C2orf69

Summary

C2orf69 (chromosome 2 open reading frame 69, HGNC:26799) is a protein-coding gene on chromosome 2q33.1, encoding Mitochondrial protein C2orf69 (Q8N8R5). May play a role in the respiratory chain.

Involved in oxidative phosphorylation. Located in mitochondrion. Implicated in combined oxidative phosphorylation deficiency 53.

Source: NCBI Gene 205327 — RefSeq curated summary.

At a glance

• Gene–disease (curated): combined oxidative phosphorylation deficiency 53 (Strong, GenCC)
• GWAS associations: 7
• Clinical variants (ClinVar): 40 total — 7 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 24
• MANE Select transcript: NM_153689

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26799
Approved symbol	C2orf69
Name	chromosome 2 open reading frame 69
Location	2q33.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ38973
Ensembl gene	ENSG00000178074
Ensembl biotype	protein_coding
OMIM	619219
Entrez	205327

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000319974, ENST00000491721

RefSeq mRNA: 1 — MANE Select: NM_153689 NM_153689

CCDS: CCDS46482

Canonical transcript exons

ENST00000319974 — 2 exons

Exon	Start	End
ENSE00001280043	199925062	199928273
ENSE00001280049	199911293	199911771

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 97.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.7846 / max 118.7326, expressed in 1783 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
24518	11.0696	1776
24517	1.0680	488
24519	0.8323	544
24520	0.7305	428
24521	0.0843	19

Top tissues by expression

256 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	97.56	gold quality
Brodmann (1909) area 46	UBERON:0006483	95.75	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.71	gold quality
endothelial cell	CL:0000115	95.63	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.34	gold quality
biceps brachii	UBERON:0001507	95.14	gold quality
upper leg skin	UBERON:0004262	94.93	gold quality
ileal mucosa	UBERON:0000331	94.87	gold quality
cartilage tissue	UBERON:0002418	94.85	gold quality
entorhinal cortex	UBERON:0002728	94.55	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.52	gold quality
trabecular bone tissue	UBERON:0002483	94.49	gold quality
corpus epididymis	UBERON:0004359	94.40	gold quality
deltoid	UBERON:0001476	94.15	gold quality
cauda epididymis	UBERON:0004360	94.11	gold quality
pigmented layer of retina	UBERON:0001782	94.06	gold quality
left ventricle myocardium	UBERON:0006566	94.03	gold quality
upper arm skin	UBERON:0004263	93.65	gold quality
postcentral gyrus	UBERON:0002581	93.63	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.62	gold quality
jejunal mucosa	UBERON:0000399	93.58	gold quality
caput epididymis	UBERON:0004358	93.47	gold quality
colonic mucosa	UBERON:0000317	93.46	gold quality
gingiva	UBERON:0001828	93.46	gold quality
gingival epithelium	UBERON:0001949	93.37	gold quality
epithelial cell of pancreas	CL:0000083	93.18	gold quality
middle temporal gyrus	UBERON:0002771	93.12	gold quality
parietal lobe	UBERON:0001872	93.03	gold quality
parietal pleura	UBERON:0002400	92.97	gold quality
superior frontal gyrus	UBERON:0002661	92.84	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.37
E-MTAB-6142	no	85.63

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

183 targeting C2orf69, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-570-3P	99.96	72.41	4910

Literature-anchored findings (GeneRIF, showing 2)

• C2orf69 mutations disrupt mitochondrial function and cause a multisystem human disorder with recurring autoinflammation. (PMID:33945503)
• Loss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen-storage-associated mitochondriopathy. (PMID:34038740)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	C9H2orf69	ENSDARG00000062425
mus_musculus	1700066M21Rik	ENSMUSG00000038323
rattus_norvegicus	C9h2orf69	ENSRNOG00000010185
drosophila_melanogaster	CG31122	FBGN0051122

Protein

Protein identifiers

Mitochondrial protein C2orf69 — Q8N8R5 (reviewed: Q8N8R5)

All UniProt accessions (1): Q8N8R5

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in the respiratory chain.

