Pro4378Arg
Coding: c.13133C>G
MANE Select: NM_004525
dbSNP: rs746070288
Type: single nucleotide variant
Location: chr2:169140521 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4378: an α-helix; the egf-like 6 domain

Full LRP2 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

LRP2 p.Pro4378= Benign/Likely benign ★★ same residue
LRP2 p.Pro4378Leu Uncertain significance ★ same residue
LRP2 p.Pro4378Thr Uncertain significance ★ same residue
LRP2 c.5227+6G>C Uncertain significance ★★ same condition
LRP2 p.Ala1007Val Uncertain significance ★★ ⚠ same condition
LRP2 p.Ala1071Val Uncertain significance ★★ same condition
LRP2 p.Ala1105Pro Uncertain significance ★★ ⚠ same condition
LRP2 p.Ala1265Val 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/lrp2-p-pro4378arg (accessed [today's date]).

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