Is ACOX1 p.Ile235Val (c.703A>G) pathogenic?

ACOX1 p.Ile235Val (c.703A>G) is classified Uncertain significance in ACOX1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-02-12). AlphaMissense: likely benign (0.0867); Ultra-rare (popmax 0.0683%, amr); Associated with Inborn genetic diseases.

What condition is associated with ACOX1 p.Ile235Val (c.703A>G)?

ACOX1 p.Ile235Val (c.703A>G) is associated with Inborn genetic diseases, peroxisomal acyl-CoA oxidase deficiency (ClinVar).

How common is ACOX1 p.Ile235Val (c.703A>G) in the general population?

ACOX1 p.Ile235Val (c.703A>G) is ultra-rare (popmax 0.0683%, amr) (gnomAD).

What do computational predictors say about ACOX1 p.Ile235Val (c.703A>G)?

AlphaMissense predicts likely benign (score 0.0867) — an in-silico prediction, not a clinical call.

ACOX1 p.Ile235Val

c.703A>G · rs199538132 · VCV1037995

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0867 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0683%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0867	likely benign
REVEL	0.27	benign-leaning
SaProt	LLR -5.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.84, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 29 kb · p 1.3e-14 · regional, not allelic
Overall
CADD	16.61	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0683% Admixed American · 41/60,012 alleles

Filtering AF 0.0517% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0459%

Overall 0.00353% 57/1,614,184 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0683%	1,464
Remaining individualsnot grpmax-eligible	0.0128%	7,813
African / African-American	0.00133%	75,050
European (non-Finnish)	0.000593%	168,574

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.Ile235Val
Coding: c.703A>G
MANE Select: NM_004035
dbSNP: rs199538132
Type: single nucleotide variant
Location: chr17:75955637 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: peroxisomal acyl-CoA oxidase deficiency

Similar variants

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
ACOX1 p.Gln114Ter Pathogenic/Likely pathogenic ★★ same condition
ACOX1 p.Glu84Ter 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-ile235val (accessed [today's date]).

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