CYB5D2

Summary

CYB5D2 (cytochrome b5 domain containing 2, HGNC:28471) is a protein-coding gene on chromosome 17p13.2, encoding Neuferricin (Q8WUJ1). Heme-binding protein which promotes neuronal but not astrocyte differentiation.

Predicted to enable heme binding activity. Predicted to be involved in nervous system development. Predicted to act upstream of or within positive regulation of neuron differentiation. Predicted to be located in extracellular region. Predicted to be active in endomembrane system and membrane.

Source: NCBI Gene 124936 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 69 total
• MANE Select transcript: NM_144611

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28471
Approved symbol	CYB5D2
Name	cytochrome b5 domain containing 2
Location	17p13.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC32124
Ensembl gene	ENSG00000167740
Ensembl biotype	protein_coding
Entrez	124936

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000301391, ENST00000573984, ENST00000575251, ENST00000575411, ENST00000577075

RefSeq mRNA: 3 — MANE Select: NM_144611 NM_001254755, NM_001254756, NM_144611

CCDS: CCDS11044, CCDS58501

Canonical transcript exons

ENST00000301391 — 4 exons

Exon	Start	End
ENSE00001132387	4156866	4157697
ENSE00001132398	4143197	4144005
ENSE00003502188	4149891	4150031
ENSE00003558008	4154674	4154860

Expression profiles

Bgee: expression breadth ubiquitous, 208 present calls, max score 92.02.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.2889 / max 229.6578, expressed in 1811 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158888	12.7710	1780
158887	6.2801	1762
158889	1.2379	401

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
kidney epithelium	UBERON:0004819	92.02	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.21	gold quality
left testis	UBERON:0004533	90.39	gold quality
right testis	UBERON:0004534	90.13	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.91	gold quality
adult organism	UBERON:0007023	89.55	gold quality
adult mammalian kidney	UBERON:0000082	89.37	gold quality
testis	UBERON:0000473	89.31	gold quality
prefrontal cortex	UBERON:0000451	89.11	gold quality
hypothalamus	UBERON:0001898	89.00	gold quality
right adrenal gland cortex	UBERON:0035827	88.92	gold quality
spinal cord	UBERON:0002240	88.81	gold quality
stromal cell of endometrium	CL:0002255	88.76	gold quality
right adrenal gland	UBERON:0001233	88.62	gold quality
corpus epididymis	UBERON:0004359	88.10	gold quality
pituitary gland	UBERON:0000007	88.02	gold quality
right uterine tube	UBERON:0001302	87.91	gold quality
putamen	UBERON:0001874	87.87	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.83	gold quality
nucleus accumbens	UBERON:0001882	87.81	gold quality
right lobe of liver	UBERON:0001114	87.69	gold quality
adenohypophysis	UBERON:0002196	87.69	gold quality
left adrenal gland	UBERON:0001234	87.67	gold quality
anterior cingulate cortex	UBERON:0009835	87.63	gold quality
amygdala	UBERON:0001876	87.61	gold quality
right frontal lobe	UBERON:0002810	87.50	gold quality
caudate nucleus	UBERON:0001873	87.41	gold quality
gall bladder	UBERON:0002110	87.39	gold quality
islet of Langerhans	UBERON:0000006	87.38	gold quality
pancreatic ductal cell	CL:0002079	87.14	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

24 targeting CYB5D2, 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-302E	99.96	70.74	2669
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698
HSA-MIR-372-3P	99.83	70.58	1691
HSA-MIR-520A-3P	99.83	70.59	1687
HSA-MIR-520B-3P	99.83	70.56	1699
HSA-MIR-520C-3P	99.83	70.56	1699
HSA-MIR-520D-3P	99.83	70.78	1676
HSA-MIR-520F-3P	99.82	71.32	1216
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-6513-3P	99.59	69.77	1102
HSA-MIR-4999-5P	99.35	69.15	926
HSA-MIR-1273H-3P	99.29	67.55	980
HSA-MIR-4721	99.26	66.05	818
HSA-MIR-7974	99.24	65.48	1137
HSA-MIR-5001-3P	98.91	67.28	1394
HSA-MIR-4446-3P	97.91	64.29	991
HSA-MIR-6839-5P	96.74	68.29	1088
HSA-MIR-764	94.16	64.85	656

Literature-anchored findings (GeneRIF, showing 1)

