Is COX18 p.Ala67Val (c.200C>T) pathogenic?

COX18 p.Ala67Val (c.200C>T) is classified Uncertain significance in COX18 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: likely benign (0.1284); Very rare (popmax 0.00537%, afr).

How common is COX18 p.Ala67Val (c.200C>T) in the general population?

COX18 p.Ala67Val (c.200C>T) is very rare (popmax 0.00537%, afr) (gnomAD).

What do computational predictors say about COX18 p.Ala67Val (c.200C>T)?

AlphaMissense predicts likely benign (score 0.1284) — an in-silico prediction, not a clinical call.

COX18 p.Ala67Val

c.200C>T · VCV4655956

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1284 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00537%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1284	likely benign
REVEL	0.183	benign-leaning
SaProt	LLR -7.40	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.36 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.4	GERP 0.94, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.064 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00537% African / African-American · 4/74,438 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000441% 7/1,586,170 alleles · very rare exomes 4/1,433,938 · genomes 3/152,232 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00537%	18,609
Admixed American	0.0018%	55,700
Remaining individualsnot grpmax-eligible	0.00163%	61,380
European (non-Finnish)	8.56e-05%	1,167,774

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.Ala67Val
Coding: c.200C>T
MANE Select: NM_001297732
Type: single nucleotide variant
Location: chr4:73069450 (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-ala67val (accessed [today's date]).

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