HDDC2

Summary

HDDC2 (HD domain containing 2, HGNC:21078) is a protein-coding gene on chromosome 6q22.31, encoding 5’-deoxynucleotidase HDDC2 (Q7Z4H3). Catalyzes the dephosphorylation of the nucleoside 5’-monophosphates deoxyadenosine monophosphate (dAMP), deoxycytidine monophosphate (dCMP), deoxyguanosine monophosphate (dGMP) and deoxythymidine monophosphate (dTMP).

Predicted to enable 5’-deoxynucleotidase activity.

Source: NCBI Gene 51020 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 49 total
• MANE Select transcript: NM_016063

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21078
Approved symbol	HDDC2
Name	HD domain containing 2
Location	6q22.31
Locus type	gene with protein product
Status	Approved
Aliases	CGI-130, dJ167O5.2
Ensembl gene	ENSG00000111906
Ensembl biotype	protein_coding
Entrez	51020

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 7 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000318787, ENST00000398153, ENST00000608284, ENST00000608295, ENST00000608456, ENST00000608461, ENST00000608532, ENST00000609021, ENST00000609477, ENST00000609574, ENST00000938866, ENST00000938867, ENST00000938868, ENST00000938869

RefSeq mRNA: 1 — MANE Select: NM_016063 NM_016063

CCDS: CCDS43503

Canonical transcript exons

ENST00000398153 — 6 exons

Exon	Start	End
ENSE00000762935	125300538	125300659
ENSE00001531875	125298714	125298816
ENSE00003706721	125301849	125301967
ENSE00003707297	125277102	125277240
ENSE00003710267	125275350	125276243
ENSE00003711048	125292841	125292909

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.08.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.0138 / max 690.2297, expressed in 1810 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
75403	29.8373	1809
75401	0.8847	629
75402	0.2918	133

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pons	UBERON:0000988	99.08	gold quality
amygdala	UBERON:0001876	98.67	gold quality
superior vestibular nucleus	UBERON:0007227	98.63	gold quality
substantia nigra	UBERON:0002038	98.46	gold quality
midbrain	UBERON:0001891	98.43	gold quality
hypothalamus	UBERON:0001898	98.34	gold quality
globus pallidus	UBERON:0001875	98.21	gold quality
medial globus pallidus	UBERON:0002477	98.21	gold quality
putamen	UBERON:0001874	98.13	gold quality
substantia nigra pars compacta	UBERON:0001965	98.08	gold quality
lateral globus pallidus	UBERON:0002476	98.08	gold quality
nucleus accumbens	UBERON:0001882	98.04	gold quality
ventral tegmental area	UBERON:0002691	97.99	gold quality
medulla oblongata	UBERON:0001896	97.98	gold quality
Ammon’s horn	UBERON:0001954	97.95	gold quality
prefrontal cortex	UBERON:0000451	97.92	gold quality
caudate nucleus	UBERON:0001873	97.87	gold quality
cranial nerve II	UBERON:0000941	97.84	gold quality
cingulate cortex	UBERON:0003027	97.76	gold quality
anterior cingulate cortex	UBERON:0009835	97.70	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.66	gold quality
choroid plexus epithelium	UBERON:0003911	97.64	gold quality
biceps brachii	UBERON:0001507	97.62	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.58	gold quality
right frontal lobe	UBERON:0002810	97.54	gold quality
spinal cord	UBERON:0002240	97.52	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.51	gold quality
subthalamic nucleus	UBERON:0001906	97.48	gold quality
parotid gland	UBERON:0001831	97.43	gold quality
pigmented layer of retina	UBERON:0001782	97.39	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-8271	yes	8.43
E-GEOD-106540	no	349.72
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

47 targeting HDDC2, 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-3162-3P	100.00	65.37	363
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-3682-3P	99.58	67.63	865
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-6083	99.47	68.73	2393
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-4427	99.34	70.33	1854
HSA-MIR-520F-5P	99.34	70.40	1632
HSA-MIR-190B-3P	99.33	68.29	1382
HSA-MIR-2116-5P	99.32	69.34	1273
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-6815-3P	99.13	68.98	1530