Subcellular location. Mitochondrion matrix.

Disease relevance. Combined oxidative phosphorylation deficiency 53 (COXPD53) [MIM:619423] An autosomal recessive mitochondrial disorder characterized by global developmental delay, hypomyelination, cerebral atrophy, microcephaly, liver dysfunction, and recurrent autoinflammation. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the C2orf69 family.

RefSeq proteins (1): NP_710156* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR018881	C2orf69_mit	Family

Pfam: PF10561

UniProt features (3 total): transit peptide 1, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N8R5-F1	79.05	0.66

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (1):

Position	Phenotype
1–24	abolishes mitochondrial localization.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 186 (showing top): FOXO1_01, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GTGCCTT_MIR506, GOBP_OXIDATIVE_PHOSPHORYLATION, ACATTCC_MIR1_MIR206, DODD_NASOPHARYNGEAL_CARCINOMA_UP, FISCHER_DREAM_TARGETS, GOBP_CELLULAR_RESPIRATION, CCCNNGGGAR_OLF1_01, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, NUYTTEN_EZH2_TARGETS_DN, GOCC_MITOCHONDRIAL_MATRIX, EPPERT_HSC_R, WHITFIELD_CELL_CYCLE_G2, MARTENS_TRETINOIN_RESPONSE_DN

GO Biological Process (1): oxidative phosphorylation (GO:0006119)

GO Molecular Function (0):

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
aerobic respiration	1
proton motive force-driven ATP synthesis	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

506 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
C2orf69	TYW5	A2RUC4	582
C2orf69	NSA2	O95478	515
C2orf69	FTCDNL1	E5RQL4	507
C2orf69	KCTD18	Q6PI47	505
C2orf69	DNAAF4	Q8WXU2	484
C2orf69	C8orf82	Q6P1X6	471
C2orf69	C15orf40	Q8WUR7	447
C2orf69	NT5DC2	Q9H857	436
C2orf69	SPATS2L	Q9NUQ6	433
C2orf69	ANKRD13C	Q8N6S4	429
C2orf69	MAIP1	Q8WWC4	418
C2orf69	G3V325	G3V325	418
C2orf69	KIAA1328	Q86T90	413
C2orf69	SAMD10	Q9BYL1	398
C2orf69	SNX19	Q92543	387

IntAct

9 interactions, top by confidence:

A	B	Type	Score
CBX1	KPNA3	psi-mi:“MI:0914”(association)	0.530
TACC3	DHRS2	psi-mi:“MI:0914”(association)	0.350
KIF11	ILVBL	psi-mi:“MI:0914”(association)	0.350
Vps28	UMAD1	psi-mi:“MI:0914”(association)	0.350
HDAC1	TRAK1	psi-mi:“MI:0914”(association)	0.350
KLC3	KLC1	psi-mi:“MI:0914”(association)	0.350
VPS26A	LCMT2	psi-mi:“MI:0914”(association)	0.350
SORT1	SH3PXD2B	psi-mi:“MI:0914”(association)	0.350

BioGRID (9): C2orf69 (Affinity Capture-MS), C2orf69 (Affinity Capture-MS), C2orf69 (Affinity Capture-MS), C2orf69 (Affinity Capture-MS), C2orf69 (Affinity Capture-MS), C2orf69 (Affinity Capture-MS), C2orf69 (Affinity Capture-MS), C2orf69 (Affinity Capture-MS), C2orf69 (Affinity Capture-RNA)

ESM2 similar proteins: A0JMH2, A1L251, A2ARP1, A7Z050, D3ZEY4, E7FCP8, E9QAM5, O00562, O35954, O42412, O95822, P0C644, P0C7A1, P12617, P16386, P40935, P49898, P49899, P52824, P53370, P54310, P70563, Q17QN2, Q2KI24, Q3URQ7, Q499U8, Q5EU90, Q5I0I8, Q5RAR6, Q5RDF1, Q5TGY1, Q5U2N3, Q5XIL6, Q68J42, Q6P5E8, Q6PD24, Q6PFW1, Q80YU0, Q8BX80, Q8CH40

