Is APOE p.Asp289Ala (c.866A>C) pathogenic?

APOE p.Asp289Ala (c.866A>C) is classified Uncertain significance in APOE (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-15). AlphaMissense: likely pathogenic (0.6229); Absent from gnomAD v4.1.

How common is APOE p.Asp289Ala (c.866A>C) in the general population?

APOE p.Asp289Ala (c.866A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APOE p.Asp289Ala (c.866A>C)?

AlphaMissense predicts likely pathogenic (score 0.6229) — an in-silico prediction, not a clinical call.

APOE p.Asp289Ala

c.866A>C · rs1568618190 · VCV1706316

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6229 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6229	likely pathogenic
REVEL	0.55	indeterminate
SaProt	LLR -6.07	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,622 bp · p 0.6 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: APOE
Protein: p.Asp289Ala
Coding: c.866A>C
MANE Select: NM_000041
dbSNP: rs1568618190
Type: single nucleotide variant
Location: chr19:44909162 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 31 PDB
Residue 289: the 'lipid-binding and lipoprotein association' region; the 'homooligomerization' region; the 'specificity for association with vldl' region; a UniProt-annotated variant site (in hlpp3; apoe3 washington); an α-helix

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

Similar variants

APOE p.Arg154Ser Pathogenic/Likely pathogenic ★★ same type
APOE p.Arg43Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
APOE p.Trp228Ter Likely pathogenic ★★ same type
APOE p.Arg246Pro Uncertain significance ★★ ⚠ same type
APOE p.Arg269Gly Uncertain significance ★★ ⚠ same type
APOE p.Arg56His Uncertain significance ★★ ⚠ same type
APOE p.Gln119Pro Uncertain significance ★★ ⚠ same type
APOE p.Gln181His 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/apoe-p-asp289ala (accessed [today's date]).

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