Is APOE p.Ala23= (c.69G>A) pathogenic?

APOE p.Ala23= (c.69G>A) is classified Likely benign in APOE (ClinVar, Multiple submitters, 4 submitters; last evaluated 2021-12-17). Ultra-rare (popmax 0.0364%, nfe); Associated with Alzheimer disease 2.

What condition is associated with APOE p.Ala23= (c.69G>A)?

APOE p.Ala23= (c.69G>A) is associated with Alzheimer disease 2, sea-blue histiocyte syndrome, age related macular degeneration 1 (ClinVar).

How common is APOE p.Ala23= (c.69G>A) in the general population?

APOE p.Ala23= (c.69G>A) is ultra-rare (popmax 0.0364%, nfe) (gnomAD).

APOE p.Ala23=

c.69G>A · rs111833428 · VCV1210034

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0364%, nfe)

Conditions

Alzheimer disease 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.11	GERP -1.8, phastCons 0.001
Overall
CADD	7.919	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0364% European (non-Finnish) · 430/1,179,880 alleles

Filtering AF 0.0336% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0324%

Overall 0.029% 467/1,612,810 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0364%	2,744
Remaining individualsnot grpmax-eligible	0.0256%	3,902
African / African-American	0.0107%	9,365
South Asian	0.00769%	13,000
Admixed American	0.00667%	14,981
East Asian	0.00223%	44,880
Finnishnot grpmax-eligible	0.00158%	63,190

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.Ala23=
Coding: c.69G>A
MANE Select: NM_000041
dbSNP: rs111833428
Type: single nucleotide variant
Location: chr19:44907785 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 31 PDB
Residue 23: a β-strand

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

Disease context

Alzheimer disease 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: sea-blue histiocyte syndrome age related macular degeneration 1 Alzheimer disease 4 Alzheimer disease 3 lipoprotein glomerulopathy 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.Arg269Gly Uncertain significance ★★ ⚠ same condition
APOE p.Glu230Lys Uncertain significance ★★ ⚠ same condition
APOE p.Gly145Asp Uncertain significance ★★ ⚠ same condition
APOE p.Trp294Cys Uncertain significance ★★ ⚠ same condition
APOE p.Ala217= Benign/Likely benign ★★ 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-ala23 (accessed [today's date]).

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