Is APOA5 p.Ala214Pro (c.640G>C) pathogenic?

APOA5 p.Ala214Pro (c.640G>C) is classified Uncertain significance in APOA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-01). AlphaMissense: ambiguous (0.4638); Very rare (popmax 8.49e-05%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with APOA5 p.Ala214Pro (c.640G>C)?

APOA5 p.Ala214Pro (c.640G>C) is associated with Cardiovascular phenotype (ClinVar).

How common is APOA5 p.Ala214Pro (c.640G>C) in the general population?

APOA5 p.Ala214Pro (c.640G>C) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about APOA5 p.Ala214Pro (c.640G>C)?

AlphaMissense predicts ambiguous (score 0.4638) — an in-silico prediction, not a clinical call.

APOA5 p.Ala214Pro

c.640G>C · VCV3931780

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4638 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4638	ambiguous · top 10% in APOA5
REVEL	0.497	indeterminate
SaProt	LLR -11.91	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 1,729 bp · p 0.086 · regional, not allelic
Overall
CADD	22.0	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 8.49e-05% European (non-Finnish) · 1/1,178,178 alleles

Overall 6.9e-05% 1/1,449,248 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: APOA5
Protein: p.Ala214Pro
Coding: c.640G>C
MANE Select: NM_001371904
Type: single nucleotide variant
Location: chr11:116790589 (GRCh38)
Gene constraint: LOEUF 1.146 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.38

Full APOA5 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

APOA5 p.Ala214Val Uncertain significance ★ ⚠ same residue
APOA5 p.Ala214= Likely benign ★ same residue
APOA5 c.161+3G>A Uncertain significance ★★ same condition
APOA5 c.161+5G>C Uncertain significance ★★ same condition
APOA5 p.Ala244Ser Uncertain significance ★★ ⚠ same condition
APOA5 p.Ala302Val Uncertain significance ★★ ⚠ same condition
APOA5 p.Ala82Val Uncertain significance ★★ ⚠ same condition
APOA5 p.Arg226Cys 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/apoa5-p-ala214pro (accessed [today's date]).

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