Is APOE p.Trp294Cys (c.882G>T) pathogenic?

APOE p.Trp294Cys (c.882G>T) is classified Uncertain significance in APOE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-12). AlphaMissense: likely pathogenic (0.9019); Ultra-rare (popmax 0.0385%, amr); Associated with Cardiovascular phenotype.

What condition is associated with APOE p.Trp294Cys (c.882G>T)?

APOE p.Trp294Cys (c.882G>T) is associated with Cardiovascular phenotype, hyperlipoproteinemia type 3 (ClinVar).

How common is APOE p.Trp294Cys (c.882G>T) in the general population?

APOE p.Trp294Cys (c.882G>T) is ultra-rare (popmax 0.0385%, amr) (gnomAD).

What do computational predictors say about APOE p.Trp294Cys (c.882G>T)?

AlphaMissense predicts likely pathogenic (score 0.9019) — an in-silico prediction, not a clinical call.

APOE p.Trp294Cys

c.882G>T · rs557715042 · VCV1764810

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9019 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0385%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9019	likely pathogenic · top 1% in APOE
REVEL	0.668	pathogenic-leaning
SaProt	LLR -10.16	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,622 bp · p 0.6 · regional, not allelic
Overall
CADD	25.1	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 0.0385% Admixed American · 23/59,760 alleles

Filtering AF 0.0262% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0223%

Overall 0.00181% 29/1,599,752 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0385%	2,598
Remaining individualsnot grpmax-eligible	0.00643%	15,546
African / African-American	0.00267%	37,498

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.Trp294Cys
Coding: c.882G>T
MANE Select: NM_000041
dbSNP: rs557715042
Type: single nucleotide variant
Location: chr19:44909178 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 31 PDB
Residue 294: the 'homooligomerization' 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

Disease context

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

Also linked: hyperlipoproteinemia type 3

Similar variants

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.Arg246Pro Uncertain significance ★★ ⚠ same condition
APOE p.Arg269Gly 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

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-trp294cys (accessed [today's date]).

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