Is LRP2 p.Pro3923= (c.11769G>A) pathogenic?

LRP2 p.Pro3923= (c.11769G>A) is classified Conflicting classifications of pathogenicity in LRP2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-27). Very rare (popmax 0.00891%, eas); Associated with Donnai-Barrow syndrome.

What condition is associated with LRP2 p.Pro3923= (c.11769G>A)?

LRP2 p.Pro3923= (c.11769G>A) is associated with Donnai-Barrow syndrome (ClinVar).

How common is LRP2 p.Pro3923= (c.11769G>A) in the general population?

LRP2 p.Pro3923= (c.11769G>A) is very rare (popmax 0.00891%, eas) (gnomAD).

LRP2 p.Pro3923=

c.11769G>A · rs772055695 · VCV332087

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Conditions

Donnai-Barrow syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.031	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.2	GERP -3.9
Overall
CADD	0.199	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,896 alleles

Filtering AF 0.00716% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00668%

Overall 0.00725% 117/1,613,976 alleles · very rare exomes 113/1,461,776 · genomes 4/152,200 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,224
European (non-Finnish)	0.00856%	11,683
South Asian	0.00659%	15,179
Remaining individualsnot grpmax-eligible	0.0048%	20,829
African / African-American	0.00267%	37,459
Finnishnot grpmax-eligible	0.00156%	64,020

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.Pro3923=
Coding: c.11769G>A
MANE Select: NM_004525
dbSNP: rs772055695
Type: single nucleotide variant
Location: chr2:169162590 (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.Pro3923Leu 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-pro3923 (accessed [today's date]).

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