Is LRP2 p.Pro2967= (c.8901C>G) pathogenic?

LRP2 p.Pro2967= (c.8901C>G) is classified Conflicting classifications of pathogenicity in LRP2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-28). Rare (popmax 0.479%, mid); Associated with Donnai-Barrow syndrome.

What condition is associated with LRP2 p.Pro2967= (c.8901C>G)?

LRP2 p.Pro2967= (c.8901C>G) is associated with Donnai-Barrow syndrome (ClinVar).

How common is LRP2 p.Pro2967= (c.8901C>G) in the general population?

LRP2 p.Pro2967= (c.8901C>G) is rare (popmax 0.479%, mid) (gnomAD).

LRP2 p.Pro2967=

c.8901C>G · rs145179638 · VCV332119

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.479%, mid)

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 0.1	GERP -4.3, phastCons 0.042
Overall
CADD	2.022	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.479% Middle Eastern · 29/6,060 alleles

Filtering AF 0.342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.296%

Overall 0.0499% 806/1,614,106 alleles · rare exomes 744/1,461,864 · genomes 62/152,242 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.479%	209
Remaining individualsnot grpmax-eligible	0.0736%	1,359
Admixed American	0.0683%	1,464
European (non-Finnish)	0.0543%	1,841
South Asian	0.0362%	2,760
African / African-American	0.016%	6,250
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
East Asian	0.00223%	44,888

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.Pro2967=
Coding: c.8901C>G
MANE Select: NM_004525
dbSNP: rs145179638
Type: single nucleotide variant
Location: chr2:169191963 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2967: the ldl-receptor class a 22 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.Pro2967Leu 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-pro2967 (accessed [today's date]).

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