Is APOC2 p.Ala66fs (c.196_197del) pathogenic?

APOC2 p.Ala66fs (c.196197del) is classified Pathogenic in APOC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-31). Ultra-rare (popmax 0.0133%, amr); Associated with Cardiovascular phenotype.

What condition is associated with APOC2 p.Ala66fs (c.196_197del)?

APOC2 p.Ala66fs (c.196_197del) is associated with Cardiovascular phenotype (ClinVar).

How common is APOC2 p.Ala66fs (c.196_197del) in the general population?

APOC2 p.Ala66fs (c.196_197del) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

APOC2 p.Ala66fs

c.196_197del · rs751214954 · VCV280159

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (3 of 4, 20 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.27	GERP -3.5
Overall
CADD	19.36	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% Admixed American · 8/60,024 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.000992% 16/1,613,462 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,503
Remaining individualsnot grpmax-eligible	0.0096%	10,418
African / African-American	0.00133%	75,044
European (non-Finnish)	8.47e-05%	1,180,027

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: APOC2
Protein: p.Ala66fs
Coding: c.196_197del
MANE Select: NM_000483
dbSNP: rs751214954
Type: Deletion
Location: chr19:44948840 (GRCh38)
Gene constraint: LOEUF 1.054 · pLI 0.07 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.81 · 4 PDB
Residue 66: the 'lipid binding' region

Full APOC2 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

APOC2 p.Gln25Ter Likely pathogenic ★★ same condition
APOC2 p.Ala54Asp Uncertain significance ★★ ⚠ same condition
APOC2 p.Ala55Thr Uncertain significance ★★ ⚠ same condition
APOC2 p.Ser76Ile Uncertain significance ★★ ⚠ same condition
APOC2 p.Thr23Ile Uncertain significance ★★ ⚠ same condition
APOC2 p.Thr86Arg Uncertain significance ★★ ⚠ same condition
APOC2 p.Val67Ile Uncertain significance ★★ ⚠ same condition
APOC2 c.56-4G>C 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/apoc2-p-ala66fs (accessed [today's date]).

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