Is LRP2 p.Ala2015= (c.6045C>T) pathogenic?

LRP2 p.Ala2015= (c.6045C>T) is classified Benign in LRP2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Common (popmax 6.31%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Donnai-Barrow syndrome.

What condition is associated with LRP2 p.Ala2015= (c.6045C>T)?

LRP2 p.Ala2015= (c.6045C>T) is associated with Donnai-Barrow syndrome (ClinVar).

LRP2 p.Ala2015=

Q: How common is LRP2 p.Ala2015= (c.6045C>T) in the general population?

LRP2 p.Ala2015= (c.6045C>T) is common (popmax 6.31%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.6045C>T · rs34834388 · VCV129531

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 6.31%, afr) — 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 0.077	GERP -2.7, phastCons 0.01
Overall
CADD	3.881	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.31% African / African-American · 4,731/74,964 alleles

Filtering AF 6.16% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.1%

Overall 0.339% 5,474/1,613,842 alleles · common exomes 2,731/1,461,674 · genomes 2,743/152,168 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.31%	16
Remaining individualsnot grpmax-eligible	0.416%	240
Admixed American	0.377%	265
Middle Eastern	0.132%	757
European (non-Finnish)	0.019%	5,267
South Asian	0.0187%	5,357
East Asian	0.0156%	6,413
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600

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.Ala2015=
Coding: c.6045C>T
MANE Select: NM_004525
dbSNP: rs34834388
Type: single nucleotide variant
Location: chr2:169212203 (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 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-ala2015 (accessed [today's date]).

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