Is LRP2 p.Pro4380fs (c.13139del) pathogenic?

LRP2 p.Pro4380fs (c.13139del) is classified Pathogenic/Likely pathogenic in LRP2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-08-14). Very rare (popmax 0.000172%, nfe); Associated with LRP2-related disorder.

What condition is associated with LRP2 p.Pro4380fs (c.13139del)?

LRP2 p.Pro4380fs (c.13139del) is associated with LRP2-related disorder, Donnai-Barrow syndrome (ClinVar).

How common is LRP2 p.Pro4380fs (c.13139del) in the general population?

LRP2 p.Pro4380fs (c.13139del) is very rare (popmax 0.000172%, nfe) (gnomAD).

LRP2 p.Pro4380fs

c.13139del · rs80338754 · VCV211391

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000172%, nfe)

Conditions

LRP2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 72 of 79
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.64	GERP -1.9, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000172% European (non-Finnish) · 2/1,160,118 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000126% 2/1,590,610 alleles · very rare exomes 2/1,438,790 · genomes 0/151,820 · 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.Pro4380fs
Coding: c.13139del
MANE Select: NM_004525
dbSNP: rs80338754
Type: Deletion
Location: chr2:169140515 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4380: an α-helix; the egf-like 6 domain

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

Disease context

LRP2-related disorder

Also linked: Donnai-Barrow syndrome

Similar variants

LRP2 p.Pro4380Ala Conflicting classifications of pathogenicity ★ same residue
LRP2 c.427+1del Likely pathogenic ★★ same condition
LRP2 c.11498-13del Benign ★★ same condition
LRP2 c.428-11_428-8del Benign/Likely benign ★★ same condition
LRP2 c.428-14_428-8del Benign/Likely benign ★★ same condition
LRP2 c.428-18_428-8del Likely benign ★★ same condition
LRP2 c.428-8del Benign/Likely benign ★★ same condition
LRP2 c.428-9_428-8del Benign/Likely benign ★★ 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-pro4380fs (accessed [today's date]).

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