Is COX18 p.Ala187Pro (c.559G>C) pathogenic?

COX18 p.Ala187Pro (c.559G>C) is classified Uncertain significance in COX18 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-04). AlphaMissense: likely pathogenic (0.8838); Absent from gnomAD v4.1.

How common is COX18 p.Ala187Pro (c.559G>C) in the general population?

COX18 p.Ala187Pro (c.559G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about COX18 p.Ala187Pro (c.559G>C)?

AlphaMissense predicts likely pathogenic (score 0.8838) — an in-silico prediction, not a clinical call.

COX18 p.Ala187Pro

c.559G>C · VCV4655958

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8838 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8838	likely pathogenic · top 3% in COX18
REVEL	0.609	indeterminate
SaProt	LLR -16.60	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 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.064 · regional, not allelic
Overall
CADD	28.5	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: COX18
Protein: p.Ala187Pro
Coding: c.559G>C
MANE Select: NM_001297732
Type: single nucleotide variant
Location: chr4:73065289 (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.Ala187Val Uncertain significance ★ same residue
COX18 p.Arg252Cys Uncertain significance ★★ ⚠ same type
COX18 p.Ala110Val Uncertain significance ★ ⚠ same type
COX18 p.Ala131Ser 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
COX18 p.Ala48Val 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-ala187pro (accessed [today's date]).

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