CYB561D2

Summary

CYB561D2 (cytochrome b561 family member D2, HGNC:30253) is a protein-coding gene on chromosome 3p21.31, encoding Transmembrane reductase CYB561D2 (O14569). Transmembrane reductase that may use ascorbate as an electron donor in the cytoplasm and transfer electrons across endoplasmic reticulum membranes to reduce monodehydro-L-ascorbate radical and iron cations Fe(3+) in the lumen of that compartment.

Enables heme binding activity and transmembrane monodehydroascorbate reductase activity. Involved in ascorbate homeostasis. Predicted to be located in vesicle. Predicted to be active in endoplasmic reticulum.

Source: NCBI Gene 11068 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 26 total
• MANE Select transcript: NM_001291284

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30253
Approved symbol	CYB561D2
Name	cytochrome b561 family member D2
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	101F6, TSP10, TSCytb
Ensembl gene	ENSG00000114395
Ensembl biotype	protein_coding
OMIM	607068
Entrez	11068

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 9 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000232508, ENST00000418577, ENST00000419046, ENST00000424512, ENST00000425346, ENST00000490926, ENST00000903835, ENST00000903836, ENST00000903837, ENST00000903838, ENST00000929048

RefSeq mRNA: 12 — MANE Select: NM_001291284 NM_001291284, NM_001414705, NM_001414706, NM_001414707, NM_001414708, NM_001414709, NM_001414710, NM_001414711, NM_001414712, NM_001414713, NM_001414714, NM_007022

CCDS: CCDS2827

Canonical transcript exons

ENST00000425346 — 4 exons

Exon	Start	End
ENSE00000769307	50352009	50352046
ENSE00001688985	50351409	50351560
ENSE00001754827	50353241	50354069
ENSE00001787209	50350862	50350984

Expression profiles

Bgee: expression breadth ubiquitous, 232 present calls, max score 94.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.9681 / max 122.2040, expressed in 1798 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36733	9.9436	1787
36735	1.6014	425
36734	1.4231	807

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	94.94	gold quality
mucosa of transverse colon	UBERON:0004991	92.30	gold quality
monocyte	CL:0000576	91.21	gold quality
leukocyte	CL:0000738	91.21	gold quality
mononuclear cell	CL:0000842	91.07	gold quality
right adrenal gland cortex	UBERON:0035827	88.54	gold quality
right adrenal gland	UBERON:0001233	88.50	gold quality
right lobe of liver	UBERON:0001114	88.49	gold quality
right lobe of thyroid gland	UBERON:0001119	88.48	gold quality
blood	UBERON:0000178	88.02	gold quality
left adrenal gland	UBERON:0001234	87.86	gold quality
body of stomach	UBERON:0001161	87.65	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.54	gold quality
left adrenal gland cortex	UBERON:0035825	87.40	gold quality
left lobe of thyroid gland	UBERON:0001120	87.35	gold quality
ileal mucosa	UBERON:0000331	87.14	gold quality
small intestine Peyer’s patch	UBERON:0003454	87.07	gold quality
metanephros cortex	UBERON:0010533	87.00	gold quality
spleen	UBERON:0002106	86.90	gold quality
minor salivary gland	UBERON:0001830	86.71	gold quality
transverse colon	UBERON:0001157	86.51	gold quality
adrenal cortex	UBERON:0001235	86.32	gold quality
rectum	UBERON:0001052	86.23	gold quality
thyroid gland	UBERON:0002046	86.05	gold quality
body of pancreas	UBERON:0001150	85.88	gold quality
gall bladder	UBERON:0002110	85.79	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.73	gold quality
adrenal gland	UBERON:0002369	85.70	gold quality
adenohypophysis	UBERON:0002196	85.59	gold quality
stromal cell of endometrium	CL:0002255	85.44	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.06

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

17 targeting CYB561D2, 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-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-4326	98.97	67.63	962
HSA-MIR-4722-5P	98.46	66.34	1611
HSA-MIR-6780A-3P	98.42	67.49	1518
HSA-MIR-10526-3P	97.86	64.97	1342
HSA-MIR-558	97.50	67.16	977

Literature-anchored findings (GeneRIF, showing 1)

