Is APOC3 p.Phe31Val (c.91T>G) pathogenic?

APOC3 p.Phe31Val (c.91T>G) is classified Uncertain significance in APOC3 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-09-10). AlphaMissense: likely benign (0.0969); Very rare (popmax 0.000763%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with APOC3 p.Phe31Val (c.91T>G)?

APOC3 p.Phe31Val (c.91T>G) is associated with Cardiovascular phenotype, apolipoprotein c-III deficiency (ClinVar).

How common is APOC3 p.Phe31Val (c.91T>G) in the general population?

APOC3 p.Phe31Val (c.91T>G) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about APOC3 p.Phe31Val (c.91T>G)?

AlphaMissense predicts likely benign (score 0.0969) — an in-silico prediction, not a clinical call.

APOC3 p.Phe31Val

c.91T>G · rs1025708722 · VCV2582727

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0969 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0969	likely benign
REVEL	0.157	moderately benign-leaning
SaProt	LLR -4.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.74	GERP -6.9
Regional constraint	o/e 0.98	unconstrained · MANE · 2,298 bp · p 0.86 · regional, not allelic
Overall
CADD	1.135	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000763% European (non-Finnish) · 9/1,179,932 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.00062% 10/1,613,078 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00158%	63,282
European (non-Finnish)grpmax	0.000763%	131,104

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe31Val
Coding: c.91T>G
MANE Select: NM_000040
dbSNP: rs1025708722
Type: single nucleotide variant
Location: chr11:116830808 (GRCh38)
Gene constraint: LOEUF 1.68 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.90 · 1 PDB
Residue 31: an α-helix

Full APOC3 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

Also linked: apolipoprotein c-III deficiency

Similar variants

APOC3 p.Phe31_Met32insIlePhe Uncertain significance ★ same residue
APOC3 p.Glu24Lys Uncertain significance ★★ ⚠ same condition
APOC3 p.Leu14Phe Uncertain significance ★★ ⚠ same condition
APOC3 p.Val50Met Uncertain significance ★★ ⚠ same condition
APOC3 p.Val91Ile Uncertain significance ★★ ⚠ same condition
APOC3 p.Ala16= Likely benign ★★ same condition
APOC3 p.Ala23= Benign/Likely benign ★★ same condition
APOC3 p.Gln33= Benign/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/apoc3-p-phe31val (accessed [today's date]).

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