Is COX15 p.Arg67Pro (c.200G>C) pathogenic?

COX15 p.Arg67Pro (c.200G>C) is classified Uncertain significance in COX15 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-09). AlphaMissense: likely benign (0.209); Very rare (popmax 8.47e-05%, nfe).

How common is COX15 p.Arg67Pro (c.200G>C) in the general population?

COX15 p.Arg67Pro (c.200G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about COX15 p.Arg67Pro (c.200G>C)?

AlphaMissense predicts likely benign (score 0.209) — an in-silico prediction, not a clinical call.

COX15 p.Arg67Pro

c.200G>C · rs377441431 · VCV2100557

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.209 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.209	likely benign
REVEL	0.316	indeterminate
SaProt	LLR -11.81	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.45	GERP 0.27, phastCons 0.035
Regional constraint	o/e 0.84	unconstrained · MANE · 17 kb · p 0.00029 · regional, not allelic
Overall
CADD	17.59	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,012 alleles

Overall 6.2e-05% 1/1,614,074 alleles · very rare exomes 1/1,461,828 · genomes 0/152,246 · joint denominator

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: COX15
Protein: p.Arg67Pro
Coding: c.200G>C
MANE Select: NM_078470
dbSNP: rs377441431
Type: single nucleotide variant
Location: chr10:99729625 (GRCh38)
Gene constraint: LOEUF 1.198 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.29

Full COX15 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COX15 p.Arg67Gln Uncertain significance ★★ ⚠ same residue
COX15 p.Arg67Trp Uncertain significance ★★ ⚠ same residue
COX15 c.272+2T>G Pathogenic/Likely pathogenic ★★ same type
COX15 c.750+1G>A Likely pathogenic ★★ same type
COX15 c.750+1G>T Likely pathogenic ★★ same type
COX15 p.Arg153Ter Pathogenic/Likely pathogenic ★★ same type
COX15 p.Arg217Trp Pathogenic ★★ same type
COX15 p.Ser151Ter Pathogenic/Likely pathogenic ★★ 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/cox15-p-arg67pro (accessed [today's date]).

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