Is COX18 p.Arg262Leu (c.785G>T) pathogenic?

COX18 p.Arg262Leu (c.785G>T) is classified Uncertain significance in COX18 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-15). AlphaMissense: likely pathogenic (0.7413); Ultra-rare (popmax 0.01%, amr).

How common is COX18 p.Arg262Leu (c.785G>T) in the general population?

COX18 p.Arg262Leu (c.785G>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about COX18 p.Arg262Leu (c.785G>T)?

AlphaMissense predicts likely pathogenic (score 0.7413) — an in-silico prediction, not a clinical call.

COX18 p.Arg262Leu

c.785G>T · VCV3269043

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7413 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7413	likely pathogenic · top 10% in COX18
REVEL	0.83	moderately pathogenic-leaning
SaProt	LLR -14.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.064 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

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

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R261L vs ClinVar R262L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/59,898 alleles

Filtering AF 0.00429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00296%

Overall 0.000434% 7/1,613,428 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,983
Remaining individualsnot grpmax-eligible	0.0016%	62,462

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.Arg262Leu
Coding: c.785G>T
MANE Select: NM_001297732
Type: single nucleotide variant
Location: chr4:73061859 (GRCh38)
Gene constraint: LOEUF 1.682 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.42

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

Similar variants

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
COX18 p.Ala195Ser Uncertain significance ★ ⚠ same type
COX18 p.Ala26Val Uncertain significance ★ ⚠ same type
COX18 p.Ala325Thr 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-arg262leu (accessed [today's date]).

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