Is ACOX2 p.Ala395Val (c.1184C>T) pathogenic?

ACOX2 p.Ala395Val (c.1184C>T) is classified Uncertain significance in ACOX2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-08-16). AlphaMissense: ambiguous (0.4094); Very rare (popmax 0.00167%, amr); Associated with ACOX2-related disorder.

What condition is associated with ACOX2 p.Ala395Val (c.1184C>T)?

ACOX2 p.Ala395Val (c.1184C>T) is associated with ACOX2-related disorder (ClinVar).

How common is ACOX2 p.Ala395Val (c.1184C>T) in the general population?

ACOX2 p.Ala395Val (c.1184C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ACOX2 p.Ala395Val (c.1184C>T)?

AlphaMissense predicts ambiguous (score 0.4094) — an in-silico prediction, not a clinical call.

ACOX2 p.Ala395Val

c.1184C>T · VCV3345921

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4094 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

ACOX2-related disorder

Computational evidence

Protein change
AlphaMissense	0.4094	ambiguous
REVEL	0.552	indeterminate
SaProt	LLR -7.42	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 30 kb · p 0.14 · regional, not allelic
Overall
CADD	27.0	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 · 1/60,004 alleles

Overall 0.000186% 3/1,614,040 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,004
South Asian	0.0011%	91,082
European (non-Finnish)	8.47e-05%	1,180,026

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: ACOX2
Protein: p.Ala395Val
Coding: c.1184C>T
MANE Select: NM_003500
Type: single nucleotide variant
Location: chr3:58526628 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.49
Residue 395: 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

Disease context

ACOX2-related disorder

Similar variants

ACOX2 p.Arg329Gln Uncertain significance ★★ ⚠ same condition
ACOX2 p.Gln146Ter Uncertain significance ★ same condition
ACOX2 p.Lys512Asn Uncertain significance ⚠ same condition
ACOX2 p.Thr465Met Uncertain significance ⚠ same condition
ACOX2 p.Val8Glu Uncertain significance ⚠ same condition
ACOX2 c.1156-3C>T Likely benign same condition
ACOX2 c.324-3C>T Likely benign same condition
ACOX2 c.*10C>T 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/acox2-p-ala395val (accessed [today's date]).

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