• alysis of CYB5D2 gene expression and genomic alteration data available from Oncomeinetrade mark detected significant reductions of CYB5D2 mRNA in 40 SCCs and CYB5D2 gene copy number in 107 SCCs. Collectively, we provide evidence that CYB5D2 is a candidate tumor suppressor of cervical tumorigenesis. (PMID:26692170)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cyb5d2	ENSDARG00000061006
mus_musculus	Cyb5d2	ENSMUSG00000057778
rattus_norvegicus	Cyb5d2	ENSRNOG00000024553
drosophila_melanogaster	CG12056	FBGN0030099
caenorhabditis_elegans		WBGENE00006478

Paralogs (3): VMP1 (ENSG00000062716), PGRMC1 (ENSG00000101856), PGRMC2 (ENSG00000164040)

Protein

Protein identifiers

Neuferricin — Q8WUJ1 (reviewed: Q8WUJ1)

Alternative names: Cytochrome b5 domain-containing protein 2

All UniProt accessions (2): I3L497, Q8WUJ1

UniProt curated annotations — full annotation on UniProt →

Function. Heme-binding protein which promotes neuronal but not astrocyte differentiation.

Subcellular location. Secreted.

Domain organisation. The cytochrome b5 heme-binding domain was proven to bind heme, although it lacks the conserved iron-binding His residues at position 73 and 106.

Miscellaneous. Non-classical progesterone receptors involved in extranuclear signaling are classified in 2 groups: the class II progestin and adipoQ receptor (PAQR) family (also called mPRs) (PAQR5, PAQR6, PAQR7, PAQR8 and PAQR9) and the b5-like heme/steroid-binding protein family (also called MAPRs) (PGRMC1, PGRMC2, NENF and CYB5D2).

Similarity. Belongs to the cytochrome b5 family. MAPR subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8WUJ1-1	1	yes
Q8WUJ1-3	2

RefSeq proteins (3): NP_001241684, NP_001241685, NP_653212* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001199	Cyt_B5-like_heme/steroid-bd	Domain
IPR036400	Cyt_B5-like_heme/steroid_sf	Homologous_superfamily
IPR050577	MAPR/NEUFC/NENF-like	Family

Pfam: PF00173

UniProt features (6 total): sequence variant 2, signal peptide 1, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WUJ1-F1	90.81	0.83

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 73 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_NEUROGENESIS, YY1_Q6, GOBP_REGULATION_OF_NEURON_DIFFERENTIATION, YY1_02, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, DOUGLAS_BMI1_TARGETS_DN, GOBP_POSITIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS, TGGAAA_NFAT_Q4_01, CGTSACG_PAX3_B, SCGGAAGY_ELK1_02, GOMF_STEROID_BINDING, AAGWWRNYGGC_UNKNOWN, GOMF_TETRAPYRROLE_BINDING

GO Biological Process (3): neuron differentiation (GO:0030182), positive regulation of neuron differentiation (GO:0045666), nervous system development (GO:0007399)

GO Molecular Function (3): steroid binding (GO:0005496), heme binding (GO:0020037), protein binding (GO:0005515)

GO Cellular Component (3): extracellular region (GO:0005576), endomembrane system (GO:0012505), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cell differentiation	1
generation of neurons	1
neuron differentiation	1
positive regulation of cell differentiation	1
regulation of neuron differentiation	1
system development	1
lipid binding	1
tetrapyrrole binding	1
binding	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

442 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CYB5D2	CYB5A	P00167	718
CYB5D2	CYB5B	O43169	659
CYB5D2	PAQR5	Q9NXK6	609
CYB5D2	PAQR6	Q6TCH4	605
CYB5D2	ANAPC16	Q96DE5	561
CYB5D2	KIAA1210	Q9ULL0	554
CYB5D2	PAQR9	Q6ZVX9	535
CYB5D2	PAQR8	Q8TEZ7	531
CYB5D2	PAQR7	Q86WK9	496
CYB5D2	ZNF714	Q96N38	462
CYB5D2	PGR	P06401	460
CYB5D2	FBLIM1	Q8WUP2	460
CYB5D2	DNASE1	P24855	447
CYB5D2	ICA1L	Q8NDH6	445
CYB5D2	CYP20A1	Q6UW02	444

IntAct

43 interactions, top by confidence:

