Is APOE p.Ala182Pro (c.544G>C) pathogenic?

APOE p.Ala182Pro (c.544G>C) is classified Uncertain significance in APOE (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-05). AlphaMissense: likely pathogenic (0.7363); Very rare (popmax 0.00276%, afr); Associated with Cardiovascular phenotype.

What condition is associated with APOE p.Ala182Pro (c.544G>C)?

APOE p.Ala182Pro (c.544G>C) is associated with Cardiovascular phenotype (ClinVar).

How common is APOE p.Ala182Pro (c.544G>C) in the general population?

APOE p.Ala182Pro (c.544G>C) is very rare (popmax 0.00276%, afr) (gnomAD).

What do computational predictors say about APOE p.Ala182Pro (c.544G>C)?

AlphaMissense predicts likely pathogenic (score 0.7363) — an in-silico prediction, not a clinical call.

APOE p.Ala182Pro

c.544G>C · rs796443813 · VCV2562132

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7363 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00276%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.7363	likely pathogenic · top 6% in APOE
REVEL	0.444	indeterminate
SaProt	LLR -12.18	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 4.4	GERP 1.6, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,622 bp · p 0.6 · regional, not allelic
Overall
CADD	21.9	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 0.00276% African / African-American · 2/72,454 alleles

Filtering AF 0.000458% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000171%

Overall 0.000131% 2/1,530,004 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.Ala182Pro
Coding: c.544G>C
MANE Select: NM_000041
dbSNP: rs796443813
Type: single nucleotide variant
Location: chr19:44908840 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 31 PDB
Residue 182: the '8 x 22 aa approximate tandem repeats' region

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.Ala182= Likely benign ★ same residue
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

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-ala182pro (accessed [today's date]).

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