Is LDLR p.Trp577fs (c.1728del) pathogenic?

LDLR p.Trp577fs (c.1728del) is classified Pathogenic in LDLR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Trp577fs (c.1728del)?

LDLR p.Trp577fs (c.1728del) is associated with familial hypercholesterolemia (ClinVar).

LDLR p.Trp577fs

c.1728del · VCV4728244

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 12 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: LDLR
Protein: p.Trp577fs
Coding: c.1728del
MANE Select: NM_000527
Type: Deletion
Location: chr19:11116881 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 577: a UniProt-annotated variant site (in fhcl1; pathogenic; results in loss of receptor expression at the cell surface); a UniProt-annotated variant site (in fhcl1; uncertain significance); a β-strand

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.Trp577Gly Pathogenic ★★★ same residue
LDLR p.Trp577Arg Pathogenic ★★ same residue
LDLR p.Trp577Ser Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Trp577Ter Pathogenic ★★ same residue
LDLR p.Trp577_Asp579del Likely pathogenic ★ same residue
LDLR p.Lys816fs Likely pathogenic ★★★ same condition
LDLR p.Tyr400_Phe402del Likely pathogenic ★★★ same condition
LDLR p.Phe86_Arg88del Uncertain significance ★★★ 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-trp577fs (accessed [today's date]).

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