Is LRP2 p.Pro1798Ser (c.5392C>T) pathogenic?

LRP2 p.Pro1798Ser (c.5392C>T) is classified Uncertain significance in LRP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-13). AlphaMissense: likely benign (0.1053); Very rare (popmax 0.00446%, eas); Associated with Donnai-Barrow syndrome.

What condition is associated with LRP2 p.Pro1798Ser (c.5392C>T)?

LRP2 p.Pro1798Ser (c.5392C>T) is associated with Donnai-Barrow syndrome (ClinVar).

How common is LRP2 p.Pro1798Ser (c.5392C>T) in the general population?

LRP2 p.Pro1798Ser (c.5392C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about LRP2 p.Pro1798Ser (c.5392C>T)?

AlphaMissense predicts likely benign (score 0.1053) — an in-silico prediction, not a clinical call.

LRP2 p.Pro1798Ser

c.5392C>T · VCV3584822

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1053 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

Donnai-Barrow syndrome

Computational evidence

Protein change
AlphaMissense	0.1053	likely benign
REVEL	0.565	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP -0.96, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 156 kb · p 7.9e-06 · regional, not allelic
Overall
CADD	20.6	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 0.00446% East Asian · 2/44,858 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000186% 3/1,612,090 alleles · very rare exomes 2/1,459,968 · genomes 1/152,122 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,429
African / African-American	0.00134%	74,842

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.Pro1798Ser
Coding: c.5392C>T
MANE Select: NM_004525
Type: single nucleotide variant
Location: chr2:169226424 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1798: a turn

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-pro1798ser (accessed [today's date]).

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