Diamond homologs: A0JMH2, Q8N8R5, Q9D9H8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

40 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	1
Uncertain significance	8
Likely benign	18
Benign	1

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
1177454	NM_153689.6(C2orf69):c.843_847del (p.Lys282fs)	Pathogenic
1177455	NM_153689.6(C2orf69):c.280del (p.Glu94fs)	Pathogenic
1177456	NM_153689.6(C2orf69):c.588_592del (p.Asn196fs)	Pathogenic
1177457	NM_153689.6(C2orf69):c.311_313del (p.Leu104_Tyr105delinsHis)	Pathogenic
1177458	NM_153689.6(C2orf69):c.909_925del (p.Ser304fs)	Pathogenic
1177459	NM_153689.6(C2orf69):c.929G>A (p.Trp310Ter)	Pathogenic
687824	GRCh37/hg19 2q33.1(chr2:198852970-201350417)x1	Pathogenic
2446879	NM_153689.6(C2orf69):c.187_191dup (p.Asp64fs)	Likely pathogenic

SpliceAI

1957 predictions. Top by Δscore:

Variant	Effect	Δscore
2:199911770:AG:A	donor_loss	1.0000
2:199911771:GG:G	donor_loss	1.0000
2:199911772:GTAA:G	donor_loss	1.0000
2:199925056:TTTCA:T	acceptor_loss	1.0000
2:199925057:TTCA:T	acceptor_loss	1.0000
2:199925058:TCAGA:T	acceptor_loss	1.0000
2:199925059:CA:C	acceptor_loss	1.0000
2:199925060:A:C	acceptor_loss	1.0000
2:199925061:GA:G	acceptor_gain	1.0000
2:199925061:GAATT:G	acceptor_gain	1.0000
2:199933319:TAAAG:T	acceptor_gain	1.0000
2:199933321:AAG:A	acceptor_gain	1.0000
2:199933323:GC:G	acceptor_loss	1.0000
2:199933324:C:CA	acceptor_loss	1.0000
2:199933324:C:CC	acceptor_gain	1.0000
2:199935924:ATCTT:A	donor_loss	1.0000
2:199935925:TCTTA:T	donor_loss	1.0000
2:199935926:CTTA:C	donor_loss	1.0000
2:199935927:TTA:T	donor_loss	1.0000
2:199935928:TACCA:T	donor_loss	1.0000
2:199935929:A:AC	donor_gain	1.0000
2:199935929:ACCA:A	donor_loss	1.0000
2:199935930:C:CA	donor_loss	1.0000
2:199935930:C:CC	donor_gain	1.0000
2:199936048:CT:C	acceptor_loss	1.0000
2:199936049:T:C	acceptor_loss	1.0000
2:199938934:T:TA	donor_gain	1.0000
2:199938997:T:TA	donor_gain	1.0000
2:199939069:TC:T	acceptor_gain	1.0000
2:199939070:CC:C	acceptor_gain	1.0000

AlphaMissense

2564 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:199925206:T:C	F160L	1.000
2:199925208:C:A	F160L	1.000
2:199925208:C:G	F160L	1.000
2:199925522:A:T	K265I	1.000
2:199925207:T:C	F160S	0.999
2:199925207:T:G	F160C	0.999
2:199925209:A:C	S161R	0.999
2:199925211:C:A	S161R	0.999
2:199925211:C:G	S161R	0.999
2:199925515:T:C	F263L	0.999
2:199925517:C:A	F263L	0.999
2:199925517:C:G	F263L	0.999
2:199925519:G:T	S264I	0.999
2:199925523:A:C	K265N	0.999
2:199925523:A:T	K265N	0.999
2:199925620:T:A	W298R	0.999
2:199925620:T:C	W298R	0.999
2:199925656:T:A	W310R	0.999
2:199925656:T:C	W310R	0.999
2:199925750:G:C	R341T	0.999
2:199925751:A:C	R341S	0.999
2:199925751:A:T	R341S	0.999
2:199925755:T:A	W343R	0.999
2:199925755:T:C	W343R	0.999
2:199911763:G:C	D109H	0.998
2:199911764:A:C	D109A	0.998
2:199911764:A:G	D109G	0.998
2:199911764:A:T	D109V	0.998
2:199925513:G:A	G262E	0.998
2:199925518:A:C	S264R	0.998

