HDDC3

Summary

HDDC3 (HD domain containing 3, HGNC:30522) is a protein-coding gene on chromosome 15q26.1, encoding Guanosine-3’,5’-bis(diphosphate) 3’-pyrophosphohydrolase MESH1 (Q8N4P3). ppGpp hydrolyzing enzyme involved in starvation response.

Predicted to enable guanosine-3’,5’-bis(diphosphate) 3’-diphosphatase activity.

Source: NCBI Gene 374659 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 27 total
• MANE Select transcript: NM_001286451

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30522
Approved symbol	HDDC3
Name	HD domain containing 3
Location	15q26.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC45386, MESH1, MYNRL15
Ensembl gene	ENSG00000184508
Ensembl biotype	protein_coding
Entrez	374659

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 5 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000330334, ENST00000394272, ENST00000438890, ENST00000448987, ENST00000494993, ENST00000559834, ENST00000559898, ENST00000561036, ENST00000643068, ENST00000646620

RefSeq mRNA: 2 — MANE Select: NM_001286451 NM_001286451, NM_198527

CCDS: CCDS10366, CCDS66866

Canonical transcript exons

ENST00000394272 — 4 exons

Exon	Start	End
ENSE00001292208	90932055	90932110
ENSE00001695560	90929968	90931405
ENSE00001812914	90932429	90932549
ENSE00003468484	90931704	90931944

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 89.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.2580 / max 95.2692, expressed in 1792 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
151585	12.1940	1787
151586	0.5585	328
151584	0.5055	247

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	89.99	gold quality
body of pancreas	UBERON:0001150	89.07	gold quality
right adrenal gland	UBERON:0001233	88.82	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.75	gold quality
mucosa of transverse colon	UBERON:0004991	88.43	gold quality
right adrenal gland cortex	UBERON:0035827	88.21	gold quality
prefrontal cortex	UBERON:0000451	88.17	gold quality
left adrenal gland cortex	UBERON:0035825	88.07	gold quality
left adrenal gland	UBERON:0001234	87.75	gold quality
adrenal cortex	UBERON:0001235	87.36	gold quality
pancreas	UBERON:0001264	87.19	gold quality
granulocyte	CL:0000094	86.83	gold quality
anterior cingulate cortex	UBERON:0009835	86.29	gold quality
Brodmann (1909) area 9	UBERON:0013540	86.29	gold quality
adrenal gland	UBERON:0002369	86.24	gold quality
apex of heart	UBERON:0002098	86.06	gold quality
right lobe of liver	UBERON:0001114	86.04	gold quality
right frontal lobe	UBERON:0002810	85.85	gold quality
islet of Langerhans	UBERON:0000006	85.82	gold quality
putamen	UBERON:0001874	85.54	gold quality
caudate nucleus	UBERON:0001873	85.03	gold quality
frontal cortex	UBERON:0001870	84.95	gold quality
nucleus accumbens	UBERON:0001882	84.77	gold quality
neocortex	UBERON:0001950	84.71	gold quality
amygdala	UBERON:0001876	84.45	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	84.39	gold quality
adult mammalian kidney	UBERON:0000082	84.33	gold quality
spleen	UBERON:0002106	84.33	gold quality
ileal mucosa	UBERON:0000331	84.21	silver quality
right uterine tube	UBERON:0001302	83.89	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.72

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

49 targeting HDDC3, 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-5196-5P	100.00	67.98	2761
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-216A-5P	99.50	68.02	1288
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-6878-3P	99.24	64.23	920
HSA-MIR-6744-3P	99.22	64.41	972
HSA-MIR-422A	99.18	65.83	550
HSA-MIR-4757-5P	99.12	64.51	981
HSA-MIR-877-3P	99.09	68.10	1637
HSA-MIR-4711-5P	98.89	68.00	965
HSA-MIR-3922-5P	98.77	66.53	1059
HSA-MIR-423-5P	98.69	67.48	1522
HSA-MIR-3184-5P	98.56	67.13	1491
HSA-MIR-378A-3P	98.43	66.10	548
HSA-MIR-378B	98.43	65.36	573

Literature-anchored findings (GeneRIF, showing 2)

• Mesh1, encoded by HDDC3 in humans, contains an active site for ppGpp hydrolysis and a conserved His-Asp-box motif for Mn(2+) binding. It catalyzes hydrolysis of ppGpp both in vitro and in vivo. (PMID:20818390)
• MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis. (PMID:32462112)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hddc3	ENSDARG00000020473
mus_musculus	Hddc3	ENSMUSG00000030532
rattus_norvegicus	Hddc3	ENSRNOG00000012236
drosophila_melanogaster	Mesh1	FBGN0039650
caenorhabditis_elegans	ZK909.3	WBGENE00014148

Protein

Protein identifiers

Guanosine-3’,5’-bis(diphosphate) 3’-pyrophosphohydrolase MESH1 — Q8N4P3 (reviewed: Q8N4P3)

Alternative names: HD domain-containing protein 3, Metazoan SpoT homolog 1, Penta-phosphate guanosine-3’-pyrophosphohydrolase

All UniProt accessions (3): Q8N4P3, H0YKT9, H0YNP9

UniProt curated annotations — full annotation on UniProt →

Function. ppGpp hydrolyzing enzyme involved in starvation response.

