Is LDLR p.Val468fs (c.1401_1402insAGCAGGGT) pathogenic?

LDLR p.Val468fs (c.14011402insAGCAGGGT) is classified Likely pathogenic in LDLR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-24). Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Val468fs (c.1401_1402insAGCAGGGT)?

LDLR p.Val468fs (c.1401_1402insAGCAGGGT) is associated with familial hypercholesterolemia (ClinVar).

LDLR p.Val468fs

c.1401_1402insAGCAGGGT · VCV4526398

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 10 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -13	GERP -3.8

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

Variant & gene context

Gene: LDLR
Protein: p.Val468fs
Coding: c.1401_1402insAGCAGGGT
MANE Select: NM_000527
Type: Insertion
Location: chr19:11113577 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 468: a UniProt-annotated variant site (in); 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.Val468Asp Uncertain significance ★★★ ⚠ same residue
LDLR p.Val468Ile Uncertain significance ★★★ ⚠ same residue
LDLR p.Val468_Ile469del Pathogenic ★ same residue
LDLR p.Val468Ala Uncertain significance ★ ⚠ same residue
LDLR p.Asp824delinsPhePhePhePhePheXaaXaaXaaXaaLeuAlaArgMetValSerIleSerTer Pathogenic ★ same condition
LDLR p.Gly37fs Pathogenic ★ same condition
LDLR p.Ile821_Asn822insGlyArgAlaArgTrpLeuThrProValIleProAlaLeuTrpGluAlaGluAlaGlyGlySerTer Pathogenic ★ same condition
LDLR p.Leu790fs 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-val468fs (accessed [today's date]).

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