mitochondrial complex IV deficiency, nuclear type 1

Summary

mitochondrial complex IV deficiency, nuclear type 1 (MONDO:0700250) is a disease caused by variants in SURF1 and COXFA4, with 23 cohort genes. The dominant Reactome pathway is Complex IV assembly (14 cohort genes).

At a glance

• Causal genes: SURF1 (GenCC Definitive), COXFA4 (GenCC Strong)
• Cohort genes: 23
• ClinVar variants: 442

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex IV deficiency, nuclear type 1
Mondo ID	MONDO:0700250
OMIM	220110
DOID	DOID:0070491
UMLS	C5435656
MedGen	1750917
GARD	0015158
Is cancer (heuristic)	no

Data availability: 442 ClinVar variants · 3 GenCC gene-disease records · 20 cell lines.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › mitochondrial respiratory chain complex deficiency › mitochondrial complex IV deficiency, nuclear-type › mitochondrial complex IV deficiency, nuclear type 1

Related subtypes (21): pancreatic insufficiency-anemia-hyperostosis syndrome, mitochondrial complex IV deficiency, nuclear type 3, mitochondrial complex IV deficiency, nuclear type 4, mitochondrial complex IV deficiency, nuclear type 7, mitochondrial complex IV deficiency, nuclear type 8, mitochondrial complex IV deficiency, nuclear type 10, mitochondrial complex IV deficiency, nuclear type 11, mitochondrial complex IV deficiency, nuclear type 12, mitochondrial complex IV deficiency, nuclear type 14, mitochondrial complex IV deficiency, nuclear type 15, mitochondrial complex IV deficiency, nuclear type 16, mitochondrial complex IV deficiency, nuclear type 17, mitochondrial complex IV deficiency, nuclear type 18, mitochondrial complex IV deficiency, nuclear type 19, mitochondrial complex IV deficiency, nuclear type 20, mitochondrial complex IV deficiency, nuclear type 21, mitochondrial complex IV deficiency, nuclear type 22, mitochondrial complex IV deficiency, nuclear type 23, COX deficiency, benign infantile mitochondrial myopathy, mitochondrial complex IV deficiency, nuclear type 24, mitochondrial complex 4 deficiency, nuclear type 25

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

442 retrieved; paginated sample, class counts are floors:

