Is LRP2 p.Arg2262Pro (c.6785G>C) pathogenic?

LRP2 p.Arg2262Pro (c.6785G>C) is classified Conflicting classifications of pathogenicity in LRP2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-04-23). AlphaMissense: likely benign (0.1054); Ultra-rare (popmax 0.0668%, eas); Associated with Inborn genetic diseases.

What condition is associated with LRP2 p.Arg2262Pro (c.6785G>C)?

LRP2 p.Arg2262Pro (c.6785G>C) is associated with Inborn genetic diseases, Donnai-Barrow syndrome (ClinVar).

How common is LRP2 p.Arg2262Pro (c.6785G>C) in the general population?

LRP2 p.Arg2262Pro (c.6785G>C) is ultra-rare (popmax 0.0668%, eas) (gnomAD).

What do computational predictors say about LRP2 p.Arg2262Pro (c.6785G>C)?

AlphaMissense predicts likely benign (score 0.1054) — an in-silico prediction, not a clinical call.

LRP2 p.Arg2262Pro

c.6785G>C · rs201740125 · VCV893818

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1054 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0668%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1054	likely benign
REVEL	0.239	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.27	GERP -4.4, phastCons 0.041
Regional constraint	o/e 0.92	unconstrained · MANE · 156 kb · p 7.9e-06 · regional, not allelic
Overall
CADD	1.775	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0668% East Asian · 30/44,888 alleles

Filtering AF 0.0481% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0417%

Overall 0.0026% 42/1,614,206 alleles · ultra-rare exomes 30/1,461,880 · genomes 12/152,326 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0668%	1,496
African / African-American	0.012%	8,340
Remaining individualsnot grpmax-eligible	0.0048%	20,837

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.Arg2262Pro
Coding: c.6785G>C
MANE Select: NM_004525
dbSNP: rs201740125
Type: single nucleotide variant
Location: chr2:169206935 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2262: a β-strand

Full LRP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Donnai-Barrow syndrome

Similar variants

LRP2 p.Arg2262Cys Uncertain significance ★★ ⚠ same residue
LRP2 p.Arg2262His Uncertain significance ★★ ⚠ same residue
LRP2 p.Arg2262Leu Uncertain significance ★★ ⚠ same residue
LRP2 p.Arg2262= Likely benign ★ 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

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-arg2262pro (accessed [today's date]).

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