Is APOE p.Ala217= (c.651C>T) pathogenic?

APOE p.Ala217= (c.651C>T) is classified Benign/Likely benign in APOE (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-05-01). Rare (popmax 0.287%, sas); Associated with Alzheimer disease 3.

What condition is associated with APOE p.Ala217= (c.651C>T)?

APOE p.Ala217= (c.651C>T) is associated with Alzheimer disease 3, Alzheimer disease 2, sea-blue histiocyte syndrome (ClinVar).

How common is APOE p.Ala217= (c.651C>T) in the general population?

APOE p.Ala217= (c.651C>T) is rare (popmax 0.287%, sas) (gnomAD).

APOE p.Ala217=

Q: How is Early-onset autosomal dominant Alzheimer disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.651C>T · rs72654468 · VCV779286

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.287%, sas)

Conditions

Alzheimer disease 3

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 -1.9	GERP -3.2
Overall
CADD	8.515	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.287% South Asian · 234/81,640 alleles

Filtering AF 0.257% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.245%

Overall 0.0991% 1,499/1,513,222 alleles · rare exomes 1,364/1,361,190 · genomes 135/152,032 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.287%	349
European (non-Finnish)	0.1%	999
Admixed American	0.0869%	1,151
Remaining individualsnot grpmax-eligible	0.0851%	1,176
Finnishnot grpmax-eligible	0.0434%	2,305
Middle Eastern	0.0231%	4,330
African / African-American	0.0154%	6,498
Ashkenazi Jewishnot grpmax-eligible	0.0109%	9,177
East Asian	0.00251%	39,826

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.Ala217=
Coding: c.651C>T
MANE Select: NM_000041
dbSNP: rs72654468
Type: single nucleotide variant
Location: chr19:44908947 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 31 PDB
Residue 217: the '8 x 22 aa approximate tandem repeats' region; the 'lipid-binding and lipoprotein association' region; an α-helix

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

Disease context

Alzheimer disease 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Alzheimer disease 2 sea-blue histiocyte syndrome age related macular degeneration 1 Alzheimer disease 4 lipoprotein glomerulopathy hyperlipoproteinemia type 3

For Early-onset autosomal dominant Alzheimer disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

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.Ala23= 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-ala217 (accessed [today's date]).

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