204 uncertain significance, 72 conflicting classifications of pathogenicity, 43 likely pathogenic, 42 pathogenic, 28 pathogenic/likely pathogenic, 26 benign, 16 benign/likely benign, 9 likely benign, 1 no classifications from unflagged records, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
638510	NM_001370595.2(COA8):c.41dup (p.Leu15fs)	COA8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7525	NM_001303.4(COX10):c.1007A>T (p.Asp336Val)	COX10	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
380082	NM_198076.6(COX20):c.157+3G>C	COX20	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
834062	NM_001861.6(COX4I1):c.303_304delinsTT (p.Lys101_Thr102delinsAsnSer)	COX4I1	Pathogenic	no assertion criteria provided
222973	NM_004074.3(COX8A):c.115-1G>C	COX8A	Pathogenic	no assertion criteria provided
561009	NM_001136193.2(FASTKD2):c.1690C>T (p.Gln564Ter)	FASTKD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
641	NM_001136193.2(FASTKD2):c.1294C>T (p.Arg432Ter)	FASTKD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9662	NC_012920.1(MT-CO2):m.7896G>A	MT-CO2	Pathogenic	reviewed by expert panel
9589	NC_012920.1(MT-TL1):m.3243A>G	MT-TL1	Pathogenic	reviewed by expert panel
9620	NC_012920.1(MT-TN):m.5703G>A	MT-TN	Pathogenic	reviewed by expert panel
42226	NC_012920.1(MT-TS1):m.7471dup	MT-TS1	Pathogenic	reviewed by expert panel
1034098	NM_004589.4(SCO1):c.263dup (p.Lys89fs)	SCO1	Pathogenic	criteria provided, single submitter
125441	NM_001171155.2(PET100):c.3G>C (p.Met1Ile)	STXBP2	Pathogenic	criteria provided, multiple submitters, no conflicts
128250	NM_001171155.2(PET100):c.142C>T (p.Gln48Ter)	STXBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686017	NM_001171155.2(PET100):c.1A>G (p.Met1Val)	STXBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1182215	NM_003172.4(SURF1):c.367_368del (p.Arg123fs)	SURF1	Pathogenic	criteria provided, multiple submitters, no conflicts
12758	NM_003172.4(SURF1):c.323+2T>C	SURF1	Pathogenic	no assertion criteria provided
12762	NM_003172.4(SURF1):c.751C>T (p.Gln251Ter)	SURF1	Pathogenic	criteria provided, multiple submitters, no conflicts
12764	NM_003172.4(SURF1):c.515+2T>G	SURF1	Pathogenic	no assertion criteria provided
12765	NM_003172.4(SURF1):c.550_551del (p.Arg184fs)	SURF1	Pathogenic	no assertion criteria provided
12766	NM_003172.4(SURF1):c.820T>G (p.Tyr274Asp)	SURF1	Pathogenic	criteria provided, single submitter
12768	NM_003172.4(SURF1):c.371G>A (p.Gly124Glu)	SURF1	Pathogenic	criteria provided, single submitter
12769	NM_003172.4(SURF1):c.574_575insCTCC (p.Arg192fs)	SURF1	Pathogenic	no assertion criteria provided
