Is ACOX1 p.Ser438fs (c.1312del) pathogenic?

ACOX1 p.Ser438fs (c.1312del) is classified Pathogenic/Likely pathogenic in ACOX1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-23). Ultra-rare (popmax 0.0117%, amr); Associated with Mitchell syndrome.

What condition is associated with ACOX1 p.Ser438fs (c.1312del)?

ACOX1 p.Ser438fs (c.1312del) is associated with Mitchell syndrome, peroxisomal acyl-CoA oxidase deficiency (ClinVar).

How common is ACOX1 p.Ser438fs (c.1312del) in the general population?

ACOX1 p.Ser438fs (c.1312del) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

How is Mitchell Syndrome inherited?

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

ACOX1 p.Ser438fs

c.1312del · rs747192384 · VCV1075695

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Conditions

Mitchell syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.4	GERP -0.67, phastCons 0.98
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/60,000 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000434% 7/1,614,080 alleles · ultra-rare

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.Ser438fs
Coding: c.1312del
MANE Select: NM_004035
dbSNP: rs747192384
Type: Deletion
Location: chr17:75949884 (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 c.1729-2del Likely pathogenic ★★ same condition
ACOX1 p.Asp573fs Pathogenic/Likely pathogenic ★★ same condition
ACOX1 p.Gln47fs Pathogenic/Likely pathogenic ★★ same condition
ACOX1 p.Val426fs Pathogenic ★★ same condition
ACOX1 c.538+13_538+14del Likely benign ★★ same condition
ACOX1 c.679_774+103del Likely pathogenic ★ same condition
ACOX1 p.Ala12fs Pathogenic ★ same condition
ACOX1 p.Ala469fs 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-ser438fs (accessed [today's date]).

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