Is APOE p.Leu89Ser (c.266T>C) pathogenic?

APOE p.Leu89Ser (c.266T>C) is classified Uncertain significance in APOE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). AlphaMissense: likely pathogenic (0.8361); Ultra-rare (popmax 0.0147%, afr); Associated with Cardiovascular phenotype.

What condition is associated with APOE p.Leu89Ser (c.266T>C)?

APOE p.Leu89Ser (c.266T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is APOE p.Leu89Ser (c.266T>C) in the general population?

APOE p.Leu89Ser (c.266T>C) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

What do computational predictors say about APOE p.Leu89Ser (c.266T>C)?

AlphaMissense predicts likely pathogenic (score 0.8361) — an in-silico prediction, not a clinical call.

APOE p.Leu89Ser

c.266T>C · rs368210726 · VCV3128000

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8361 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.8361	likely pathogenic · top 3% in APOE
REVEL	0.566	indeterminate
SaProt	LLR -10.08	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,622 bp · p 0.6 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0147% African / African-American · 11/74,916 alleles

Filtering AF 0.00815% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.000868% 14/1,613,602 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,811
European (non-Finnish)	0.000254%	393,239

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.Leu89Ser
Coding: c.266T>C
MANE Select: NM_000041
dbSNP: rs368210726
Type: single nucleotide variant
Location: chr19:44908562 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 31 PDB
Residue 89: 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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

APOE p.Arg43Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
APOE p.Arg246Pro Uncertain significance ★★ same condition
APOE p.Arg56His Uncertain significance ★★ ⚠ same condition
APOE p.Gln119Pro Uncertain significance ★★ same condition
APOE p.Gln181His Uncertain significance ★★ ⚠ same condition
APOE p.Ser112Tyr Uncertain significance ★★ ⚠ same condition
APOE p.Trp294Cys Uncertain significance ★★ ⚠ same condition
APOE p.Val213Gly 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-leu89ser (accessed [today's date]).

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