Is APOE p.Glu238Asp (c.714G>T) pathogenic?

APOE p.Glu238Asp (c.714G>T) is classified Uncertain significance in APOE (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-09). AlphaMissense: likely benign (0.1313); Very rare (popmax 0.00548%, afr); Associated with Cardiovascular phenotype.

What condition is associated with APOE p.Glu238Asp (c.714G>T)?

APOE p.Glu238Asp (c.714G>T) is associated with Cardiovascular phenotype (ClinVar).

How common is APOE p.Glu238Asp (c.714G>T) in the general population?

APOE p.Glu238Asp (c.714G>T) is very rare (popmax 0.00548%, afr) (gnomAD).

What do computational predictors say about APOE p.Glu238Asp (c.714G>T)?

AlphaMissense predicts likely benign (score 0.1313) — an in-silico prediction, not a clinical call.

APOE p.Glu238Asp

c.714G>T · rs892532644 · VCV2219434

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1313 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00548%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1313	likely benign
REVEL	0.142	moderately benign-leaning
SaProt	LLR -7.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Regional constraint	o/e 1.02	unconstrained · MANE · 2,622 bp · p 0.6 · regional, not allelic
Overall
CADD	16.05	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00548% African / African-American · 4/73,036 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00106%

Overall 0.00026% 4/1,537,006 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.Glu238Asp
Coding: c.714G>T
MANE Select: NM_000041
dbSNP: rs892532644
Type: single nucleotide variant
Location: chr19:44909010 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 31 PDB
Residue 238: the '8 x 22 aa approximate tandem repeats' region; the 'lipid-binding and lipoprotein association' 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

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-glu238asp (accessed [today's date]).

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