Is LRP2 p.Pro519Ser (c.1555C>T) pathogenic?

LRP2 p.Pro519Ser (c.1555C>T) is classified Uncertain significance in LRP2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-05). AlphaMissense: likely pathogenic (0.7258); Ultra-rare (popmax 0.0548%, afr); Associated with Donnai-Barrow syndrome.

What condition is associated with LRP2 p.Pro519Ser (c.1555C>T)?

LRP2 p.Pro519Ser (c.1555C>T) is associated with Donnai-Barrow syndrome, intellectual disability (ClinVar).

How common is LRP2 p.Pro519Ser (c.1555C>T) in the general population?

LRP2 p.Pro519Ser (c.1555C>T) is ultra-rare (popmax 0.0548%, afr) (gnomAD).

What do computational predictors say about LRP2 p.Pro519Ser (c.1555C>T)?

AlphaMissense predicts likely pathogenic (score 0.7258) — an in-silico prediction, not a clinical call.

LRP2 p.Pro519Ser

c.1555C>T · rs147981204 · VCV975594

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.7258 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0548%, afr)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Donnai-Barrow syndrome

Computational evidence

Protein change
AlphaMissense	0.7258	likely pathogenic
REVEL	0.943	strongly pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 156 kb · p 7.9e-06 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0548% African / African-American · 41/74,864 alleles

Filtering AF 0.0414% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0368%

Overall 0.00285% 46/1,612,900 alleles · ultra-rare exomes 22/1,460,834 · genomes 24/152,066 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0548%	1,826
Admixed American	0.00834%	11,996

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.Pro519Ser
Coding: c.1555C>T
MANE Select: NM_004525
dbSNP: rs147981204
Type: single nucleotide variant
Location: chr2:169279382 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 519: 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

Also linked: intellectual disability

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-pro519ser (accessed [today's date]).

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