Is LDLR p.Lys225Phe (c.673_675inv) pathogenic?

LDLR p.Lys225Phe (c.673675inv) is classified Uncertain significance in LDLR (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-12). Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Lys225Phe (c.673_675inv)?

LDLR p.Lys225Phe (c.673_675inv) is associated with familial hypercholesterolemia (ClinVar).

LDLR p.Lys225Phe

c.673_675inv · VCV2125439

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.8	GERP -2.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic

Variant & gene context

Gene: LDLR
Protein: p.Lys225Phe
Coding: c.673_675inv
MANE Select: NM_000527
Type: Inversion
Location: chr19:11105579 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 225: the 'binding to getah virus e1-e2 spike glycoproteins' region; the ldl-receptor class a 5 domain

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

Disease context

familial hypercholesterolemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LDLR p.Lys225_Asp227dup Likely pathogenic ★★ same residue
LDLR p.Lys225_Glu228delinsCysLys Pathogenic ★★ same residue
LDLR p.Lys225_Glu229del Likely pathogenic ★ same residue
LDLR p.Lys225fs Pathogenic ★ same residue
LDLR c.1060+10_1060+11inv Likely benign ★ same condition
LDLR c.1186+5G>A Likely pathogenic ★★★ same condition
LDLR c.1359-1G>A Pathogenic ★★★ same condition
LDLR c.1359-5C>G 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/ldlr-p-lys225phe (accessed [today's date]).

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