• The protein exhibits the characteristics typical of members of the cytochrome b561 family, being a hydrophobic, transmembrane heme protein. It is capable of oxidation-reduction reaction and is a candidate tumor suppressor gene product. (PMID:19734123)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cyb561d2	ENSDARG00000044114
mus_musculus	Cyb561d2	ENSMUSG00000037190
rattus_norvegicus	Cyb561d2	ENSRNOG00000021887
drosophila_melanogaster	CG10165	FBGN0032801
drosophila_melanogaster	CG13078	FBGN0032809
drosophila_melanogaster	CG13077	FBGN0032810

Paralogs (1): CYB561D1 (ENSG00000174151)

Protein

Protein identifiers

Transmembrane reductase CYB561D2 — O14569 (reviewed: O14569)

Alternative names: Cytochrome b561 domain-containing protein 2, Putative tumor suppressor protein 101F6

All UniProt accessions (1): O14569

UniProt curated annotations — full annotation on UniProt →

Function. Transmembrane reductase that may use ascorbate as an electron donor in the cytoplasm and transfer electrons across endoplasmic reticulum membranes to reduce monodehydro-L-ascorbate radical and iron cations Fe(3+) in the lumen of that compartment.

Subcellular location. Endoplasmic reticulum membrane. Cytoplasmic vesicle membrane.

Cofactor. Binds 2 heme b groups non-covalently.

RefSeq proteins (12): NP_001278213, NP_001401634, NP_001401635, NP_001401636, NP_001401637, NP_001401638, NP_001401639, NP_001401640, NP_001401641, NP_001401642, NP_001401643, NP_008953 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006593	Cyt_b561/ferric_Rdtase_TM	Domain
IPR045150

Pfam: PF03188

Catalyzed reactions (Rhea), 2 shown:

• Fe(3+)(out) + L-ascorbate(in) = monodehydro-L-ascorbate radical(in) + Fe(2+)(out) + H(+) (RHEA:30403)
• monodehydro-L-ascorbate radical(out) + L-ascorbate(in) = monodehydro-L-ascorbate radical(in) + L-ascorbate(out) (RHEA:66524)

UniProt features (20 total): topological domain 7, transmembrane region 6, binding site 4, initiator methionine 1, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14569-F1	93.27	0.85

Functional residue map

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

Ligand- & substrate-binding residues (4): 48 (axial binding residue); 86 (axial binding residue); 120 (axial binding residue); 159 (axial binding residue)

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 123 (showing top): TGCGCANK_UNKNOWN, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, HESSON_TUMOR_SUPPRESSOR_CLUSTER_3P21_3, RADAEVA_RESPONSE_TO_IFNA1_UP, TATA_C, RYTTCCTG_ETS2_B, ACEVEDO_LIVER_CANCER_UP, DANG_BOUND_BY_MYC, MODULE_82, GOBP_TRANSMEMBRANE_TRANSPORT, GOBP_HOMEOSTATIC_PROCESS, GOBP_CHEMICAL_HOMEOSTASIS, GOCC_NUCLEAR_OUTER_MEMBRANE_ENDOPLASMIC_RETICULUM_MEMBRANE_NETWORK, BENPORATH_MYC_MAX_TARGETS, SCGGAAGY_ELK1_02

GO Biological Process (2): ascorbate homeostasis (GO:0140576), transmembrane transport (GO:0055085)

GO Molecular Function (6): heme binding (GO:0020037), metal ion binding (GO:0046872), transmembrane ascorbate ferrireductase activity (GO:0140571), transmembrane monodehydroascorbate reductase activity (GO:0140575), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (6): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytoplasmic vesicle membrane (GO:0030659), vesicle (GO:0031982), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
carbohydrate homeostasis	1
transport	1
cellular process	1
tetrapyrrole binding	1
cation binding	1
oxidoreduction-driven active transmembrane transporter activity	1
oxidoreductase activity, acting on metal ions	1
oxidoreductase activity	1
binding	1
catalytic activity	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
vesicle membrane	1
cytoplasmic vesicle	1
membrane-bounded organelle	1
cellular anatomical structure	1
intracellular vesicle	1

