Is LRP2 p.Asp4252= (c.12756C>T) pathogenic?

LRP2 p.Asp4252= (c.12756C>T) is classified Conflicting classifications of pathogenicity in LRP2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-28). Ultra-rare (popmax 0.0512%, eas); Associated with Donnai-Barrow syndrome.

What condition is associated with LRP2 p.Asp4252= (c.12756C>T)?

LRP2 p.Asp4252= (c.12756C>T) is associated with Donnai-Barrow syndrome (ClinVar).

How common is LRP2 p.Asp4252= (c.12756C>T) in the general population?

LRP2 p.Asp4252= (c.12756C>T) is ultra-rare (popmax 0.0512%, eas) (gnomAD).

LRP2 p.Asp4252=

c.12756C>T · rs201793817 · VCV332078

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0512%, eas)

Conditions

Donnai-Barrow syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.66 · evaluated, not missing
Constraint at this position
Conservation	phyloP -2	GERP -5.3
Overall
CADD	2.355	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0512% East Asian · 23/44,886 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0296%

Overall 0.0039% 63/1,613,970 alleles · ultra-rare exomes 43/1,461,858 · genomes 20/152,112 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0512%	1,952
Admixed American	0.02%	5,000
African / African-American	0.00934%	10,709
Remaining individualsnot grpmax-eligible	0.0048%	20,831
South Asian	0.0022%	45,529
Finnishnot grpmax-eligible	0.00156%	64,012
European (non-Finnish)	0.00127%	78,665

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.Asp4252=
Coding: c.12756C>T
MANE Select: NM_004525
dbSNP: rs201793817
Type: single nucleotide variant
Location: chr2:169146794 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4252: 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 p.Asp4252Tyr Uncertain significance ★ 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
LRP2 p.Arg2225Ter Pathogenic/Likely pathogenic ★★ same condition
LRP2 p.Arg278Ter 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-asp4252 (accessed [today's date]).

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