Is COX18 p.Arg298Pro (c.893G>C) pathogenic?

COX18 p.Arg298Pro (c.893G>C) is classified Pathogenic in COX18 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2026-02-02). AlphaMissense: likely pathogenic (0.6968); Very rare (popmax 0.00212%, nfe); Associated with charcot-marie-tooth disease, axonal, type 2MM.

What condition is associated with COX18 p.Arg298Pro (c.893G>C)?

COX18 p.Arg298Pro (c.893G>C) is associated with charcot-marie-tooth disease, axonal, type 2MM (ClinVar).

How common is COX18 p.Arg298Pro (c.893G>C) in the general population?

COX18 p.Arg298Pro (c.893G>C) is very rare (popmax 0.00212%, nfe) (gnomAD).

What do computational predictors say about COX18 p.Arg298Pro (c.893G>C)?

AlphaMissense predicts likely pathogenic (score 0.6968) — an in-silico prediction, not a clinical call.

COX18 p.Arg298Pro

c.893G>C · VCV4688186

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6968 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

charcot-marie-tooth disease, axonal, type 2MM

Computational evidence

Protein change
AlphaMissense	0.6968	likely pathogenic ✓ concordant with ClinVar
REVEL	0.294	indeterminate
SaProt	LLR -12.73	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.4, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.064 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R297P vs ClinVar R298P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00212% European (non-Finnish) · 25/1,179,882 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00161% 26/1,613,834 alleles · very rare exomes 26/1,461,676 · genomes 0/152,158 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00212%	47,195
South Asian	0.0011%	91,058

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: COX18
Protein: p.Arg298Pro
Coding: c.893G>C
MANE Select: NM_001297732
Type: single nucleotide variant
Location: chr4:73058226 (GRCh38)
Gene constraint: LOEUF 1.682 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.42
Residue 297 UniProt numbering: a UniProt-annotated variant site (in cmt2mm; uncertain significance)

Full COX18 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

charcot-marie-tooth disease, axonal, type 2MM — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COX18 p.Leu72Arg Uncertain significance ★ ⚠ same condition
COX18 c.435-6A>G Pathogenic same condition
COX18 p.Ala110Pro Pathogenic same condition
COX18 p.Arg252Cys Uncertain significance ★★ ⚠ same type
COX18 p.Ala110Val Uncertain significance ★ ⚠ same type
COX18 p.Ala131Ser Uncertain significance ★ ⚠ same type
COX18 p.Ala187Pro Uncertain significance ★ ⚠ same type
COX18 p.Ala187Val 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/cox18-p-arg298pro (accessed [today's date]).

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