Similarity. Belongs to the MESH1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8N4P3-1	1	yes
Q8N4P3-2	2

RefSeq proteins (2): NP_001273380, NP_940929 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003607	HD/PDEase_dom	Domain
IPR006674	HD_domain	Domain
IPR052194	MESH1	Family

Pfam: PF13328

Catalyzed reactions (Rhea), 1 shown:

• guanosine 3’,5’-bis(diphosphate) + H2O = GDP + diphosphate + H(+) (RHEA:14253)

UniProt features (30 total): helix 10, modified residue 4, binding site 4, mutagenesis site 3, splice variant 2, turn 2, active site 2, initiator methionine 1, chain 1, domain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3NR1	X-RAY DIFFRACTION	1.9
9CHY	X-RAY DIFFRACTION	1.9
5VXA	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N4P3-F1	97.97	0.99

Functional residue map

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

Catalytic / active sites (2): 65 (nucleophile); 66 (nucleophile)

Ligand- & substrate-binding residues (4): 35; 61; 62; 122

Post-translational modifications (4): 25, 97, 123, 2

Mutagenesis-validated functional residues (3):

Position	Phenotype
24	abrogates ppgpp hydrolase activity.
65	abrogates ppgpp hydrolase activity.
66	reduces ppgpp hydrolase activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 88 (showing top): RNGTGGGC_UNKNOWN, TGCTGAY_UNKNOWN, COATES_MACROPHAGE_M1_VS_M2_UP, RYTTCCTG_ETS2_B, TGGAAA_NFAT_Q4_01, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_ESTER_BONDS, GOMF_PHOSPHORIC_ESTER_HYDROLASE_ACTIVITY, MZF1_01, chr15q26, COLINA_TARGETS_OF_4EBP1_AND_4EBP2, VANDESLUIS_COMMD1_TARGETS_GROUP_3_DN, GOBERT_OLIGODENDROCYTE_DIFFERENTIATION_DN, WAKABAYASHI_ADIPOGENESIS_PPARG_BOUND_8D, CREB3L4_TARGET_GENES, FOXE1_TARGET_GENES

GO Biological Process (0):

GO Molecular Function (4): guanosine-3’,5’-bis(diphosphate) 3’-diphosphatase activity (GO:0008893), 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
diphosphoric monoester hydrolase activity	1
cation binding	1
binding	1
catalytic activity	1

Protein interactions and networks

STRING

2431 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HDDC3	TARS3	A2RTX5	511
HDDC3	TARS2	Q9BW92	508
HDDC3	TARS1	P26639	498
HDDC3	CARS1	P49589	479
HDDC3	CARS2	Q9HA77	474
HDDC3	SCAMP2	O15127	463
HDDC3	MTIF2	P46199	458
HDDC3	SLC49A4	Q96SL1	447
HDDC3	NADK	O95544	434
HDDC3	ST3GAL3	Q11203	433
HDDC3	MRPL58	Q14197	417
HDDC3	EIF5B	O60841	414
HDDC3	MTRF1L	Q9UGC7	399
HDDC3	MTRF1	O75570	399
HDDC3	PDF	Q9HBH1	397

IntAct

45 interactions, top by confidence:

