Is COX18 p.Pro276Ser (c.826C>T) pathogenic?

COX18 p.Pro276Ser (c.826C>T) is classified Uncertain significance in COX18 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: ambiguous (0.4961); Ultra-rare (popmax 0.0148%, afr).

How common is COX18 p.Pro276Ser (c.826C>T) in the general population?

COX18 p.Pro276Ser (c.826C>T) is ultra-rare (popmax 0.0148%, afr) (gnomAD).

What do computational predictors say about COX18 p.Pro276Ser (c.826C>T)?

AlphaMissense predicts ambiguous (score 0.4961) — an in-silico prediction, not a clinical call.

COX18 p.Pro276Ser

c.826C>T · VCV4655953

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4961 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0148%, afr)

Computational evidence

Protein change
AlphaMissense	0.4961	ambiguous
REVEL	0.556	indeterminate
SaProt	LLR -8.20	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.064 · regional, not allelic
Overall
CADD	24.7	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 P275S vs ClinVar P276S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0148% African / African-American · 11/74,518 alleles

Filtering AF 0.0082% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00636%

Overall 0.000689% 11/1,596,842 alleles · ultra-rare

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.Pro276Ser
Coding: c.826C>T
MANE Select: NM_001297732
Type: single nucleotide variant
Location: chr4:73061818 (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-pro276ser (accessed [today's date]).

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