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hddc2	ENSDARG00000034957
mus_musculus	Hddc2	ENSMUSG00000000295
rattus_norvegicus	Hddc2	ENSRNOG00000021442
drosophila_melanogaster	CG11050	FBGN0031836
caenorhabditis_elegans		WBGENE00018481

Protein

Protein identifiers

5’-deoxynucleotidase HDDC2 — Q7Z4H3 (reviewed: Q7Z4H3)

Alternative names: HD domain-containing protein 2, Hepatitis C virus NS5A-transactivated protein 2

All UniProt accessions (4): Q7Z4H3, A0A140VJK7, V9GYS5, V9GZ04

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the dephosphorylation of the nucleoside 5’-monophosphates deoxyadenosine monophosphate (dAMP), deoxycytidine monophosphate (dCMP), deoxyguanosine monophosphate (dGMP) and deoxythymidine monophosphate (dTMP).

Subunit / interactions. Homodimer.

Cofactor. Binds 2 divalent metal cations (Ref.9). Shows activity with Mn(2+), Co(2+) and Mg(2+) but shows no activity with Zn(2+).

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the HDDC2 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q7Z4H3-1	1	yes
Q7Z4H3-2	2
Q7Z4H3-3	3

RefSeq proteins (1): NP_057147* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003607	HD/PDEase_dom	Domain
IPR006674	HD_domain	Domain
IPR039356	YfbR/HDDC2	Family

Pfam: PF13023

Catalyzed reactions (Rhea), 1 shown:

• a 2’-deoxyribonucleoside 5’-phosphate + H2O = a 2’-deoxyribonucleoside + phosphate (RHEA:36167)

UniProt features (35 total): helix 12, binding site 7, modified residue 4, splice variant 3, turn 3, sequence conflict 2, initiator methionine 1, chain 1, sequence variant 1, domain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4L1J	X-RAY DIFFRACTION	1.82
4DMB	X-RAY DIFFRACTION	1.9
4L7E	X-RAY DIFFRACTION	2.23
4L7W	X-RAY DIFFRACTION	2.31

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z4H3-F1	95.36	0.93

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 (7): 49; 77; 78; 81; 86; 87; 143

Post-translational modifications (4): 2, 3, 5, 204

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 175 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, MORF_DNMT1, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, MORF_BUB1, BASSO_B_LYMPHOCYTE_NETWORK, MORF_RRM1, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, MORF_HDAC2, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, MORF_BUB3, MORF_RFC4, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_13

GO Biological Process (1): deoxyribonucleoside monophosphate catabolic process (GO:0009159)

GO Molecular Function (4): 5’-deoxynucleotidase activity (GO:0002953), metal ion binding (GO:0046872), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nucleoside monophosphate catabolic process	1
5’-nucleotidase activity	1
cation binding	1
binding	1
catalytic activity	1

Protein interactions and networks

STRING

882 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HDDC2	ZNF316	A6NFI3	462
HDDC2	C2orf68	Q2NKX9	447
HDDC2	DRICH1	Q6PGQ1	447
HDDC2	OR51F1	A6NGY5	447
HDDC2	OR8B8	Q15620	435
HDDC2	DCUN1D3	Q8IWE4	404
HDDC2	CFAP95	Q5VTT2	400
HDDC2	METTL15	A6NJ78	394
HDDC2	DPCD	Q9BVM2	379
HDDC2	SLC25A3	Q00325	374
HDDC2	OR2B6	P58173	370
HDDC2	MVB12A	Q96EY5	368
HDDC2	PCED1B	Q96HM7	348
HDDC2	CCDC42	Q96M95	329
HDDC2	NDOR1	Q9UHB4	322
HDDC2	THUMPD1	Q9NXG2	322

IntAct

19 interactions, top by confidence:

