Is LRP2 p.Ser1165= (c.3495G>A) pathogenic?

LRP2 p.Ser1165= (c.3495G>A) is classified Conflicting classifications of pathogenicity in LRP2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-14). Ultra-rare (popmax 0.04%, amr); Associated with Donnai-Barrow syndrome.

What condition is associated with LRP2 p.Ser1165= (c.3495G>A)?

LRP2 p.Ser1165= (c.3495G>A) is associated with Donnai-Barrow syndrome (ClinVar).

How common is LRP2 p.Ser1165= (c.3495G>A) in the general population?

LRP2 p.Ser1165= (c.3495G>A) is ultra-rare (popmax 0.04%, amr) (gnomAD).

LRP2 p.Ser1165=

c.3495G>A · rs186494101 · VCV332180

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, amr)

Conditions

Donnai-Barrow syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.34	GERP -4.2
Overall
CADD	3.26	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.04% Admixed American · 24/60,022 alleles

Filtering AF 0.0275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0234%

Overall 0.00316% 51/1,614,092 alleles · ultra-rare exomes 43/1,461,832 · genomes 8/152,260 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.04%	2,501
Middle Eastern	0.0165%	6,062
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
African / African-American	0.00267%	37,513
South Asian	0.0022%	45,539
European (non-Finnish)	0.00169%	58,999
Finnishnot grpmax-eligible	0.00156%	64,014

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.Ser1165=
Coding: c.3495G>A
MANE Select: NM_004525
dbSNP: rs186494101
Type: single nucleotide variant
Location: chr2:169243458 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1165: the ldl-receptor class a 11 domain; an α-helix

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.Ser1165Leu 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-ser1165 (accessed [today's date]).

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