Is LRP1 p.Pro486= (c.1458G>A) pathogenic?

LRP1 p.Pro486= (c.1458G>A) is classified Benign/Likely benign in LRP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-08-01). Rare (popmax 0.219%, sas).

How common is LRP1 p.Pro486= (c.1458G>A) in the general population?

LRP1 p.Pro486= (c.1458G>A) is rare (popmax 0.219%, sas) (gnomAD).

LRP1 p.Pro486=

c.1458G>A · rs138966453 · VCV728775

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.219%, sas)

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 -9.2	GERP -5
Overall
CADD	1.993	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.219% South Asian · 199/90,814 alleles

Filtering AF 0.194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.185%

Overall 0.0405% 651/1,609,352 alleles · rare exomes 577/1,456,978 · genomes 74/152,374 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.517%	193
South Asiangrpmax	0.219%	456
Remaining individualsnot grpmax-eligible	0.0627%	1,596
Admixed American	0.0567%	1,764
African / African-American	0.0333%	3,000
Middle Eastern	0.0207%	4,830
European (non-Finnish)	0.0167%	5,981
East Asian	0.00669%	14,941

Ashkenazi Jewish 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: LRP1
Protein: p.Pro486=
Coding: c.1458G>A
MANE Select: NM_002332
dbSNP: rs138966453
Type: single nucleotide variant
Location: chr12:57156817 (GRCh38)
Structure: AlphaFold pLDDT 88.37

Full LRP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LRP1 p.Ala1564Thr Uncertain significance ★★ same type
LRP1 p.Arg228Gln Uncertain significance ★★ same type
LRP1 p.Arg2440Trp Uncertain significance ★★ ⚠ same type
LRP1 p.Arg539Gln Uncertain significance ★★ same type
LRP1 p.Asp4483Tyr Uncertain significance ★★ same type
LRP1 p.Ser2907Pro Uncertain significance ★★ same type
LRP1 p.Val3296Ile Uncertain significance ★★ ⚠ same type
C1D p.Glu4= Benign ★★ same type

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/lrp1-p-pro486 (accessed [today's date]).

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