Is APOE p.Gln119Pro (c.356A>C) pathogenic?

APOE p.Gln119Pro (c.356A>C) is classified Uncertain significance in APOE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-07). AlphaMissense: ambiguous (0.5307); Ultra-rare (popmax 0.0456%, afr); Associated with Cardiovascular phenotype.

What condition is associated with APOE p.Gln119Pro (c.356A>C)?

APOE p.Gln119Pro (c.356A>C) is associated with Cardiovascular phenotype (ClinVar).

How common is APOE p.Gln119Pro (c.356A>C) in the general population?

APOE p.Gln119Pro (c.356A>C) is ultra-rare (popmax 0.0456%, afr) (gnomAD).

What do computational predictors say about APOE p.Gln119Pro (c.356A>C)?

AlphaMissense predicts ambiguous (score 0.5307) — an in-silico prediction, not a clinical call.

APOE p.Gln119Pro

c.356A>C · rs777291619 · VCV1710568

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5307 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0456%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.5307	ambiguous
REVEL	0.541	indeterminate
SaProt	LLR -13.06	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.76, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,622 bp · p 0.6 · regional, not allelic
Overall
CADD	24.0	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 0.0456% African / African-American · 34/74,506 alleles

Filtering AF 0.0335% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0294%

Overall 0.00245% 39/1,593,992 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0456%	2,191
Remaining individualsnot grpmax-eligible	0.00324%	30,847
Admixed American	0.00177%	56,482
South Asian	0.00112%	88,900
European (non-Finnish)	8.54e-05%	1,170,426

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.Gln119Pro
Coding: c.356A>C
MANE Select: NM_000041
dbSNP: rs777291619
Type: single nucleotide variant
Location: chr19:44908652 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 31 PDB
Residue 119: 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.Arg43Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
APOE p.Arg246Pro Uncertain significance ★★ same condition
APOE p.Arg56His 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
APOE p.Val213Gly Uncertain significance ★★ ⚠ same condition
APOE p.Arg209= 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-gln119pro (accessed [today's date]).

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