A	B	Type	Score
COQ5	COQ9	psi-mi:“MI:0914”(association)	0.590
LCN2	HDDC2	psi-mi:“MI:0915”(physical association)	0.560
POMC	HDDC2	psi-mi:“MI:0915”(physical association)	0.560
HDDC2	IKBKG	psi-mi:“MI:0915”(physical association)	0.560
HDDC2		psi-mi:“MI:0915”(physical association)	0.500
PRNP	WDR91	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
pipB2	PSMD12	psi-mi:“MI:0914”(association)	0.350
MTUS2	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
	PLOD2	psi-mi:“MI:0914”(association)	0.350
HDDC2	IKBKG	psi-mi:“MI:0915”(physical association)	0.000
HDDC2	LCN2	psi-mi:“MI:0915”(physical association)	0.000
HDDC2	POMC	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (23): HDDC2 (Co-fractionation), HDDC2 (Affinity Capture-MS), HDDC2 (Affinity Capture-MS), HDDC2 (Affinity Capture-MS), HDDC2 (Affinity Capture-MS), HDDC2 (Affinity Capture-MS), HDDC2 (Affinity Capture-RNA), POMC (Two-hybrid), LCN2 (Two-hybrid), IKBKG (Two-hybrid), HDDC2 (Affinity Capture-MS), HDDC2 (Affinity Capture-MS), HDDC2 (Affinity Capture-MS), HDDC2 (Affinity Capture-MS), HDDC2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0E3D8M9, A0A1D8PH78, A0A1V0QSA8, A0A2L0VXR5, A0A2V5HP22, A0A343W970, A0A3S5XFG0, A0A6S6QJ62, A0A858E4Y6, A0A858E4Y8, A0A858E6N7, A0A858E7G0, A0A858E7J4, A0A858E899, A0A858EAD5, B0D6H2, B4JSP3, B4YA15, C9SE96, D7PHZ5, E9F5E9, F9WWF1, F9XLC1, H1VQB1, J7FIX8, O14230, O59703, P08524, P0C565, P0CM22, P0CM23, P49349, P9WER5, P9WEW8, P9WEX3, P9WEX9, Q01637, Q12051, Q3SXD3, Q4WEB8

Diamond homologs: P38331, P53144, P87242, Q0P565, Q1LUI2, Q3SXD3, Q54FK1, Q66L17, Q7Z4H3, B2VIV0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	32
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2453 predictions. Top by Δscore:

Variant	Effect	Δscore
6:125220064:A:AG	acceptor_gain	1.0000
6:125220069:T:A	acceptor_gain	1.0000
6:125220167:G:GT	donor_gain	1.0000
6:125220190:TCAG:T	donor_loss	1.0000
6:125220191:CAGGT:C	donor_loss	1.0000
6:125220193:GGTA:G	donor_loss	1.0000
6:125220194:G:C	donor_loss	1.0000
6:125220195:T:G	donor_loss	1.0000
6:125229108:C:CA	acceptor_gain	1.0000
6:125229114:GTA:G	acceptor_loss	1.0000
6:125229115:TAGC:T	acceptor_loss	1.0000
6:125229116:A:AG	acceptor_gain	1.0000
6:125229116:A:G	acceptor_loss	1.0000
6:125229117:G:GA	acceptor_gain	1.0000
6:125229117:G:T	acceptor_loss	1.0000
6:125229117:GCTA:G	acceptor_gain	1.0000
6:125229262:ACTGC:A	donor_gain	1.0000
6:125229263:CTGC:C	donor_gain	1.0000
6:125229264:TGC:T	donor_gain	1.0000
6:125229265:GC:G	donor_gain	1.0000
6:125229265:GCG:G	donor_gain	1.0000
6:125229266:CGT:C	donor_loss	1.0000
6:125229267:G:GG	donor_gain	1.0000
6:125229267:G:T	donor_loss	1.0000
6:125229268:TA:T	donor_loss	1.0000
6:125229269:AA:A	donor_loss	1.0000
6:125248280:A:AG	acceptor_gain	1.0000
6:125248281:G:GA	acceptor_gain	1.0000
6:125248281:GC:G	acceptor_gain	1.0000
6:125248281:GCTA:G	acceptor_gain	1.0000

