Is LRP2 p.Pro22Ser (c.64C>T) pathogenic?

LRP2 p.Pro22Ser (c.64C>T) is classified Uncertain significance in LRP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-29). AlphaMissense: likely benign (0.1058); Very rare (popmax 0.000433%, nfe); Associated with Donnai-Barrow syndrome.

What condition is associated with LRP2 p.Pro22Ser (c.64C>T)?

LRP2 p.Pro22Ser (c.64C>T) is associated with Donnai-Barrow syndrome (ClinVar).

How common is LRP2 p.Pro22Ser (c.64C>T) in the general population?

LRP2 p.Pro22Ser (c.64C>T) is very rare (popmax 0.000433%, nfe) (gnomAD).

What do computational predictors say about LRP2 p.Pro22Ser (c.64C>T)?

AlphaMissense predicts likely benign (score 0.1058) — an in-silico prediction, not a clinical call.

LRP2 p.Pro22Ser

c.64C>T · rs759114383 · VCV332209

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1058 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000433%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Donnai-Barrow syndrome

Computational evidence

Protein change
AlphaMissense	0.1058	likely benign
REVEL	0.165	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP 0.61, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 156 kb · p 7.9e-06 · regional, not allelic
Overall
CADD	20.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000433% European (non-Finnish) · 5/1,155,768 alleles

Filtering AF 0.000127% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.2e-05%

Overall 0.00032% 5/1,564,594 alleles · very rare exomes 4/1,412,418 · genomes 1/152,176 · 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.Pro22Ser
Coding: c.64C>T
MANE Select: NM_004525
dbSNP: rs759114383
Type: single nucleotide variant
Location: chr2:169362336 (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.Pro22Leu Uncertain significance ★ ⚠ same residue
LRP2 p.Pro22Thr Uncertain significance ★ ⚠ same residue
LRP2 p.Pro22= Likely benign ★ same residue
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

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-pro22ser (accessed [today's date]).

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