A	B	Type	Score
TNFSF8	TOR1B	psi-mi:“MI:0914”(association)	0.640
SLC39A5	FAM171A2	psi-mi:“MI:0914”(association)	0.640
HCK	CYB5D2	psi-mi:“MI:0915”(physical association)	0.560
TMEM11	CYB5D2	psi-mi:“MI:0915”(physical association)	0.560
POMK	TMEM120B	psi-mi:“MI:0914”(association)	0.530
CYB5D2	ABLIM1	psi-mi:“MI:0914”(association)	0.530
ADAM21	PLXNA2	psi-mi:“MI:0914”(association)	0.530
TNFSF8	LGALS8	psi-mi:“MI:0914”(association)	0.530
CYB5D2	SUN1	psi-mi:“MI:0914”(association)	0.530
CYB5D2	SMARCB1	psi-mi:“MI:0915”(physical association)	0.370
CYB5D2	CBX6	psi-mi:“MI:0914”(association)	0.350
TNFSF8	NME4	psi-mi:“MI:0914”(association)	0.350
PTPRN	SGSM2	psi-mi:“MI:0914”(association)	0.350
NAXD	KDELR3	psi-mi:“MI:0914”(association)	0.350
POMK	ESYT2	psi-mi:“MI:0914”(association)	0.350
HFE	PODXL	psi-mi:“MI:0914”(association)	0.350
NAXD	CANX	psi-mi:“MI:0914”(association)	0.350
APOM	ESYT2	psi-mi:“MI:0914”(association)	0.350
HLA-G	TMEM131L	psi-mi:“MI:0914”(association)	0.350
BTNL2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
KLRD1	TMEM131L	psi-mi:“MI:0914”(association)	0.350
HLA-DRB1	TMEM131L	psi-mi:“MI:0914”(association)	0.350
ASIC4	TMEM131L	psi-mi:“MI:0914”(association)	0.350
LDLRAD1	ZNF316	psi-mi:“MI:0914”(association)	0.350
PTPRN	KCNK1	psi-mi:“MI:0914”(association)	0.350

BioGRID (54): CYB5D2 (Affinity Capture-MS), NPTX2 (Affinity Capture-MS), AGTRAP (Affinity Capture-MS), PTX3 (Affinity Capture-MS), ABLIM1 (Affinity Capture-MS), NPTXR (Affinity Capture-MS), GRIPAP1 (Affinity Capture-MS), SLC30A5 (Affinity Capture-MS), CYB5D2 (Affinity Capture-MS), POLDIP3 (Affinity Capture-MS), KLHL42 (Affinity Capture-MS), CYB5D2 (Affinity Capture-MS), NPTX1 (Affinity Capture-MS), CYB5D2 (Affinity Capture-MS), CYB5D2 (Affinity Capture-MS)

ESM2 similar proteins: D3ZU57, O08600, O09127, O15197, O19179, O43323, O88941, P08466, P0C0K6, P21709, P23377, P26640, P28339, P28340, P29322, P38447, P51840, P52785, P54760, P54761, P55203, P81203, P81204, Q00653, Q02846, Q08DH8, Q0IH72, Q10480, Q13724, Q14249, Q1HG60, Q2KIF8, Q3U6U5, Q502K1, Q60HD0, Q61488, Q69ZQ1, Q6NSJ0, Q6P1J0, Q80SX8

Diamond homologs: A2CES0, O00264, O13995, O15173, O55022, P70580, Q12091, Q17QC0, Q1JQA5, Q28FI8, Q29HF1, Q2HIW2, Q5RED0, Q5SSH8, Q5XIU9, Q5ZKN2, Q60YT6, Q6AY62, Q6IUR5, Q80UU9, Q8WUJ1, Q95250, Q9CQ45, Q9FVZ7, Q9FVZ9, Q9M2Z4, Q9SK39, Q9UMX5, Q9W376, Q9XFM6, Q9XXA7, Q7YZW5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3782 predictions. Top by Δscore:

