Is LRP2 p.Arg2820Ser (c.8458C>A) pathogenic?

LRP2 p.Arg2820Ser (c.8458C>A) is classified Conflicting classifications of pathogenicity in LRP2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-18). AlphaMissense: ambiguous (0.3834); Ultra-rare (popmax 0.092%, nfe); Associated with Donnai-Barrow syndrome.

What condition is associated with LRP2 p.Arg2820Ser (c.8458C>A)?

LRP2 p.Arg2820Ser (c.8458C>A) is associated with Donnai-Barrow syndrome, intellectual disability (ClinVar).

How common is LRP2 p.Arg2820Ser (c.8458C>A) in the general population?

LRP2 p.Arg2820Ser (c.8458C>A) is ultra-rare (popmax 0.092%, nfe) (gnomAD).

What do computational predictors say about LRP2 p.Arg2820Ser (c.8458C>A)?

AlphaMissense predicts ambiguous (score 0.3834) — an in-silico prediction, not a clinical call.

LRP2 p.Arg2820Ser

c.8458C>A · rs140586887 · VCV975598

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.3834 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.092%, nfe)

Conditions

Donnai-Barrow syndrome

Computational evidence

Protein change
AlphaMissense	0.3834	ambiguous
REVEL	0.273	benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5	GERP -1.4, phastCons 0.99
Regional constraint	o/e 0.83	unconstrained · MANE · 30 kb · p 2.4e-10 · regional, not allelic
Overall
CADD	21.6	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 0.092% European (non-Finnish) · 1,085/1,179,454 alleles

Filtering AF 0.0874% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0856%

Overall 0.0709% 1,144/1,612,940 alleles · ultra-rare exomes 1,085/1,460,764 · genomes 59/152,176 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.092%	1,087
Remaining individualsnot grpmax-eligible	0.0593%	1,687
African / African-American	0.0214%	4,681
Admixed American	0.005%	19,993
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,584
Finnishnot grpmax-eligible	0.00314%	31,886

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.Arg2820Ser
Coding: c.8458C>A
MANE Select: NM_004525
dbSNP: rs140586887
Type: single nucleotide variant
Location: chr2:169198906 (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

Also linked: intellectual disability

Similar variants

LRP2 p.Arg2820His Uncertain significance ★ ⚠ same residue
LRP2 p.Arg2820Leu 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-arg2820ser (accessed [today's date]).

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