COX4I2

cytochrome c oxidase subunit 4I2

2 disorders 1 no genetic record 1 causative 20q11.21 gene with protein product

HGNC:16232 Monarch NCBI Gene 84701 ENSG00000131055 UniProt Q96KJ9 OMIM 607976

Previous symbols: COX4L2. Aliases: COXIV-2, COX4B, dJ857M17.2, COX4-2.

Curated summary · agent-written · kb/genes/curated/hgnc_16232.md

All 12 claims checked against the KB draft

COX4I2 across dismech

COX4I2 (cytochrome c oxidase subunit 4I2) is named by 2 disorder entries.

Normal function

COX4I2 is a tissue-biased, nuclear-encoded subunit of Complex IV. It does not catalyse the oxidase reaction itself; ai-gene-review records that it contributes to cytochrome-c oxidase activity and acts in mitochondrial electron transport, cytochrome c to oxygen.

Causative records

COX4I2-Related Pancreatic Insufficiency-Anemia-Hyperostosis Syndrome types COX4I2 as causative with germline variants, placing the gene on 3 nodes, including Proposed Tissue-Specific Complex IV Dysfunction. COX4I1-Related COX Deficiency also names COX4I2, on the node COX4I2 Upregulation, but has no genetic record for it, as expected for a compensating paralog.

Where the layers agree

The KB and ai-gene-review share mitochondrial electron transport, cytochrome c to oxygen. ClinGen's only COX4I2 classification is for mitochondrial disease, which has no matching dismech entry.

Underlined values are claims re-computed from the knowledge base each time this page is built. The tables below are the source of truth.

Normal function · from ai-gene-review (Q96KJ9, commit 79fe13b38970) · AI-generated, not KB evidence

Cytochrome c oxidase subunit 4 isoform 2 (COX4-2) is a nuclear-encoded, tissue-biased alternative COX4 subunit of mitochondrial Complex IV. COX4I2 is homologous to the ubiquitous COX4I1 subunit and is incorporated into cytochrome c oxidase as a supernumerary, non-catalytic subunit rather than as one of the mtDNA-encoded redox-core subunits. Its annotations should therefore distinguish Complex IV membership and participation in mitochondrial electron transport from independent cytochrome-c oxidase catalytic activity. COX4I2 is an inner mitochondrial membrane protein with intermembrane-space topology and is highly expressed in lung; pathogenic variants cause exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis (EPIDACH).

COX4I2 is the tissue-biased COX4 isoform used as a non-catalytic, supernumerary subunit of mitochondrial respiratory chain Complex IV. It contributes to cytochrome-c oxidase activity only in the context of the assembled complex and directly participates in electron transport from cytochrome c to oxygen as part of that complex. Distinct from the ubiquitous COX4I1 isoform, COX4I2 acts as a regulatory/kinetic tuning subunit that lowers Complex IV oxygen affinity (a COX4I2-containing complex has ~2-fold higher p50 than a COX4I1-containing complex) and is required for acute oxygen sensing in specialized tissues — COX4I2-null mice show selectively impaired hypoxic ventilatory response, and conditional Cox4i2 knockout strongly inhibits hypoxic L-type Ca2+ channel modulation in arterial smooth muscle. COX4I2 expression is enriched in lung, carotid body, and pulmonary/arterial smooth muscle — canonical O2-sensing cell types — making oxygen-affinity tuning and acute O2 sensing its defining functional distinction from COX4I1.

contributes to molecular function: cytochrome-c oxidase activity · directly involved in: mitochondrial electron transport, cytochrome c to oxygen · locations: mitochondrial inner membrane; mitochondrial intermembrane space · in complex: respiratory chain complex IV

In the knowledge base · computed from kb/ at build time

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

Disorder	Relationship	Where the gene appears
COX4I2-Related Pancreatic Insufficiency-Anemia-Hyperostosis Syndrome	causative germline	mechanism: Attenuated Hypoxia-Mimetic Transcript Induction; Proposed Tissue-Specific Complex IV Dysfunction; Reduced COX4I2 Transcript Abundance dataset: geo:GDS1096
COX4I1-Related COX Deficiency	no genetic record	mechanism: COX4I2 Upregulation

ClinGen gene–disease validity · snapshot 2026-10-03 · matched to entries by MONDO

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.

ClinGen disease	MOI	Classification	dismech entry
mitochondrial disease MONDO:0044970	AR	Limited 2024-03-18	no dismech entry

Identity from HGNC (snapshot 2026-10-01). Page layers are described in the gene pages documentation.