12770	NM_003172.4(SURF1):c.845_846del (p.Ser282fs)	SURF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1323662	NM_003172.4(SURF1):c.152dup (p.Ser52fs)	SURF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1329011	NM_003172.4(SURF1):c.575G>A (p.Arg192Gln)	SURF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1413577	NM_003172.4(SURF1):c.632_642del (p.Glu211fs)	SURF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1416074	NM_003172.4(SURF1):c.552del (p.Lys185fs)	SURF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1939932	NM_003172.4(SURF1):c.769G>A (p.Gly257Arg)	SURF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2147072	NM_003172.4(SURF1):c.606_610dup (p.Ile204fs)	SURF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 38 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SURF1	Definitive	Autosomal recessive	mitochondrial complex IV deficiency, nuclear type 1	9
COXFA4	Strong	Autosomal recessive	mitochondrial complex IV deficiency, nuclear type 1	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SURF1	Orphanet:391351	SURF1-related Charcot-Marie-Tooth disease type 4
SCO1	Orphanet:1561	Fatal infantile cytochrome C oxidase deficiency
SCO2	Orphanet:1561	Fatal infantile cytochrome C oxidase deficiency
SCO2	Orphanet:521411	Autosomal recessive axonal Charcot-Marie-Tooth disease due to copper metabolism defect
SCO2	Orphanet:98619	Rare isolated myopia
STXBP2	Orphanet:540	Familial hemophagocytic lymphohistiocytosis
MRPL44	Orphanet:352563	Infantile hypertrophic cardiomyopathy due to MRPL44 deficiency
COA8	Orphanet:436271	Non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy
COX10	Orphanet:254905	Isolated cytochrome C oxidase deficiency
COX4I1	Orphanet:254905	Isolated cytochrome C oxidase deficiency
COX6B1	Orphanet:254905	Isolated cytochrome C oxidase deficiency
COX8A	Orphanet:254905	Isolated cytochrome C oxidase deficiency
COA3	Orphanet:254905	Isolated cytochrome C oxidase deficiency
COX20	Orphanet:254905	Isolated cytochrome C oxidase deficiency
FASTKD2	Orphanet:166105	FASTKD2-related infantile mitochondrial encephalomyopathy
MT-CO1	Orphanet:104	Leber hereditary optic neuropathy
MT-CO1	Orphanet:254905	Isolated cytochrome C oxidase deficiency
MT-CO1	Orphanet:550	MELAS
MT-CO1	Orphanet:90641	Rare mitochondrial non-syndromic sensorineural deafness
MT-CO1	Orphanet:99845	Genetic recurrent myoglobinuria
MT-CO2	Orphanet:254905	Isolated cytochrome C oxidase deficiency
MT-CO2	Orphanet:550	MELAS
MT-CO3	Orphanet:104	Leber hereditary optic neuropathy
MT-CO3	Orphanet:254905	Isolated cytochrome C oxidase deficiency
MT-CO3	Orphanet:550	MELAS
MT-CO3	Orphanet:99845	Genetic recurrent myoglobinuria
MT-TL1	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-TL1	Orphanet:324525	Hypertrophic cardiomyopathy with kidney anomalies due to mitochondrial DNA mutation
MT-TL1	Orphanet:480	Kearns-Sayre syndrome
MT-TL1	Orphanet:550	MELAS
MT-TL1	Orphanet:551	MERRF
MT-TL1	Orphanet:663	Mitochondrial DNA-related progressive external ophthalmoplegia
MT-TN	Orphanet:663	Mitochondrial DNA-related progressive external ophthalmoplegia
MT-TS1	Orphanet:2202	Palmoplantar keratoderma-deafness syndrome
MT-TS1	Orphanet:550	MELAS
MT-TS1	Orphanet:551	MERRF
MT-TS1	Orphanet:663	Mitochondrial DNA-related progressive external ophthalmoplegia
MT-TS1	Orphanet:90641	Rare mitochondrial non-syndromic sensorineural deafness