Protein interactions and networks

STRING

300 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CYB561D2	NPRL2	Q8WTW4	628
CYB561D2	FRRS1	Q6ZNA5	622
CYB561D2	HYAL2	Q12891	608
CYB561D2	CACNA2D2	Q9NY47	588
CYB561D2	OVCH1	Q7RTY7	576
CYB561D2	CYB561A3	Q8NBI2	571
CYB561D2	CYB561	P49447	542
CYB561D2	M0QYV0	M0QYV0	507
CYB561D2	ZMYND10	O75800	491
CYB561D2	HYAL1	Q12794	450
CYB561D2	SPAM1	P38567	401
CYB561D2	METAP1	P53582	396
CYB561D2	CYBRD1	Q53TN4	392
CYB561D2	RASSF1	Q9NS23	392
CYB561D2	TMEM115	Q12893	384

IntAct

59 interactions, top by confidence:

A	B	Type	Score
CYB561D2		psi-mi:“MI:0915”(physical association)	0.560
CYB561D2	SLC30A2	psi-mi:“MI:0915”(physical association)	0.560
CYB561D2	CLEC14A	psi-mi:“MI:0915”(physical association)	0.560
CYB561D2	PDE4A	psi-mi:“MI:0915”(physical association)	0.560
CYB561D2	CLDN7	psi-mi:“MI:0915”(physical association)	0.560
	CYB561D2	psi-mi:“MI:0915”(physical association)	0.560
CYB561D2	TMEM154	psi-mi:“MI:0915”(physical association)	0.560
CYB561D2	CD79A	psi-mi:“MI:0915”(physical association)	0.560
CYB561D2	COQ9	psi-mi:“MI:0915”(physical association)	0.560
CYB561D2	RMDN3	psi-mi:“MI:0915”(physical association)	0.560
CYB561D2	PGRMC2	psi-mi:“MI:0915”(physical association)	0.560
CYB561D2	TMEM45B	psi-mi:“MI:0915”(physical association)	0.560
CYB561D2	PTPN5	psi-mi:“MI:0915”(physical association)	0.560
CYB561D2	GPX8	psi-mi:“MI:0915”(physical association)	0.560
CYB561D2	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560
CYB561D2	FAM209A	psi-mi:“MI:0915”(physical association)	0.560
CYB561D2	SLC18A1	psi-mi:“MI:0915”(physical association)	0.560
CYB561D2	CREB3L1	psi-mi:“MI:0915”(physical association)	0.560
CYB561D2	ARL13B	psi-mi:“MI:0915”(physical association)	0.560
CYB561D2	CLNK	psi-mi:“MI:0915”(physical association)	0.490
CLNK	CYB561D2	psi-mi:“MI:0915”(physical association)	0.490
CYB561D2	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
CYB561D2	SLC30A2	psi-mi:“MI:0915”(physical association)	0.000
CYB561D2	PDE4A	psi-mi:“MI:0915”(physical association)	0.000
CYB561D2	CLDN7	psi-mi:“MI:0915”(physical association)	0.000
CYB561D2	TMEM154	psi-mi:“MI:0915”(physical association)	0.000
CYB561D2	CD79A	psi-mi:“MI:0915”(physical association)	0.000
CYB561D2	COQ9	psi-mi:“MI:0915”(physical association)	0.000
CYB561D2	RMDN3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (31): CYB561D2 (Two-hybrid), CYB561D2 (Two-hybrid), UNC119 (Two-hybrid), CYB561D2 (Two-hybrid), CYB561D2 (Two-hybrid), CYB561D2 (Two-hybrid), CYB561D2 (Two-hybrid), CYB561D2 (Two-hybrid), FAM209A (Two-hybrid), ERGIC3 (Two-hybrid), RMDN3 (Two-hybrid), TMEM45B (Two-hybrid), CREB3L1 (Two-hybrid), SLC30A2 (Two-hybrid), PGRMC2 (Two-hybrid)

ESM2 similar proteins: A2AE42, A3A9H6, A5D7C9, A5D9A7, A6NM10, B3SHH9, B5DFH9, B9EJG8, F1NZP5, O14569, P10897, P49447, P82352, Q08DE1, Q14714, Q148G2, Q3ZCD2, Q5E965, Q5ND56, Q5RCZ2, Q5U2W7, Q5ZJX0, Q60720, Q62147, Q641Y1, Q6GPL4, Q6P0C6, Q6P1H1, Q71RH2, Q7TNV1, Q80ZE4, Q86TG1, Q8BMD6, Q8C8S3, Q8IXF9, Q8N8Q1, Q8NBI2, Q8TBR7, Q8VHW3, Q8VHW7

