Is ACOX3 p.Pro482Leu (c.1445C>T) pathogenic?

ACOX3 p.Pro482Leu (c.1445C>T) is classified Uncertain significance in ACOX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: likely benign (0.2639); Ultra-rare (popmax 0.04%, amr).

How common is ACOX3 p.Pro482Leu (c.1445C>T) in the general population?

ACOX3 p.Pro482Leu (c.1445C>T) is ultra-rare (popmax 0.04%, amr) (gnomAD).

What do computational predictors say about ACOX3 p.Pro482Leu (c.1445C>T)?

AlphaMissense predicts likely benign (score 0.2639) — an in-silico prediction, not a clinical call.

ACOX3 p.Pro482Leu

c.1445C>T · VCV4636859

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2639 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2639	likely benign
REVEL	0.585	indeterminate
SaProt	LLR -10.74	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 0.27, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 50 kb · p 0.53 · regional, not allelic
Overall
CADD	25.2	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 0.04% Admixed American · 24/59,948 alleles

Filtering AF 0.0276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0234%

Overall 0.00397% 64/1,613,322 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.04%	2,498
South Asian	0.0165%	6,057
African / African-American	0.012%	8,338
Remaining individualsnot grpmax-eligible	0.0048%	20,829
East Asian	0.00223%	44,860
European (non-Finnish)	0.00102%	98,312

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: ACOX3
Protein: p.Pro482Leu
Coding: c.1445C>T
MANE Select: NM_003501
Type: single nucleotide variant
Location: chr4:8389265 (GRCh38)
Gene constraint: LOEUF 1.114 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.43

Full ACOX3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACOX3 p.Ala28= Benign ★★ same type
ACOX3 p.Arg75= Likely benign ★★ same type
ACOX3 p.Ala157Ser Uncertain significance ★ ⚠ same type
ACOX3 p.Ala207Thr Uncertain significance ★ ⚠ same type
ACOX3 p.Ala261Ser Uncertain significance ★ ⚠ same type
ACOX3 p.Ala261Thr Uncertain significance ★ ⚠ same type
ACOX3 p.Ala2Thr Uncertain significance ★ ⚠ same type
ACOX3 p.Ala2Val 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/acox3-p-pro482leu (accessed [today's date]).

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