AlphaMissense

1342 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:125298790:T:A	D78V	0.999
6:125298790:T:G	D78A	0.999
6:125298765:G:C	D86E	0.998
6:125298765:G:T	D86E	0.998
6:125298766:T:A	D86V	0.998
6:125298766:T:C	D86G	0.998
6:125298766:T:G	D86A	0.998
6:125298794:G:C	H77D	0.998
6:125300639:C:A	W35C	0.998
6:125300639:C:G	W35C	0.998
6:125300641:A:G	W35R	0.998
6:125300641:A:T	W35R	0.998
6:125277118:G:C	F167L	0.997
6:125277118:G:T	F167L	0.997
6:125277120:A:G	F167L	0.997
6:125298767:C:G	D86H	0.997
6:125300597:G:C	H49Q	0.997
6:125300597:G:T	H49Q	0.997
6:125300599:G:C	H49D	0.997
6:125277168:C:G	A151P	0.996
6:125298780:T:A	E81D	0.996
6:125298780:T:G	E81D	0.996
6:125298790:T:C	D78G	0.996
6:125277191:T:A	D143V	0.995
6:125298717:T:A	E102D	0.995
6:125298717:T:G	E102D	0.995
6:125298791:C:G	D78H	0.995
6:125298792:A:C	H77Q	0.995
6:125298792:A:T	H77Q	0.995
6:125300589:C:G	R52P	0.995

dbSNP variants (sampled 300 via entrez): RS1000135485 (6:125288666 C>T), RS1000177464 (6:125295010 A>G), RS1000356610 (6:125292112 G>C), RS1000424650 (6:125285582 G>A,C), RS1000437611 (6:125282688 G>A), RS1000556729 (6:125296280 G>A), RS1000737752 (6:125290551 C>T), RS1000893319 (6:125282865 A>G), RS1000913388 (6:125301320 T>A), RS1000934118 (6:125278581 C>T), RS1001108811 (6:125296058 T>C), RS1001387028 (6:125283573 G>A), RS1001420582 (6:125301769 C>G,T), RS1001564783 (6:125292386 C>G), RS1001585848 (6:125296330 G>T)

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

8 associations (top):

Study	Trait	p-value
GCST003542_126	Night sleep phenotypes	9.000000e-06
GCST003542_18	Night sleep phenotypes	6.000000e-06
GCST004284_3	Midgestational circulating levels of PCBs (fetal genetic effect)	3.000000e-07
GCST010796_1872	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST90002383_454	Hematocrit	2.000000e-17
GCST90002384_63	Hemoglobin	3.000000e-17
GCST90002403_173	Red blood cell count	1.000000e-19
GCST90086158_9	Brugada syndrome	1.000000e-08

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0007042	polychlorinated biphenyls measurement
EFO:0007959	fetal genotype effect measurement
EFO:0007964	gestational serum measurement
EFO:0004327	electrocardiography
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0004305	erythrocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, increases expression	4
sodium arsenite	decreases expression, increases abundance, increases expression	3
Air Pollutants	increases abundance, increases expression, decreases expression, affects cotreatment	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
Acetaminophen	decreases expression	2
Arsenic	increases abundance, increases expression, affects methylation	2
Tretinoin	decreases expression	2
Particulate Matter	increases expression, decreases expression, increases abundance	2
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
bisphenol A	decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
chloropicrin	increases expression	1
monomethylarsonous acid	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, increases expression	1
Vorinostat	increases expression	1
Acrolein	increases expression, increases abundance, affects cotreatment	1
Caffeine	increases phosphorylation	1
Calcitriol	increases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Hydrogen Peroxide	increases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Nicotine	increases expression	1
Ozone	affects cotreatment, increases expression, increases abundance	1
Phthalic Acids	decreases methylation	1

Clinical trials (associated diseases)

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