Is APOC3 p.Ser69Phe (c.206C>T) pathogenic?

APOC3 p.Ser69Phe (c.206C>T) is classified Uncertain significance in APOC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-20). AlphaMissense: ambiguous (0.5168); Very rare (popmax 0.00167%, amr).

How common is APOC3 p.Ser69Phe (c.206C>T) in the general population?

APOC3 p.Ser69Phe (c.206C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about APOC3 p.Ser69Phe (c.206C>T)?

AlphaMissense predicts ambiguous (score 0.5168) — an in-silico prediction, not a clinical call.

APOC3 p.Ser69Phe

c.206C>T · VCV4530831

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5168 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
AlphaMissense	0.5168	ambiguous
REVEL	0.606	indeterminate
SaProt	LLR -7.74	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 4.1, phastCons 0.36
Regional constraint	o/e 0.98	unconstrained · MANE · 2,298 bp · p 0.86 · regional, not allelic
Overall
CADD	25.6	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 0.00167% Admixed American · 1/60,030 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,846 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,030
European (non-Finnish)	0.000169%	590,009

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: APOC3
Protein: p.Ser69Phe
Coding: c.206C>T
MANE Select: NM_000040
Type: single nucleotide variant
Location: chr11:116832790 (GRCh38)
Gene constraint: LOEUF 1.68 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.90 · 1 PDB
Residue 69: an α-helix; the 'lipid-binding' region

Full APOC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APOC3 p.Asp65Asn Uncertain significance ★★ ⚠ same type
APOC3 p.Glu24Lys Uncertain significance ★★ ⚠ same type
APOC3 p.Leu14Phe Uncertain significance ★★ ⚠ same type
APOC3 p.Met36Val Uncertain significance ★★ ⚠ same type
APOC3 p.Val50Met Uncertain significance ★★ ⚠ same type
APOC3 p.Val91Ile Uncertain significance ★★ ⚠ same type
APOC3 c.179+221G>A Benign ★★ same type
APOC3 c.179+238T>C Benign ★★ same type

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/apoc3-p-ser69phe (accessed [today's date]).

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