Is APOE p.Arg246Pro (c.737G>C) pathogenic?

APOE p.Arg246Pro (c.737G>C) is classified Uncertain significance in APOE (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-24). AlphaMissense: ambiguous (0.4744); Very rare (popmax 0.000521%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with APOE p.Arg246Pro (c.737G>C)?

APOE p.Arg246Pro (c.737G>C) is associated with Cardiovascular phenotype (ClinVar).

How common is APOE p.Arg246Pro (c.737G>C) in the general population?

APOE p.Arg246Pro (c.737G>C) is very rare (popmax 0.000521%, nfe) (gnomAD).

What do computational predictors say about APOE p.Arg246Pro (c.737G>C)?

AlphaMissense predicts ambiguous (score 0.4744) — an in-silico prediction, not a clinical call.

APOE p.Arg246Pro

c.737G>C · rs1330553726 · VCV2572764

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4744 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000521%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4744	ambiguous
REVEL	0.519	indeterminate
SaProt	LLR -9.08	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP -3.2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,622 bp · p 0.6 · regional, not allelic
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000521% European (non-Finnish) · 6/1,151,360 alleles

Filtering AF 0.000187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000123%

Overall 0.00043% 6/1,394,000 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.Arg246Pro
Coding: c.737G>C
MANE Select: NM_000041
dbSNP: rs1330553726
Type: single nucleotide variant
Location: chr19:44909033 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 31 PDB
Residue 246: the '8 x 22 aa approximate tandem repeats' region; the 'lipid-binding and lipoprotein association' region; a UniProt-annotated variant site (in hlpp3; apoe3 washington); a UniProt-annotated variant site (in apoe2 dunedin)

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.Arg246His Uncertain significance ★ ⚠ same residue
APOE p.Arg246Cys Pathogenic ⚠ same residue
APOE p.Arg43Cys Pathogenic/Likely pathogenic ★★ ⚠ 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-arg246pro (accessed [today's date]).

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