Is APOE p.Arg209= (c.627G>A) pathogenic?

APOE p.Arg209= (c.627G>A) is classified Likely benign in APOE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-30). Rare (popmax 0.115%, sas); Associated with Cardiovascular phenotype.

What condition is associated with APOE p.Arg209= (c.627G>A)?

APOE p.Arg209= (c.627G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is APOE p.Arg209= (c.627G>A) in the general population?

APOE p.Arg209= (c.627G>A) is rare (popmax 0.115%, sas) (gnomAD).

APOE p.Arg209=

c.627G>A · rs774452222 · VCV1752588

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.115%, sas)

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 -1.2	GERP -2.9
Overall
CADD	1.569	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.115% South Asian · 87/75,842 alleles

Filtering AF 0.0952% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.088%

Overall 0.00648% 96/1,481,440 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.115%	872
Remaining individualsnot grpmax-eligible	0.00524%	19,085
European (non-Finnish)	0.000534%	187,343

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.Arg209=
Coding: c.627G>A
MANE Select: NM_000041
dbSNP: rs774452222
Type: single nucleotide variant
Location: chr19:44908923 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 31 PDB
Residue 209: 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

Similar variants

APOE p.Arg209Gln Uncertain significance ★ ⚠ same residue
APOE p.Arg209Trp Uncertain significance ★ ⚠ 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

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-arg209 (accessed [today's date]).

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