Is LRP2 p.Ser258fs (c.772dup) pathogenic?

LRP2 p.Ser258fs (c.772dup) is classified Likely pathogenic in LRP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-20). Associated with Donnai-Barrow syndrome.

What condition is associated with LRP2 p.Ser258fs (c.772dup)?

LRP2 p.Ser258fs (c.772dup) is associated with Donnai-Barrow syndrome (ClinVar).

LRP2 p.Ser258fs

c.772dup · VCV4880545

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

Donnai-Barrow syndrome

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 8 of 79
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.3	GERP 0.97, phastCons 1

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

Variant & gene context

Gene: LRP2
Protein: p.Ser258fs
Coding: c.772dup
MANE Select: NM_004525
Type: Duplication
Location: chr2:169290994 (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

Disease context

Donnai-Barrow syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LRP2 p.Cys4381fs Pathogenic/Likely pathogenic ★★ same condition
LRP2 c.1975+2_1975+5dup Uncertain significance ★★ same condition
LRP2 c.7384_7390+8dup Uncertain significance ★★ same condition
LRP2 c.7716-13dup Benign/Likely benign ★★ same condition
LRP2 p.Ser258= Likely benign ★★ same residue
LRP2 p.Gln1058fs Likely pathogenic ★ same condition
LRP2 p.Leu4433fs Likely pathogenic ★ same condition
LRP2 c.310+2dup 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-ser258fs (accessed [today's date]).

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