Diamond homologs: A2AE42, O14569, Q5E965, Q641Y1, Q8N8Q1, Q9WUE3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	18
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

960 predictions. Top by Δscore:

Variant	Effect	Δscore
3:50351556:CTCCA:C	donor_gain	1.0000
3:50351558:CCA:C	donor_gain	1.0000
3:50351559:CA:C	donor_gain	1.0000
3:50351559:CAGTA:C	donor_loss	1.0000
3:50351560:AGTA:A	donor_loss	1.0000
3:50351561:G:C	donor_loss	1.0000
3:50351561:G:GG	donor_gain	1.0000
3:50351562:T:A	donor_loss	1.0000
3:50355545:TGC:T	acceptor_gain	1.0000
3:50355545:TGCC:T	acceptor_loss	1.0000
3:50355546:GCC:G	acceptor_loss	1.0000
3:50355547:CCTGG:C	acceptor_loss	1.0000
3:50355548:C:CA	acceptor_loss	1.0000
3:50355548:C:CC	acceptor_gain	1.0000
3:50355549:T:G	acceptor_loss	1.0000
3:50355555:C:CT	acceptor_gain	1.0000
3:50355555:C:T	acceptor_gain	1.0000
3:50355556:A:T	acceptor_gain	1.0000
3:50358208:AGTAC:A	donor_loss	1.0000
3:50358209:GTACC:G	donor_loss	1.0000
3:50358210:TAC:T	donor_loss	1.0000
3:50358211:A:AG	donor_loss	1.0000
3:50358212:C:A	donor_loss	1.0000
3:50358212:CCTT:C	donor_gain	1.0000
3:50351557:TCCA:T	donor_gain	0.9900
3:50351560:AGT:A	donor_loss	0.9900
3:50351561:G:A	donor_loss	0.9900
3:50351562:TA:T	donor_loss	0.9900
3:50351563:AA:A	donor_loss	0.9900
3:50351563:AAGTA:A	donor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000111239 (3:50359764 G>A), RS1000120147 (3:50353767 C>A), RS1000320674 (3:50353983 A>G), RS1000619900 (3:50360067 A>G), RS1000647187 (3:50351863 G>A), RS1000658447 (3:50352209 G>A), RS1001118108 (3:50361342 T>G), RS1001170245 (3:50361595 G>C), RS1001573807 (3:50353900 T>C), RS1001583584 (3:50354138 G>A), RS1001681732 (3:50367041 T>C), RS1001852784 (3:50365232 C>A,G,T), RS1002140246 (3:50360439 T>G), RS1002415449 (3:50365274 C>T), RS1002576811 (3:50355036 A>G)

Disease associations

OMIM: gene MIM:607068 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST007559_24	Sleep duration (short sleep)	3.000000e-08
GCST008843_1	Depressive symptom (appetite changes) (binary trait)	9.000000e-09
GCST008848_2	Depressive symptoms (sum-score)	1.000000e-09
GCST008849_3	Depressive symptoms (binary sum-score)	1.000000e-10
GCST010698_80	Subcortical volume (min-P)	3.000000e-24
GCST010699_110	Brain morphology (min-P)	4.000000e-08
GCST010701_52	Cortical surface area (MOSTest)	1.000000e-16
GCST010702_36	Subcortical volume (MOSTest)	1.000000e-10
GCST010703_262	Brain morphology (MOSTest)	2.000000e-13

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007006	depressive symptom measurement
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

31 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	increases expression, affects response to substance	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
alpha phellandrene	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
abrine	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
jinfukang	increases expression	1
Temozolomide	increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Calcitriol	increases expression, affects cotreatment	1
Catechin	affects cotreatment, decreases expression	1
Cisplatin	increases expression	1
Methylnitronitrosoguanidine	decreases expression	1
Phenobarbital	affects expression	1
Selenium	increases expression	1
Smoke	decreases expression	1
Testosterone	increases expression, affects cotreatment	1
Tobacco Smoke Pollution	decreases expression	1
Cyclosporine	decreases methylation	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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