Is LRP2 p.Pro3549= (c.10647G>A) pathogenic?

LRP2 p.Pro3549= (c.10647G>A) is classified Benign in LRP2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 7.55%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Donnai-Barrow syndrome.

What condition is associated with LRP2 p.Pro3549= (c.10647G>A)?

LRP2 p.Pro3549= (c.10647G>A) is associated with Donnai-Barrow syndrome (ClinVar).

LRP2 p.Pro3549=

Q: How common is LRP2 p.Pro3549= (c.10647G>A) in the general population?

LRP2 p.Pro3549= (c.10647G>A) is common (popmax 7.55%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.10647G>A · rs17848184 · VCV332102

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 7.55%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

Donnai-Barrow syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -14	GERP -3.9
Overall
CADD	0.249	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.55% East Asian · 3,389/44,874 alleles

Filtering AF 7.34% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.25%

Overall 0.254% 4,098/1,614,154 alleles · common exomes 3,638/1,461,872 · genomes 460/152,282 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	7.55%	13
Remaining individualsnot grpmax-eligible	0.438%	228
South Asian	0.28%	357
Ashkenazi Jewishnot grpmax-eligible	0.101%	987
African / African-American	0.0386%	2,587
Admixed American	0.0367%	2,728
European (non-Finnish)	0.00839%	11,919

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.Pro3549=
Coding: c.10647G>A
MANE Select: NM_004525
dbSNP: rs17848184
Type: single nucleotide variant
Location: chr2:169175314 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 3549: the ldl-receptor class a 26 domain

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.Pro3549Leu 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-pro3549 (accessed [today's date]).

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