Is ACOX2 p.Arg76His (c.227G>A) pathogenic?

ACOX2 p.Arg76His (c.227G>A) is classified Uncertain significance in ACOX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-04). AlphaMissense: likely benign (0.1432); Very rare (popmax 0.00534%, afr).

How common is ACOX2 p.Arg76His (c.227G>A) in the general population?

ACOX2 p.Arg76His (c.227G>A) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about ACOX2 p.Arg76His (c.227G>A)?

AlphaMissense predicts likely benign (score 0.1432) — an in-silico prediction, not a clinical call.

ACOX2 p.Arg76His

c.227G>A · rs375089953 · VCV2892997

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1432 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1432	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -10.36	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.5	GERP -4.4
Regional constraint	o/e 0.95	unconstrained · MANE · 30 kb · p 0.14 · regional, not allelic
Overall
CADD	6.355	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 0.00534% African / African-American · 4/74,926 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00124% 20/1,614,054 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,732
South Asian	0.00329%	30,361
East Asian	0.00223%	44,888
Admixed American	0.00167%	59,996
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.000847%	118,004

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: ACOX2
Protein: p.Arg76His
Coding: c.227G>A
MANE Select: NM_003500
dbSNP: rs375089953
Type: single nucleotide variant
Location: chr3:58534456 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.49
Residue 76: a UniProt-annotated variant site (in cbas6; patient liver samples show absence of the protein; complete loss of fatty acid beta-oxidation activity)

Full ACOX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACOX2 p.Arg76Cys Uncertain significance ★★ ⚠ same residue
ACOX2 p.Arg76Ser Uncertain significance ★ ⚠ same residue
ACOX2 p.Ala106Val Uncertain significance ★★ ⚠ same type
ACOX2 p.Ala48Glu Uncertain significance ★★ ⚠ same type
ACOX2 p.Arg197Gln Uncertain significance ★★ ⚠ same type
ACOX2 p.Arg197Trp Uncertain significance ★★ ⚠ same type
ACOX2 p.Arg215Trp Uncertain significance ★★ ⚠ same type
ACOX2 p.Arg318His 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/acox2-p-arg76his (accessed [today's date]).

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