| Annotation area | Key claim | Supporting evidence (brief) | Citation IDs |
|---|---|---|---|
| Identity / isoforms | COX6B1 (UniProt P14854) is the human, nuclear-encoded somatic/ubiquitous cytochrome c oxidase subunit VIb1; it is distinct from the testis-enriched paralog COX6B2. | Reviews identify COX6B1 as COX VIb1/Cox12p, broadly expressed across tissues, while COX6B2 is testes-specific; COX6B1 is the relevant human somatic isoform for complex IV. | (pqac-00000011, pqac-00000012, pqac-00000014) |
| Subcellular localization / topology | COX6B1 is an intermembrane-space-facing subunit of mitochondrial complex IV, positioned on the outer/IMS side of the holoenzyme. | Structural and review sources place VIb1 on the IMS side of cytochrome c oxidase, where it is exposed at the dimer interface; figure evidence also shows COX6B1 on the IMS side. | (pqac-00000011, pqac-00000012, pqac-00000009) |
| Primary molecular function within complex IV | COX6B1 is an accessory structural/regulatory subunit of complex IV rather than a catalytic center; it supports cytochrome c oxidase function and is positioned near the cytochrome c interaction region. | COX catalyzes electron transfer from cytochrome c to O2 in the core subunits, while COX6B1 is a small nuclear-encoded subunit modeled near the cytochrome c binding site and required for proper complex IV activity. | (pqac-00000011, pqac-00000017) |
| Role in dimerization / cooperativity | COX6B1 helps bridge the two complex IV monomers, stabilizing the dimer and modulating inter-monomer cooperativity; removal/absence can monomerize COX and increase activity about twofold. | Reviews report that VIb connects monomers on the IMS side; mild solubilization causing COX6B1 loss leads to monomerization and ~2-fold higher activity without changing proton stoichiometry, consistent with altered cytochrome c binding cooperativity. | (pqac-00000012, pqac-00000014) |
| Role in assembly (early vs late) | Earlier models placed COX6B1 as a late-added subunit, but recent mechanistic work indicates it is also essential for an early redox-sensitive assembly step involving MT-CO2 maturation/metalation. | Patient-cell and review data linked mutant COX6B1 to reduced incorporation and accumulation of late intermediate S3; newer KO/complementation data show total loss of complex IV, block at MT-CO2 maturation, altered COA6/SCO factors, and support an indispensable early assembly role. | (pqac-00000016, pqac-00000013, pqac-00000008, pqac-00000010) |
| Disease-causing variants / phenotypes | Pathogenic homozygous missense variants in conserved Arg20/Arg19 region (reported as R20H/R20C or R19H/R19C depending on numbering) cause isolated complex IV deficiency with severe infantile mitochondrial disease. | Reported phenotypes include infantile encephalomyopathy; hydrocephalus and hypertrophic cardiomyopathy with the more severe Arg20Cys variant; mutant cells show reduced COX6B1 steady-state levels, poor incorporation into holoenzyme, and reduced complex IV activity, rescued by WT COX6B1 expression. | (pqac-00000014, pqac-00000016, pqac-00000018) |
| Recent applications (biomarker / prognostic) | Recent studies use COX6B1 in translational contexts mainly as a biomarker/prognostic-gene component rather than a validated standalone clinical marker. | In 2024 uveal melanoma, COX6B1 was one of 9 OXPHOS-related genes in a prognostic model built from 80 TCGA-UVM cases, with 1–5 year AUC values all >0.88 and external validation in GSE22138/GSE39717; a 2023 dietary-restriction review also discusses Cox6b1 conceptually in complex IV/supercomplex regulation, but without COX6B1-specific quantitative biomarker metrics. | (pqac-00000022, pqac-00000023, pqac-00000019) |


*Table: This table summarizes the main functional annotation points for human COX6B1, including identity, localization, molecular role, assembly biology, disease relevance, and recent translational uses. It is useful as a compact evidence map tied directly to the available context sources.*