dbSNP variants (sampled 300 via entrez): RS1000199366 (2:199910522 GCC>G), RS1000543718 (2:199927914 T>C), RS1001063519 (2:199917392 G>C,T), RS1001121677 (2:199924628 G>A), RS1001186372 (2:199920320 T>A), RS1001314010 (2:199910670 T>A,C), RS1001504386 (2:199912693 TGCAGTGGC>T), RS1001531968 (2:199924222 C>T), RS1001603417 (2:199919693 C>G), RS1001807890 (2:199926566 C>T), RS1002025635 (2:199910162 A>C), RS1002036921 (2:199909776 A>G), RS1002115448 (2:199927015 A>G), RS1002137989 (2:199917321 G>A), RS1002212580 (2:199918837 T>C)

Disease associations

OMIM: gene MIM:619219 | disease phenotypes: MIM:619423

GenCC curated gene-disease

Disease	Classification	Inheritance
combined oxidative phosphorylation deficiency 53	Strong	Autosomal recessive

Mondo (1): combined oxidative phosphorylation deficiency 53 (MONDO:0030378)

Orphanet (0):

HPO phenotypes

24 total (24 of 24 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001369	Arthritis
HP:0001508	Failure to thrive
HP:0001522	Death in infancy
HP:0001954	Recurrent fever
HP:0002240	Hepatomegaly
HP:0002754	Osteomyelitis
HP:0003095	Septic arthritis
HP:0003270	Abdominal distention
HP:0003429	CNS hypomyelination
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0003700	Generalized amyotrophy
HP:0003819	Death in childhood
HP:0004322	Short stature
HP:0004840	Hypochromic microcytic anemia
HP:0005484	Secondary microcephaly
HP:0006989	Dysplastic corpus callosum
HP:0011227	Elevated circulating C-reactive protein concentration

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002149_16	Schizophrenia	1.000000e-08
GCST004521_125	Autism spectrum disorder or schizophrenia	3.000000e-12
GCST006803_6	Schizophrenia	4.000000e-17
GCST007561_69	Sleep duration	2.000000e-08
GCST009600_102	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	1.000000e-12
GCST010396_254	Gut microbiota (bacterial taxa, hurdle binary method)	2.000000e-07
GCST010988_198	Adult body size	5.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007874	gut microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	affects expression, decreases expression	3
Air Pollutants	decreases expression, increases abundance	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chloropicrin	increases expression	1
ICG 001	affects expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
jinfukang	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Catechin	affects cotreatment, increases expression	1
Coumestrol	affects cotreatment, increases expression	1
Formaldehyde	decreases expression	1
Smoke	decreases expression, increases abundance	1
Valproic Acid	increases expression	1
Cyclosporine	increases expression	1
Asbestos, Crocidolite	decreases expression	1
Okadaic Acid	increases expression	1
Copper Sulfate	decreases expression	1
Particulate Matter	increases abundance, decreases expression	1

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D9AG	Ubigene HEK293 C2orf69 KO	Transformed cell line	Female
CVCL_SG29	HAP1 C2orf69 (-) 1	Cancer cell line	Male
CVCL_XM30	HAP1 C2orf69 (-) 2	Cancer cell line	Male
CVCL_XM31	HAP1 C2orf69 (-) 3	Cancer cell line	Male
CVCL_XM32	HAP1 C2orf69 (-) 4	Cancer cell line	Male
CVCL_XM33	HAP1 C2orf69 (-) 5	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.