Is ACOX3 p.Ala559Val (c.1676C>T) pathogenic?

ACOX3 p.Ala559Val (c.1676C>T) is classified Uncertain significance in ACOX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-21). AlphaMissense: ambiguous (0.5055); Very rare (popmax 0.00272%, afr).

How common is ACOX3 p.Ala559Val (c.1676C>T) in the general population?

ACOX3 p.Ala559Val (c.1676C>T) is very rare (popmax 0.00272%, afr) (gnomAD).

What do computational predictors say about ACOX3 p.Ala559Val (c.1676C>T)?

AlphaMissense predicts ambiguous (score 0.5055) — an in-silico prediction, not a clinical call.

ACOX3 p.Ala559Val

c.1676C>T · rs1716771453 · VCV3138400

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5055 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00272%, afr)

Computational evidence

Protein change
AlphaMissense	0.5055	ambiguous
REVEL	0.441	indeterminate
SaProt	LLR -11.95	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 0.63, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 50 kb · p 0.53 · regional, not allelic
Overall
CADD	25.0	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 0.00272% African / African-American · 2/73,560 alleles

Filtering AF 0.000451% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000169%

Overall 0.000323% 5/1,549,532 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00272%	36,780
Admixed American	0.00196%	50,936
European (non-Finnish)	0.000175%	572,744

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.Ala559Val
Coding: c.1676C>T
MANE Select: NM_003501
dbSNP: rs1716771453
Type: single nucleotide variant
Location: chr4:8375130 (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.Ala559Pro Uncertain significance ★ ⚠ same residue
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

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-ala559val (accessed [today's date]).

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