Cohort genes → proteins

23 cohort genes, 20 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	23

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SURF1	HGNC:11474	ENSG00000148290	Q15526	Surfeit locus protein 1	gencc,clinvar
COXFA4	HGNC:7687	ENSG00000189043	O00483	Cytochrome c oxidase subunit FA4	gencc
SCO1	HGNC:10603	ENSG00000133028	O75880	Cytochrome c oxidase assembly factor SCO1	clinvar
SCO2	HGNC:10604	ENSG00000284194	O43819	Cytochrome c oxidase assembly factor SCO2	clinvar
STXBP2	HGNC:11445	ENSG00000076944	Q15833	Syntaxin-binding protein 2	clinvar
MRPL44	HGNC:16650	ENSG00000135900	Q9H9J2	Large ribosomal subunit protein mL44	clinvar
COA8	HGNC:20492	ENSG00000256053	Q96IL0	Cytochrome c oxidase assembly factor 8	clinvar
COX10	HGNC:2260	ENSG00000006695	Q12887	Protoheme IX farnesyltransferase, mitochondrial	clinvar
COX4I1	HGNC:2265	ENSG00000131143	P13073	Cytochrome c oxidase subunit 4 isoform 1, mitochondrial	clinvar
COX6B1	HGNC:2280	ENSG00000126267	P14854	Cytochrome c oxidase subunit 6B1	clinvar
COX8A	HGNC:2294	ENSG00000176340	P10176	Cytochrome c oxidase subunit 8A, mitochondrial	clinvar
TACO1	HGNC:24316	ENSG00000136463	Q9BSH4	Translational activator of cytochrome c oxidase 1	clinvar
COA3	HGNC:24990	ENSG00000183978	Q9Y2R0	Cytochrome c oxidase assembly factor 3 homolog, mitochondrial	clinvar
NCAPH2	HGNC:25071	ENSG00000025770	Q6IBW4	Condensin-2 complex subunit H2	clinvar
COX18	HGNC:26801	ENSG00000163626	Q8N8Q8	Cytochrome c oxidase assembly protein COX18, mitochondrial	clinvar
COX20	HGNC:26970	ENSG00000203667	Q5RI15	Cytochrome c oxidase assembly protein COX20, mitochondrial	clinvar
FASTKD2	HGNC:29160	ENSG00000118246	Q9NYY8	FAST kinase domain-containing protein 2, mitochondrial	clinvar
MT-CO1	HGNC:7419	ENSG00000198804	P00395	Cytochrome c oxidase subunit 1	clinvar
MT-CO2	HGNC:7421	ENSG00000198712	P00403	Cytochrome c oxidase subunit 2	clinvar
MT-CO3	HGNC:7422	ENSG00000198938	P00414	Cytochrome c oxidase subunit 3	clinvar
MT-TL1	HGNC:7490	ENSG00000209082		mitochondrially encoded tRNA-Leu (UUA/G) 1	clinvar
MT-TN	HGNC:7493	ENSG00000210135		mitochondrially encoded tRNA-Asn (AAU/C)	clinvar
MT-TS1	HGNC:7497	ENSG00000210151		mitochondrially encoded tRNA-Ser (UCN) 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SURF1	Surfeit locus protein 1	Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly.
COXFA4	Cytochrome c oxidase subunit FA4	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
SCO1	Cytochrome c oxidase assembly factor SCO1	Copper metallochaperone essential for the maturation of cytochrome c oxidase subunit II (MT-CO2/COX2).
SCO2	Cytochrome c oxidase assembly factor SCO2	Copper metallochaperone essential for the synthesis and maturation of cytochrome c oxidase subunit II (MT-CO2/COX2); together with SCO1, facilitates the incorporation of copper into the Cu(A) site of MT-CO2/COX2.
STXBP2	Syntaxin-binding protein 2	Involved in intracellular vesicle trafficking and vesicle fusion with membranes.
MRPL44	Large ribosomal subunit protein mL44	Component of the 39S subunit of mitochondrial ribosome.
COA8	Cytochrome c oxidase assembly factor 8	Required for cytochrome c complex (COX) IV assembly and function Protects COX assembly from oxidation-induced degradation, COX being the terminal component of the mitochondrial respiratory chain.
COX10	Protoheme IX farnesyltransferase, mitochondrial	Converts protoheme IX and farnesyl diphosphate to heme O.
COX4I1	Cytochrome c oxidase subunit 4 isoform 1, mitochondrial	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
COX6B1	Cytochrome c oxidase subunit 6B1	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
COX8A	Cytochrome c oxidase subunit 8A, mitochondrial	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
TACO1	Translational activator of cytochrome c oxidase 1	Acts as a translational activator of mitochondrially-encoded cytochrome c oxidase 1.
COA3	Cytochrome c oxidase assembly factor 3 homolog, mitochondrial	Core component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly.
NCAPH2	Condensin-2 complex subunit H2	Regulatory subunit of the condensin-2 complex, a complex that seems to provide chromosomes with an additional level of organization and rigidity and in establishing mitotic chromosome architecture.
COX18	Cytochrome c oxidase assembly protein COX18, mitochondrial	Mitochondrial membrane insertase required for the translocation of the C-terminus of cytochrome c oxidase subunit II (MT-CO2/COX2) across the mitochondrial inner membrane.
COX20	Cytochrome c oxidase assembly protein COX20, mitochondrial	Essential for the assembly of the mitochondrial respiratory chain complex IV (CIV), also known as cytochrome c oxidase.
FASTKD2	FAST kinase domain-containing protein 2, mitochondrial	Plays an important role in assembly of the mitochondrial large ribosomal subunit.
MT-CO1	Cytochrome c oxidase subunit 1	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
MT-CO2	Cytochrome c oxidase subunit 2	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
MT-CO3	Cytochrome c oxidase subunit 3	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 20 · Druggable fraction: 0.13

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	20	1.6×	0.005
Kinase	1	1.2×	0.583
Enzyme (other)	2	1.0×	0.583

