Is LRP2 p.Arg2759= (c.8277C>T) pathogenic?

LRP2 p.Arg2759= (c.8277C>T) is classified Likely benign in LRP2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-24). Ultra-rare (popmax 0.012%, nfe); Associated with Donnai-Barrow syndrome.

What condition is associated with LRP2 p.Arg2759= (c.8277C>T)?

LRP2 p.Arg2759= (c.8277C>T) is associated with Donnai-Barrow syndrome (ClinVar).

How common is LRP2 p.Arg2759= (c.8277C>T) in the general population?

LRP2 p.Arg2759= (c.8277C>T) is ultra-rare (popmax 0.012%, nfe) (gnomAD).

LRP2 p.Arg2759=

c.8277C>T · rs546544412 · VCV1463846

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, 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	GERP -2.4, phastCons 1
Overall
CADD	3.467	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% European (non-Finnish) · 142/1,180,046 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0098%

Overall 0.00929% 150/1,614,090 alleles · ultra-rare exomes 135/1,461,886 · genomes 15/152,204 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.012%	8,310
Finnishnot grpmax-eligible	0.00937%	10,672
Remaining individualsnot grpmax-eligible	0.0032%	31,244

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.Arg2759=
Coding: c.8277C>T
MANE Select: NM_004525
dbSNP: rs546544412
Type: single nucleotide variant
Location: chr2:169201803 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2759: the ldl-receptor class a 17 domain; 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.Arg2759Cys Uncertain significance ★★ ⚠ same residue
LRP2 p.Arg2759His 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-arg2759 (accessed [today's date]).

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