Is LRP1 p.Pro224Ala (c.670C>G) pathogenic?

LRP1 p.Pro224Ala (c.670C>G) is classified Pathogenic in LRP1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-01-26). AlphaMissense: likely benign (0.0799); Very rare (popmax 0.00668%, eas); Associated with developmental dysplasia of the hip 3.

What condition is associated with LRP1 p.Pro224Ala (c.670C>G)?

LRP1 p.Pro224Ala (c.670C>G) is associated with developmental dysplasia of the hip 3 (ClinVar).

How common is LRP1 p.Pro224Ala (c.670C>G) in the general population?

LRP1 p.Pro224Ala (c.670C>G) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about LRP1 p.Pro224Ala (c.670C>G)?

AlphaMissense predicts likely benign (score 0.0799) — an in-silico prediction, not a clinical call.

LRP1 p.Pro224Ala

c.670C>G · rs2548053933 · VCV2691745

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0799 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Conditions

developmental dysplasia of the hip 3

Computational evidence

Protein change
AlphaMissense	0.0799	likely benign ⚠ discordant with ClinVar
REVEL	0.323	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.4, phastCons 1
Overall
CADD	21.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00668% East Asian · 3/44,878 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000205% 3/1,461,856 alleles · very rare

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.Pro224Ala
Coding: c.670C>G
MANE Select: NM_173177 · reported on NM_002332
dbSNP: rs2548053933
Type: single nucleotide variant
Location: chr12:57145319 (GRCh38)
Structure: AlphaFold pLDDT 88.37

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

Disease context

developmental dysplasia of the hip 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LRP1 p.Asp100= Conflicting classifications of pathogenicity ★ same condition
LRP1 p.Gly169Asp Uncertain significance ★ ⚠ same condition
LRP1 p.Ile405Thr Uncertain significance ★ ⚠ same condition
LRP1 p.Ser428= Uncertain significance ★ same condition
LRP1 c.2798-4C>A Pathogenic same condition
LRP1 p.Arg1783Trp Pathogenic ⚠ same condition
LRP1 p.Thr2129Lys Pathogenic ⚠ same condition
LRP1 p.Ala1564Thr Uncertain significance ★★ 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-pro224ala (accessed [today's date]).

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