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SURF1	Other/Unknown	no		Surf1/Shy1, Surf1/Surf4
COXFA4	Other/Unknown	no		B12D
SCO1	Other/Unknown	no		SCO1/SenC, Synth_of_cyt-c-oxidase_Sco1/2, Thioredoxin-like_sf
SCO2	Other/Unknown	no		SCO1/SenC, Thioredoxin_domain, Synth_of_cyt-c-oxidase_Sco1/2
STXBP2	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
MRPL44	Other/Unknown	no		dsRBD_dom, RNase_III_sf, Ribosomal_mL44_DSRM_metazoa
COA8	Other/Unknown	no		COA8
COX10	Enzyme (other)	yes	2.5.1.141	UbiA_prenyltransferase, Protohaem_IX_farnesylTrfase, Protohaem_IX_farnesylTrfase_mt
COX4I1	Other/Unknown	no		Cyt_c_oxidase_su4_fam, Cyt_c_oxidase_su4, Cyt_c_oxidase_su4_sf
COX6B1	Other/Unknown	no		Cyt_c_oxidase_su6B, CX6/COA6-like_sf, COX6B-like
COX8A	Other/Unknown	no		Cyt_c_oxidase_su8, Cyt_c_oxidase_su8_sf
TACO1	Other/Unknown	no		Transcrip_reg_TACO1-like, Integrase-like_N, Transcrip_reg_TACO1-like_dom3
COA3	Other/Unknown	no		Coa3_CC, Coa3
NCAPH2	Other/Unknown	no		H2_N, H2_M, CNDH2_C
COX18	Other/Unknown	no		YidC/ALB3/OXA1/COX18, YidC/Oxa/ALB_C
COX20	Other/Unknown	no		Cox20
FASTKD2	Kinase	yes		FAST_Leu-rich, FAST_2, RAP
MT-CO1	Enzyme (other)	yes	7.1.1.9	Cyt_C_Oxase_1, Cyt_c_Oxase_su1_BS, Cyt_c_oxase-like_su1_dom
MT-CO2	Other/Unknown	no		Copper_CuA, CcO_II-like_C, Cupredoxin
MT-CO3	Other/Unknown	no		Cyt_c_oxidase-like_su3, Cyt_c_oxidase_su3_a-hlx, Cyt_c/ubiquinol_Oxase_su3
MT-TL1	Other/Unknown	no
MT-TN	Other/Unknown	no
MT-TS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

20 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	23
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	6
mucosa of transverse colon	5
granulocyte	4
heart left ventricle	3
rectum	3
right lobe of liver	2
left ventricle myocardium	2
primordial germ cell in gonad	2
cortical plate	2
cardiac ventricle	2
duodenum	2
vermiform appendix	2
body of pancreas	1
cerebellar vermis	1
heart right ventricle	1
myocardium	1
right uterine tube	1
leukocyte	1
monocyte	1
oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SURF1	183	ubiquitous	marker	apex of heart, body of pancreas, right lobe of liver
COXFA4	288	ubiquitous	marker	heart right ventricle, myocardium, cerebellar vermis
SCO1	243	ubiquitous	marker	left ventricle myocardium, primordial germ cell in gonad, mucosa of transverse colon
SCO2	260	ubiquitous	yes	right uterine tube, granulocyte, mucosa of transverse colon
STXBP2	227	ubiquitous	marker	granulocyte, monocyte, leukocyte
MRPL44	253	ubiquitous	marker	oocyte, primordial germ cell in gonad, cortical plate
COA8	248	ubiquitous	marker	left testis, right testis, hindlimb stylopod muscle
COX10	245	ubiquitous	marker	tibialis anterior, diaphragm, left ventricle myocardium
COX4I1	306	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle
COX6B1	295	ubiquitous	marker	apex of heart, cardiac ventricle, heart left ventricle
COX8A	302	ubiquitous	marker	apex of heart, mucosa of transverse colon, heart left ventricle
TACO1	265	ubiquitous	marker	apex of heart, mucosa of transverse colon, right lobe of liver
COA3	285	ubiquitous	marker	mucosa of transverse colon, corpus epididymis, renal medulla
NCAPH2	260	ubiquitous	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
COX18	254	ubiquitous	marker	tibia, pigmented layer of retina, retina
COX20	255	ubiquitous	marker	kidney epithelium, endothelial cell, cortical plate
FASTKD2	276	ubiquitous	marker	adrenal tissue, secondary oocyte, gastrocnemius
MT-CO1	134	ubiquitous	marker	granulocyte, stromal cell of endometrium, rectum
MT-CO2	134	ubiquitous	marker	granulocyte, rectum, transverse colon
MT-CO3	134	ubiquitous	marker	zone of skin, endocervix, rectum
MT-TL1	118	ubiquitous	marker	frontal cortex, right frontal lobe, caudate nucleus
MT-TN	118	tissue_specific	yes	duodenum, skeletal muscle tissue, vermiform appendix
MT-TS1	118	tissue_specific	yes	duodenum, apex of heart, vermiform appendix

