Is ACOX1 p.Arg490His (c.1469G>A) pathogenic?

ACOX1 p.Arg490His (c.1469G>A) is classified Uncertain significance in ACOX1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-08-17). AlphaMissense: likely pathogenic (0.638); Ultra-rare (popmax 0.0285%, sas); Associated with Mitchell syndrome.

What condition is associated with ACOX1 p.Arg490His (c.1469G>A)?

ACOX1 p.Arg490His (c.1469G>A) is associated with Mitchell syndrome, peroxisomal acyl-CoA oxidase deficiency (ClinVar).

How common is ACOX1 p.Arg490His (c.1469G>A) in the general population?

ACOX1 p.Arg490His (c.1469G>A) is ultra-rare (popmax 0.0285%, sas) (gnomAD).

How is Mitchell Syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ACOX1 p.Arg490His (c.1469G>A)?

AlphaMissense predicts likely pathogenic (score 0.638) — an in-silico prediction, not a clinical call.

ACOX1 p.Arg490His

c.1469G>A · rs762956777 · VCV991135

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.638 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0285%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Mitchell syndrome

Computational evidence

Protein change
AlphaMissense	0.638	likely pathogenic
REVEL	0.515	indeterminate
SaProt	LLR -9.16	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 3,123 bp · p 0.16 · regional, not allelic
Overall
CADD	32.0	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 0.0285% South Asian · 26/91,088 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0171%

Overall 0.00551% 89/1,614,024 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0285%	3,503
European (non-Finnish)	0.00517%	19,345
Admixed American	0.00167%	59,974
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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: ACOX1
Protein: p.Arg490His
Coding: c.1469G>A
MANE Select: NM_004035
dbSNP: rs762956777
Type: single nucleotide variant
Location: chr17:75949727 (GRCh38)
Gene constraint: LOEUF 0.67 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.95

Full ACOX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Mitchell syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: peroxisomal acyl-CoA oxidase deficiency

For Mitchell Syndrome (Orphanet):

Inheritance: Autosomal dominant

Similar variants

ACOX1 p.Arg490Cys Uncertain significance ★★ ⚠ same residue
ACOX1 p.Arg490Gly Uncertain significance ★★ ⚠ same residue
ACOX1 c.538+1G>A Pathogenic/Likely pathogenic ★★ same condition
ACOX1 c.945-1G>C Likely pathogenic ★★ same condition
ACOX1 p.Arg148Ter Pathogenic ★★ same condition
ACOX1 p.Arg302Ter Pathogenic ★★ same condition
ACOX1 p.Arg94Ter Pathogenic ★★ same condition
ACOX1 p.Asn237Ser Pathogenic/Likely pathogenic ★★ 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/acox1-p-arg490his (accessed [today's date]).

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