Is LPL p.Arg255fs (c.763_766del) pathogenic?

LPL p.Arg255fs (c.763766del) is classified Pathogenic in LPL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-07). Very rare (popmax 8.48e-05%, nfe).

How common is LPL p.Arg255fs (c.763_766del) in the general population?

LPL p.Arg255fs (c.763_766del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

LPL p.Arg255fs

c.763_766del · rs1563575291 · VCV1452004

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

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 5 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,828 alleles

Overall 6.84e-05% 1/1,461,642 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: LPL
Protein: p.Arg255fs
Coding: c.763_766del
MANE Select: NM_000237
dbSNP: rs1563575291
Type: Microsatellite
Location: chr8:19954337 (GRCh38)
Gene constraint: LOEUF 1.075 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.36 · 5 PDB
Residue 255: a disulfide bond; the 'essential for determining substrate specificity' region

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

Similar variants

LPL p.Arg255Thr Uncertain significance ★★ ⚠ same residue
LPL p.Gly256fs Pathogenic ★★ same type
LPL p.Val111del Uncertain significance ★★ same type
LPL c.250-8_250-6del Likely benign ★★ same type
LPL p.Glu396fs Pathogenic ★ same type
LPL p.Leu279fs Pathogenic ★ same type
LPL p.Ser390_Phe391insTer Pathogenic ★ same type
LPL c.433_435delGAG Uncertain significance ★ same type

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-arg255fs (accessed [today's date]).

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