Is COX18 p.Arg4Gln (c.11G>A) pathogenic?

COX18 p.Arg4Gln (c.11G>A) is classified Uncertain significance in COX18 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-07). AlphaMissense: likely benign (0.1642); Ultra-rare (popmax 0.0704%, sas).

How common is COX18 p.Arg4Gln (c.11G>A) in the general population?

COX18 p.Arg4Gln (c.11G>A) is ultra-rare (popmax 0.0704%, sas) (gnomAD).

What do computational predictors say about COX18 p.Arg4Gln (c.11G>A)?

AlphaMissense predicts likely benign (score 0.1642) — an in-silico prediction, not a clinical call.

COX18 p.Arg4Gln

c.11G>A · rs775857810 · VCV2554429

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1642 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0704%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1642	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -9.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 1.8, phastCons 0.008
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.064 · regional, not allelic
Overall
CADD	22.3	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 0.0704% South Asian · 60/85,188 alleles

Filtering AF 0.0561% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0509%

Overall 0.0042% 65/1,549,412 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0704%	1,420
Remaining individualsnot grpmax-eligible	0.00828%	12,074

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.Arg4Gln
Coding: c.11G>A
MANE Select: NM_001297732
dbSNP: rs775857810
Type: single nucleotide variant
Location: chr4:73069639 (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-arg4gln (accessed [today's date]).

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