Is LRP2 p.Arg577= (c.1731G>A) pathogenic?

LRP2 p.Arg577= (c.1731G>A) is classified Conflicting classifications of pathogenicity in LRP2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-13). Ultra-rare (popmax 0.0172%, nfe); Associated with Donnai-Barrow syndrome.

What condition is associated with LRP2 p.Arg577= (c.1731G>A)?

LRP2 p.Arg577= (c.1731G>A) is associated with Donnai-Barrow syndrome (ClinVar).

How common is LRP2 p.Arg577= (c.1731G>A) in the general population?

LRP2 p.Arg577= (c.1731G>A) is ultra-rare (popmax 0.0172%, nfe) (gnomAD).

LRP2 p.Arg577=

c.1731G>A · rs142698246 · VCV737826

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0172%, nfe)

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 -1.9	GERP -4.2
Overall
CADD	3.907	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0172% European (non-Finnish) · 203/1,179,994 alleles

Filtering AF 0.0152% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0145%

Overall 0.0289% 467/1,614,108 alleles · ultra-rare exomes 423/1,461,842 · genomes 44/152,266 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.265%	377
Ashkenazi Jewishnot grpmax-eligible	0.233%	429
Remaining individualsnot grpmax-eligible	0.04%	2,500
European (non-Finnish)grpmax	0.0172%	5,813

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg577=
Coding: c.1731G>A
MANE Select: NM_004525
dbSNP: rs142698246
Type: single nucleotide variant
Location: chr2:169277786 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 577: 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.Arg577Trp Uncertain significance ★★ ⚠ same residue
LRP2 p.Arg577Gln 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

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-arg577 (accessed [today's date]).

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