Is ACOX1 p.Lys89Thr (c.266A>C) pathogenic?

ACOX1 p.Lys89Thr (c.266A>C) is classified Uncertain significance in ACOX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-10). AlphaMissense: likely pathogenic (0.7617); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with ACOX1 p.Lys89Thr (c.266A>C)?

ACOX1 p.Lys89Thr (c.266A>C) is associated with Inborn genetic diseases (ClinVar).

How common is ACOX1 p.Lys89Thr (c.266A>C) in the general population?

ACOX1 p.Lys89Thr (c.266A>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about ACOX1 p.Lys89Thr (c.266A>C)?

AlphaMissense predicts likely pathogenic (score 0.7617) — an in-silico prediction, not a clinical call.

ACOX1 p.Lys89Thr

c.266A>C · VCV3824629

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7617 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7617	likely pathogenic
REVEL	0.299	indeterminate
SaProt	LLR -4.07	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 29 kb · p 1.3e-14 · regional, not allelic
Overall
CADD	23.2	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 0.00333% Admixed American · 2/60,000 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000186% 3/1,614,122 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,000
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Lys89Thr
Coding: c.266A>C
MANE Select: NM_004035
Type: single nucleotide variant
Location: chr17:75978537 (GRCh38)
Gene constraint: LOEUF 0.67 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.95
Residue 89: a modified residue (n6-succinyllysine)

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

Similar variants

ACOX1 p.Ala296Val Uncertain significance ★★ ⚠ same condition
ACOX1 p.Ala346Val Uncertain significance ★★ ⚠ same condition
ACOX1 p.Ala375Thr Uncertain significance ★★ ⚠ same condition
ACOX1 p.Ala499Ser Uncertain significance ★★ ⚠ same condition
ACOX1 p.Ala553Thr Uncertain significance ★★ ⚠ same condition
ACOX1 p.Ala571Val Uncertain significance ★★ ⚠ same condition
ACOX1 p.Arg122His Uncertain significance ★★ same condition
ACOX1 p.Arg210Cys Uncertain significance ★★ ⚠ 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-lys89thr (accessed [today's date]).

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