Is ACOX2 p.Arg261Trp (c.781C>T) pathogenic?

ACOX2 p.Arg261Trp (c.781C>T) is classified Uncertain significance in ACOX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). AlphaMissense: likely benign (0.2781); Ultra-rare (popmax 0.0363%, mid).

How common is ACOX2 p.Arg261Trp (c.781C>T) in the general population?

ACOX2 p.Arg261Trp (c.781C>T) is ultra-rare (popmax 0.0363%, mid) (gnomAD).

What do computational predictors say about ACOX2 p.Arg261Trp (c.781C>T)?

AlphaMissense predicts likely benign (score 0.2781) — an in-silico prediction, not a clinical call.

ACOX2 p.Arg261Trp

c.781C>T · rs200178010 · VCV1361070

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2781 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0363%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2781	likely benign
REVEL	0.628	indeterminate
SaProt	LLR -14.07	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.65	donor gain · deltas
Constraint at this position
Conservation	phyloP 3.2	GERP -1.1, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 30 kb · p 0.14 · regional, not allelic
Overall
CADD	34.0	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 0.0363% Middle Eastern · 2/5,510 alleles

Filtering AF 0.0138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0131%

Overall 0.0151% 244/1,613,318 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0844%	1,184
Middle Easterngrpmax	0.0363%	2,755
Remaining individualsnot grpmax-eligible	0.0224%	4,458
European (non-Finnish)	0.0157%	6,378
Admixed American	0.015%	6,667
African / African-American	0.00534%	18,722
South Asian	0.00439%	22,764
East Asian	0.00223%	44,870

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg261Trp
Coding: c.781C>T
MANE Select: NM_003500
dbSNP: rs200178010
Type: single nucleotide variant
Location: chr3:58531289 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.49
Residue 261: 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.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
ACOX2 p.Arg323Cys Uncertain significance ★★ ⚠ same type
ACOX2 p.Arg323His 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-arg261trp (accessed [today's date]).

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