Protein interactions among cohort

Intra-cohort edges: 65.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MRPL44	4,429
COX4I1	3,929
MT-CO1	3,547
MT-CO2	3,057
COX18	2,353
COXFA4	2,279
COX6B1	2,232
TACO1	2,209
SCO1	2,050
SCO2	2,043

Intra-cohort edges

A	B	Sources
COA3	COX10	string_interaction
COA3	COX20	string_interaction
COA3	COX4I1	biogrid_interaction, intact
COA3	MT-CO1	intact
COA3	MT-CO3	intact
COA3	SURF1	biogrid_interaction, intact, string_interaction
COA3	TACO1	intact, string_interaction
COA8	COX10	intact
COA8	COX18	string_interaction
COA8	SURF1	string_interaction
COX10	COX18	string_interaction
COX10	COX6B1	string_interaction
COX10	FASTKD2	string_interaction
COX10	MT-CO1	string_interaction
COX10	MT-CO2	string_interaction
COX10	MT-CO3	string_interaction
COX10	SCO1	string_interaction
COX10	SCO2	string_interaction
COX10	SURF1	string_interaction
COX10	TACO1	string_interaction
COX18	COX20	string_interaction
COX18	MT-CO2	string_interaction
COX18	SCO1	string_interaction
COX18	SCO2	string_interaction
COX20	COXFA4	biogrid_interaction
COX20	MT-CO2	string_interaction
COX20	SCO1	string_interaction
COX20	SCO2	string_interaction
COX20	SURF1	string_interaction
COX4I1	COX6B1	string_interaction
COX4I1	COX8A	biogrid_interaction
COX4I1	MT-CO1	intact, string_interaction
COX4I1	MT-CO2	biogrid_interaction, intact, string_interaction
COX4I1	MT-CO3	intact
COX4I1	SCO2	string_interaction
COX4I1	SURF1	intact
COX6B1	COXFA4	string_interaction
COX6B1	FASTKD2	string_interaction
COX6B1	MT-CO2	intact, string_interaction
COX6B1	MT-CO3	string_interaction
COX6B1	SCO1	string_interaction
COX6B1	SCO2	string_interaction
COX6B1	SURF1	string_interaction
COX6B1	TACO1	string_interaction
COX8A	COXFA4	biogrid_interaction
FASTKD2	SCO1	string_interaction
FASTKD2	TACO1	string_interaction
MT-CO1	MT-CO2	string_interaction
MT-CO1	MT-CO3	string_interaction
MT-CO1	SCO1	string_interaction

