Is APOE p.Asp83= (c.249C>T) pathogenic?

APOE p.Asp83= (c.249C>T) is classified Likely benign in APOE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-01-04). Ultra-rare (popmax 0.0165%, mid); Associated with Cardiovascular phenotype.

What condition is associated with APOE p.Asp83= (c.249C>T)?

APOE p.Asp83= (c.249C>T) is associated with Cardiovascular phenotype, Alzheimer disease 2, sea-blue histiocyte syndrome (ClinVar).

How common is APOE p.Asp83= (c.249C>T) in the general population?

APOE p.Asp83= (c.249C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

APOE p.Asp83=

c.249C>T · rs767980905 · VCV760030

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

Cardiovascular phenotype

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 -1.3	GERP -3.5
Overall
CADD	3.924	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.00378% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00345%

Overall 0.00384% 62/1,613,546 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
European (non-Finnish)	0.00483%	20,697
Remaining individualsnot grpmax-eligible	0.0032%	31,225
African / African-American	0.00267%	37,450

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.Asp83=
Coding: c.249C>T
MANE Select: NM_000041
dbSNP: rs767980905
Type: single nucleotide variant
Location: chr19:44908545 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 31 PDB
Residue 83: the '8 x 22 aa approximate tandem repeats' region; 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: Alzheimer disease 2 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.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-asp83 (accessed [today's date]).

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