Is APOA5 p.Pro221= (c.663C>T) pathogenic?

APOA5 p.Pro221= (c.663C>T) is classified Likely benign in APOA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-08-24). Very rare (popmax 0.0017%, amr); Associated with Cardiovascular phenotype.

What condition is associated with APOA5 p.Pro221= (c.663C>T)?

APOA5 p.Pro221= (c.663C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is APOA5 p.Pro221= (c.663C>T) in the general population?

APOA5 p.Pro221= (c.663C>T) is very rare (popmax 0.0017%, amr) (gnomAD).

APOA5 p.Pro221=

c.663C>T · rs1038579905 · VCV1754621

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0017%, amr)

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 -6.9	GERP -3.1
Overall
CADD	5.249	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0017% Admixed American · 1/58,928 alleles

Filtering AF 0.000248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000565% 9/1,593,982 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0017%	58,928
South Asian	0.00111%	90,152
European (non-Finnish)	0.000595%	167,933

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.Pro221=
Coding: c.663C>T
MANE Select: NM_001371904
dbSNP: rs1038579905
Type: single nucleotide variant
Location: chr11:116790566 (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 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
APOA5 p.Arg233Gln Uncertain significance ★★ ⚠ same condition
APOA5 p.Arg40Gly 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-pro221 (accessed [today's date]).

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