Structural data

PDB: 13 · AlphaFold-only: 7 · No structure: 3

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MRPL44	Q9H9J2	85
SCO1	O75880	10
TACO1	Q9BSH4	7
COX8A	P10176	4
MT-CO2	P00403	4
COX4I1	P13073	3
COX6B1	P14854	3
MT-CO1	P00395	3
MT-CO3	P00414	3
COXFA4	O00483	2
SCO2	O43819	1
STXBP2	Q15833	1
NCAPH2	Q6IBW4	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COX18	Q8N8Q8	83.42
SURF1	Q15526	82.62
COA8	Q96IL0	81.19
COA3	Q9Y2R0	77.32
COX10	Q12887	77.11
FASTKD2	Q9NYY8	75.39
COX20	Q5RI15	66.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 34. Enrichment computed across 23 evidence-associated genes (19 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 19 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Complex IV assembly	14	168.3×	5e-29	SURF1, SCO1, SCO2, COX4I1, COX6B1, COX8A, TACO1, COA3 (+6 more)
Respiratory electron transport	11	55.1×	1e-16	SURF1, SCO1, SCO2, COX4I1, COX6B1, COX8A, TACO1, MT-CO1 (+3 more)
TP53 Regulates Metabolic Genes	8	54.6×	7e-12	SCO2, COX4I1, COX6B1, COX8A, MT-CO1, MT-CO2, MT-CO3, COXFA4
Cytoprotection by HMOX1	7	67.9×	4e-11	COX4I1, COX6B1, COX8A, MT-CO1, MT-CO2, MT-CO3, COXFA4
Aerobic respiration and respiratory electron transport	5	23.3×	1e-05	SURF1, SCO1, SCO2, TACO1, COXFA4
Mitochondrial translation termination	4	23.1×	1e-04	MRPL44, MT-CO1, MT-CO2, MT-CO3
Mitochondrial protein degradation	3	18.0×	0.003	COX4I1, MT-CO1, MT-CO2
FASTK family proteins regulate processing and stability of mitochondrial RNAs	1	150.3×	0.028	FASTKD2
Mitochondrial mRNA modification	1	54.6×	0.066	FASTKD2
rRNA modification in the mitochondrion	1	46.2×	0.066	FASTKD2
Metabolism	5	3.1×	0.066	SURF1, SCO1, SCO2, TACO1, COXFA4
Heme biosynthesis	1	40.1×	0.070	COX10
Other interleukin signaling	1	25.0×	0.095	STXBP2
Transcriptional Regulation by TP53	2	6.5×	0.095	SCO2, COXFA4
Response to elevated platelet cytosolic Ca2+	1	8.6×	0.233	STXBP2
Condensation of Prophase Chromosomes	1	8.2×	0.233	NCAPH2
Cellular response to chemical stress	1	7.5×	0.233	COXFA4
Mitochondrial translation	1	7.2×	0.233	MRPL44
Mitochondrial translation initiation	1	6.7×	0.233	MRPL44
Mitochondrial translation elongation	1	6.7×	0.233	MRPL44
Mitochondrial ribosome-associated quality control	1	6.5×	0.233	MRPL44
Platelet activation, signaling and aggregation	1	5.6×	0.255	STXBP2
Platelet degranulation	1	4.6×	0.289	STXBP2
RNA Polymerase II Transcription	2	2.4×	0.291	SCO2, COXFA4
Signaling by Interleukins	1	3.4×	0.347	STXBP2
Translation	1	3.3×	0.347	MRPL44
Gene expression (Transcription)	2	1.9×	0.364	SCO2, COXFA4
Generic Transcription Pathway	2	1.6×	0.439	SCO2, COXFA4
Cytokine Signaling in Immune system	1	2.1×	0.441	STXBP2
Cellular responses to stress	1	1.9×	0.455	COXFA4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 20 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial respiratory chain complex IV assembly	8	249.7×	1e-16	SURF1, SCO1, SCO2, COA8, TACO1, COA3, COX18, COX20
mitochondrial electron transport, cytochrome c to oxygen	7	268.1×	5e-15	COX4I1, COX6B1, COX8A, MT-CO1, MT-CO2, MT-CO3, COXFA4
cellular respiration	7	151.2×	3e-13	COX4I1, COX6B1, COX8A, MT-CO1, MT-CO2, MT-CO3, COXFA4
respiratory chain complex IV assembly	4	481.5×	8e-10	SURF1, COX10, COX18, MT-CO3
aerobic respiration	3	37.2×	8e-04	SURF1, COX10, MT-CO1
intracellular copper ion homeostasis	2	93.6×	0.002	SCO1, SCO2
respiratory electron transport chain	2	84.3×	0.002	SCO2, MT-CO1
leukocyte mediated cytotoxicity	1	842.6×	0.008	STXBP2
ATP synthesis coupled electron transport	1	842.6×	0.008	MT-CO2
generation of precursor metabolites and energy	2	34.4×	0.009	COX4I1, COX8A
female meiosis chromosome separation	1	421.3×	0.013	NCAPH2
muscle system process	1	210.7×	0.016	SCO2
protein insertion into mitochondrial membrane	1	210.7×	0.016	COX18
copper ion homeostasis	1	210.7×	0.016	COX10
mitochondrial translational elongation	1	210.7×	0.016	MRPL44
presynaptic dense core vesicle exocytosis	1	210.7×	0.016	STXBP2
leukocyte differentiation	1	168.5×	0.016	COX10
protein insertion into mitochondrial inner membrane from matrix	1	168.5×	0.016	COX18
neutrophil degranulation	1	168.5×	0.016	STXBP2
mitotic sister chromatid separation	1	168.5×	0.016	NCAPH2
RNA processing	2	21.9×	0.016	MRPL44, FASTKD2
mitochondrial translation	2	17.4×	0.016	MRPL44, FASTKD2
mitochondrial RNA processing	1	140.4×	0.018	FASTKD2
meiotic chromosome condensation	1	140.4×	0.018	NCAPH2
regulation of mitochondrial mRNA stability	1	120.4×	0.018	FASTKD2
motor learning	1	120.4×	0.018	TACO1
regulation of mitochondrial translation	1	120.4×	0.018	TACO1
positive regulation of chromosome condensation	1	105.3×	0.020	NCAPH2
regulation of mast cell degranulation	1	93.6×	0.022	STXBP2
positive regulation of chromosome separation	1	84.3×	0.024	NCAPH2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 22

