Is LDLR p.Lys596fs (c.1785dup) pathogenic?

LDLR p.Lys596fs (c.1785dup) is classified Likely pathogenic in LDLR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-12). Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Lys596fs (c.1785dup)?

LDLR p.Lys596fs (c.1785dup) is associated with familial hypercholesterolemia (ClinVar).

LDLR p.Lys596fs

c.1785dup · VCV4076986

Likely pathogenic Single submitter

Classification

Likely 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 1.4	GERP 0.26, phastCons 0.97

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

Variant & gene context

Gene: LDLR
Protein: p.Lys596fs
Coding: c.1785dup
MANE Select: NM_000527
Type: Duplication
Location: chr19:11116936 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 596: 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.Lys596= Likely benign ★★ same residue
LDLR p.Lys596Glu Uncertain significance ★ ⚠ same residue
LDLR p.Cys803_Leu808dup Uncertain significance ★★★ same condition
LDLR c.313+2dup Pathogenic/Likely pathogenic ★★ same condition
LDLR p.Ala459fs Pathogenic ★★ same condition
LDLR p.Asn564fs Pathogenic ★★ same condition
LDLR p.Asp178fs Pathogenic ★★ same condition
LDLR p.Asp217Ter 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/ldlr-p-lys596fs (accessed [today's date]).

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