Is LPL p.Ala458fs (c.1373del) pathogenic?

LPL p.Ala458fs (c.1373del) is classified Likely pathogenic in LPL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-22). Associated with familial lipoprotein lipase deficiency.

What condition is associated with LPL p.Ala458fs (c.1373del)?

LPL p.Ala458fs (c.1373del) is associated with familial lipoprotein lipase deficiency, hyperlipidemia, familial combined, LPL related (ClinVar).

LPL p.Ala458fs

c.1373del · VCV3595459

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

familial lipoprotein lipase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.2	GERP -4.9

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

Variant & gene context

Gene: LPL
Protein: p.Ala458fs
Coding: c.1373del
MANE Select: NM_000237
Type: Deletion
Location: chr8:19962165 (GRCh38)
Gene constraint: LOEUF 1.075 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.36 · 5 PDB
Residue 458: the plat domain; a disulfide bond; the 'interaction with gpihbp1' region

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

Disease context

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

Also linked: hyperlipidemia, familial combined, LPL related

Similar variants

LPL p.Ala458Val Uncertain significance ★★ ⚠ same residue
LPL p.Val230fs Pathogenic/Likely pathogenic ★★ same condition
LPL p.Cys266fs Likely pathogenic ★ same condition
LPL p.Glu396_Val397insTer Likely pathogenic ★ same condition
LPL p.Ile376fs Pathogenic ★ same condition
LPL p.Lys129fs Likely pathogenic ★ same condition
LPL p.Trp113fs Likely pathogenic ★ same condition
LPL p.Ala458Ser Uncertain significance ★ ⚠ same residue

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/lpl-p-ala458fs (accessed [today's date]).

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