Druggability breadth: 7 of 23 evidence-associated genes (30%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MT-CO2	CELECOXIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MT-CO2	6	4
SURF1	0	0
COXFA4	0	0
SCO1	0	0
SCO2	0	0
STXBP2	0	0
MRPL44	0	0
COA8	0	0
COX10	0	0
COX4I1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CELECOXIB	4	MT-CO2
ROFECOXIB	4	MT-CO2
DICLOFENAC	4	MT-CO2
INDOMETHACIN	4	MT-CO2
VALDECOXIB	4	MT-CO2
TOLFENAMIC ACID	2	MT-CO2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MT-CO2	47	Binding:41, ADMET:5, Toxicity:1
MT-CO1	19	Binding:12, Functional:4, ADMET:2, Toxicity:1
COXFA4	7	Binding:7
SCO2	1	Binding:1
COX4I1	1	Binding:1
COX6B1	1	Binding:1
MT-CO3	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
COX10	2.5.1.141	heme o synthase
MT-CO1	7.1.1.9	cytochrome-c oxidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 23; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

6 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
CELECOXIB	4	MT-CO2
ROFECOXIB	4	MT-CO2
DICLOFENAC	4	MT-CO2
INDOMETHACIN	4	MT-CO2
VALDECOXIB	4	MT-CO2
TOLFENAMIC ACID	2	MT-CO2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MT-CO2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	MT-CO1
D	Druggable family + AlphaFold only, no drug	2	COX10, FASTKD2
E	Difficult family or no structure, no drug	19	SURF1, COXFA4, SCO1, SCO2, STXBP2, MRPL44, COA8, COX4I1, COX6B1, COX8A (+9 more)

Undrugged target profiles

22 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SCO1	0	MT-CO2
SCO2	1	MT-CO2
COX4I1	1	MT-CO2
COX18	0	MT-CO2
COX20	0	MT-CO2
MT-CO1	19	MT-CO2
MT-CO3	1	MT-CO2
SURF1	0	—
COXFA4	7	—
STXBP2	0	—
MRPL44	0	—
COA8	0	—
COX10	0	—
COX6B1	1	—
COX8A	0	—
TACO1	0	—
COA3	0	—
NCAPH2	0	—
FASTKD2	0	—
MT-TL1	0	—
MT-TN	0	—
MT-TS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.