Is ACOX2 p.Val321Ile (c.961G>A) pathogenic?

ACOX2 p.Val321Ile (c.961G>A) is classified Uncertain significance in ACOX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.0993); Absent from gnomAD v4.1.

How common is ACOX2 p.Val321Ile (c.961G>A) in the general population?

ACOX2 p.Val321Ile (c.961G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACOX2 p.Val321Ile (c.961G>A)?

AlphaMissense predicts likely benign (score 0.0993) — an in-silico prediction, not a clinical call.

ACOX2 p.Val321Ile

c.961G>A · VCV4741056

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0993	likely benign
REVEL	0.135	moderately benign-leaning
SaProt	LLR -7.20	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 3.3	GERP 2.2, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 30 kb · p 0.14 · regional, not allelic
Overall
CADD	17.63	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACOX2
Protein: p.Val321Ile
Coding: c.961G>A
MANE Select: NM_003500
Type: single nucleotide variant
Location: chr3:58530497 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.49
Residue 321: a UniProt-annotated variant site (in cbas6; patient liver samples show absence of the protein; complete loss of fatty acid beta-oxidation activity)

Full ACOX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACOX2 p.Ala106Val Uncertain significance ★★ ⚠ same type
ACOX2 p.Ala48Glu Uncertain significance ★★ ⚠ same type
ACOX2 p.Arg197Gln Uncertain significance ★★ ⚠ same type
ACOX2 p.Arg197Trp Uncertain significance ★★ ⚠ same type
ACOX2 p.Arg215Trp Uncertain significance ★★ ⚠ same type
ACOX2 p.Arg318His Uncertain significance ★★ ⚠ same type
ACOX2 p.Arg323Cys Uncertain significance ★★ ⚠ same type
ACOX2 p.Arg323His Uncertain significance ★★ ⚠ 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/acox2-p-val321ile (accessed [today's date]).

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