Is LRP2 p.Pro1746Ser (c.5236C>T) pathogenic?

LRP2 p.Pro1746Ser (c.5236C>T) is classified Uncertain significance in LRP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-12). AlphaMissense: likely benign (0.1659); Absent from gnomAD v4.1; Associated with Donnai-Barrow syndrome.

What condition is associated with LRP2 p.Pro1746Ser (c.5236C>T)?

LRP2 p.Pro1746Ser (c.5236C>T) is associated with Donnai-Barrow syndrome (ClinVar).

How common is LRP2 p.Pro1746Ser (c.5236C>T) in the general population?

LRP2 p.Pro1746Ser (c.5236C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LRP2 p.Pro1746Ser (c.5236C>T)?

AlphaMissense predicts likely benign (score 0.1659) — an in-silico prediction, not a clinical call.

LRP2 p.Pro1746Ser

c.5236C>T · VCV3584823

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1659 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Donnai-Barrow syndrome

Computational evidence

Protein change
AlphaMissense	0.1659	likely benign
REVEL	0.642	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 156 kb · p 7.9e-06 · regional, not allelic
Overall
CADD	22.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: LRP2
Protein: p.Pro1746Ser
Coding: c.5236C>T
MANE Select: NM_004525
Type: single nucleotide variant
Location: chr2:169226580 (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 c.12019+1G>A Likely pathogenic ★★ same condition
LRP2 c.2639+1G>A Pathogenic/Likely pathogenic ★★ same condition
LRP2 c.3667+1G>A Pathogenic/Likely pathogenic ★★ same condition
LRP2 c.8452+1G>A Pathogenic ★★ same condition
LRP2 p.Arg1953Ter Pathogenic/Likely pathogenic ★★ same condition
LRP2 p.Arg2225Ter Pathogenic/Likely pathogenic ★★ same condition
LRP2 p.Arg278Ter Pathogenic/Likely pathogenic ★★ same condition
LRP2 p.Arg3184Ter Pathogenic/Likely pathogenic ★★ 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-pro1746ser (accessed [today's date]).

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