Is APOE p.Arg110fs (c.327dup) pathogenic?

APOE p.Arg110fs (c.327dup) is classified Uncertain significance in APOE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-25). Very rare (popmax 0.000425%, nfe); Associated with hyperlipoproteinemia type 3.

What condition is associated with APOE p.Arg110fs (c.327dup)?

APOE p.Arg110fs (c.327dup) is associated with hyperlipoproteinemia type 3 (ClinVar).

How common is APOE p.Arg110fs (c.327dup) in the general population?

APOE p.Arg110fs (c.327dup) is very rare (popmax 0.000425%, nfe) (gnomAD).

How is Dysbetalipoproteinemia inherited?

Typically Autosomal dominant, Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

APOE p.Arg110fs

c.327dup · rs761350032 · VCV3066201

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000425%, nfe)

Conditions

hyperlipoproteinemia type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (4 of 4) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.9	GERP 0.65, phastCons 0.25

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000425% European (non-Finnish) · 5/1,177,192 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000343% 5/1,455,778 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: APOE
Protein: p.Arg110fs
Coding: c.327dup
MANE Select: NM_000041
dbSNP: rs761350032
Type: Duplication
Location: chr19:44908622 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 31 PDB
Residue 110: the '8 x 22 aa approximate tandem repeats' region; an α-helix

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

Disease context

hyperlipoproteinemia type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Dysbetalipoproteinemia (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adolescent, Adult, Childhood, Elderly
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

APOE p.Glu139_Gly145dup Pathogenic same condition
APOE p.Arg154Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
APOE p.Arg43Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
APOE p.Trp228Ter Likely pathogenic ★★ same condition
APOE p.Arg269Gly Uncertain significance ★★ ⚠ same condition
APOE p.Glu230Lys Uncertain significance ★★ ⚠ same condition
APOE p.Gly145Asp Uncertain significance ★★ same condition
APOE p.Trp294Cys 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/apoe-p-arg110fs (accessed [today's date]).

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