Variant	Effect	Δscore
17:4149885:TTCCA:T	acceptor_loss	1.0000
17:4149886:TCCAG:T	acceptor_loss	1.0000
17:4149888:CA:C	acceptor_loss	1.0000
17:4149889:A:AG	acceptor_gain	1.0000
17:4149890:G:GG	acceptor_gain	1.0000
17:4149890:GGCC:G	acceptor_gain	1.0000
17:4150028:GTTG:G	donor_gain	1.0000
17:4150031:GGTA:G	donor_loss	1.0000
17:4150032:G:GC	donor_loss	1.0000
17:4150032:G:GG	donor_gain	1.0000
17:4151033:G:GT	donor_gain	1.0000
17:4154669:CACA:C	acceptor_loss	1.0000
17:4154670:ACAG:A	acceptor_gain	1.0000
17:4154671:CAGGG:C	acceptor_gain	1.0000
17:4154672:A:AG	acceptor_gain	1.0000
17:4154672:A:C	acceptor_loss	1.0000
17:4154672:AG:A	acceptor_gain	1.0000
17:4154672:AGG:A	acceptor_gain	1.0000
17:4154672:AGGGA:A	acceptor_gain	1.0000
17:4154673:G:A	acceptor_loss	1.0000
17:4154673:G:GG	acceptor_gain	1.0000
17:4154673:GG:G	acceptor_gain	1.0000
17:4154673:GGG:G	acceptor_gain	1.0000
17:4154673:GGGA:G	acceptor_gain	1.0000
17:4154673:GGGAG:G	acceptor_gain	1.0000
17:4169191:GTCTT:G	donor_loss	1.0000
17:4169192:TCTTA:T	donor_loss	1.0000
17:4169193:CTTAC:C	donor_loss	1.0000
17:4169194:TTAC:T	donor_loss	1.0000
17:4169195:TACCA:T	donor_loss	1.0000

AlphaMissense

1688 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:4154691:T:C	F137L	0.982
17:4154693:C:A	F137L	0.982
17:4154693:C:G	F137L	0.982
17:4154847:T:A	C189S	0.979
17:4154848:G:C	C189S	0.979
17:4149903:C:T	S88F	0.976
17:4149896:G:C	D86H	0.973
17:4156902:G:C	R205S	0.970
17:4156902:G:T	R205S	0.970
17:4149903:C:A	S88Y	0.969
17:4154805:T:A	C175S	0.969
17:4154806:G:C	C175S	0.969
17:4156942:T:A	C219S	0.968
17:4156943:G:C	C219S	0.968
17:4154806:G:A	C175Y	0.967
17:4156887:G:C	W200C	0.965
17:4156887:G:T	W200C	0.965
17:4149891:G:A	G84D	0.964
17:4156901:G:C	R205T	0.964
17:4143937:G:T	G61V	0.963
17:4156942:T:C	C219R	0.956
17:4154847:T:C	C189R	0.955
17:4149911:T:C	F91L	0.954
17:4149913:C:A	F91L	0.954
17:4149913:C:G	F91L	0.954
17:4154807:C:G	C175W	0.954
17:4149997:G:C	W119C	0.951
17:4149997:G:T	W119C	0.951
17:4150004:T:C	F122L	0.951
17:4150006:C:A	F122L	0.951

dbSNP variants (sampled 300 via entrez): RS1000365433 (17:4157897 C>A,T), RS1000396584 (17:4158081 C>G,T), RS1000496539 (17:4151779 C>A,T), RS1000627352 (17:4146415 G>A), RS1000784917 (17:4141543 G>A), RS1000885432 (17:4151124 C>G), RS1000972803 (17:4152151 T>C), RS1000996241 (17:4144931 C>T), RS1001056745 (17:4156945 G>GT), RS1001214197 (17:4141795 T>G), RS1001367392 (17:4156145 G>A), RS1001399961 (17:4156458 C>A), RS1001536978 (17:4148207 A>G), RS1001634298 (17:4145047 A>T), RS1001652204 (17:4143219 A>C)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002188_5	Functional impairment in major depressive disorder, bipolar disorder and schizophrenia	5.000000e-06
GCST006585_1201	Blood protein levels	2.000000e-13
GCST010002_118	Refractive error	6.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005412	functional impairment measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
bisphenol A	increases expression, affects cotreatment	2
Arsenic	decreases expression, increases abundance, affects cotreatment	2
Estradiol	affects cotreatment, decreases expression	2
Hydrogen Peroxide	affects expression	2
Cyclosporine	decreases expression	2
Cadmium Chloride	increases expression	2
GSK-J4	decreases expression	1
afuresertib	increases expression	1
bisphenol F	affects cotreatment, increases expression	1
urushiol	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
ferrous chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Carbamazepine	affects expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Silicon Dioxide	decreases expression	1

Clinical trials (associated diseases)

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