A	B	Type	Score
CCDC172	HDDC3	psi-mi:“MI:0915”(physical association)	0.670
NMI	HDDC3	psi-mi:“MI:0915”(physical association)	0.670
TNIP1	HDDC3	psi-mi:“MI:0915”(physical association)	0.670
HDDC3	NMI	psi-mi:“MI:0915”(physical association)	0.670
HDDC3	CCDC172	psi-mi:“MI:0915”(physical association)	0.670
GOLGA8F	HDDC3	psi-mi:“MI:0915”(physical association)	0.560
HDDC3	GOLGA8DP	psi-mi:“MI:0915”(physical association)	0.560
GKAP1	HDDC3	psi-mi:“MI:0915”(physical association)	0.560
HDDC3	TPM3	psi-mi:“MI:0915”(physical association)	0.560
EXOC5	HDDC3	psi-mi:“MI:0915”(physical association)	0.560
CEP57L1	HDDC3	psi-mi:“MI:0915”(physical association)	0.560
HDDC3	GOLGA8F	psi-mi:“MI:0915”(physical association)	0.560
HDDC3	GKAP1	psi-mi:“MI:0915”(physical association)	0.560
HDDC3	CEP57L1	psi-mi:“MI:0915”(physical association)	0.560
HDDC3	EXOC5	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (61): HDDC3 (Two-hybrid), HDDC3 (Two-hybrid), HDDC3 (Two-hybrid), HDDC3 (Two-hybrid), HDDC3 (Two-hybrid), HDDC3 (Two-hybrid), HDDC3 (Two-hybrid), GOLGA8EP (Two-hybrid), GOLGA8F (Two-hybrid), HDDC3 (Affinity Capture-MS), HDDC3 (Two-hybrid), ATP6V1C1 (Co-fractionation), HDDC3 (Co-fractionation), HDDC3 (Affinity Capture-MS), HDDC3 (Two-hybrid)

ESM2 similar proteins: A1ADE0, A4WEI8, A7ZPA5, A8A2G0, A9MJ94, A9N4B8, B1IXQ1, B1LLP5, B1X903, B2TW72, B4SZ04, B4TBJ9, B4TQ66, B5BCL4, B5EZL4, B5FPH3, B5R313, B5RCF7, B5YXT1, B6I7L3, B7LBE5, B7M5X0, B7MG55, B7MXX0, B7N5Q3, B7NNX0, B7UFU9, C0Q034, C4ZVI4, P29941, P42506, P76491, Q0T2J6, Q0TFF5, Q1R9C4, Q28C98, Q2Y681, Q3V7K9, Q3YZR9, Q568P1

Diamond homologs: A5VPI9, F4JHA2, O51216, O52177, O54408, O67012, O85709, O87331, P0A0E9, P0A0F0, P0AG20, P0AG21, P0AG22, P0AG23, P0AG24, P0AG25, P0AG26, P0DKG8, P29941, P39583, P43811, P47520, P52560, P55133, P66015, P74007, P75386, P9WHG8, P9WHG9, Q28C98, Q2YN11, Q49640, Q54089, Q568P1, Q57E90, Q5HNR8, Q67UU0, Q6ATB4, Q6G8T5, Q6GG70

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

499 predictions. Top by Δscore:

Variant	Effect	Δscore
15:90931702:AC:A	donor_gain	1.0000
15:90931703:CC:C	donor_gain	1.0000
15:90931703:CCCT:C	donor_gain	1.0000
15:90931941:CCGC:C	acceptor_gain	1.0000
15:90931942:CGCC:C	acceptor_gain	1.0000
15:90932050:GTTAC:G	donor_loss	1.0000
15:90932051:TTACC:T	donor_loss	1.0000
15:90932052:TAC:T	donor_loss	1.0000
15:90932053:ACCTG:A	donor_loss	1.0000
15:90932054:C:CA	donor_loss	1.0000
15:90932468:T:TA	donor_gain	1.0000
15:90931697:AGCGT:A	donor_loss	0.9900
15:90931698:GCGT:G	donor_loss	0.9900
15:90931699:CGTA:C	donor_loss	0.9900
15:90931700:GTA:G	donor_loss	0.9900
15:90931701:TACC:T	donor_loss	0.9900
15:90931702:A:AC	donor_gain	0.9900
15:90931703:C:CC	donor_gain	0.9900
15:90931758:TC:T	donor_gain	0.9900
15:90931942:CGC:C	acceptor_gain	0.9900
15:90931945:C:CC	acceptor_gain	0.9900
15:90931945:CT:C	acceptor_loss	0.9900
15:90931946:T:A	acceptor_loss	0.9900
15:90932385:C:CT	donor_gain	0.9900
15:90932386:C:CT	donor_gain	0.9900
15:90932464:T:TA	donor_gain	0.9900
15:90931401:CCATC:C	acceptor_gain	0.9800
15:90931402:CATCC:C	acceptor_gain	0.9800
15:90932374:C:A	donor_gain	0.9800
15:90931728:C:A	donor_gain	0.9700

AlphaMissense

1143 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:90931928:T:A	D62V	0.998
15:90931927:G:C	D62E	0.997
15:90931927:G:T	D62E	0.997
15:90931928:T:G	D62A	0.997
15:90932438:G:C	H35D	0.996
15:90931928:T:C	D62G	0.995
15:90931932:G:C	H61D	0.995
15:90932436:G:C	H35Q	0.995
15:90932436:G:T	H35Q	0.995
15:90931747:G:C	D122E	0.994
15:90931747:G:T	D122E	0.994
15:90931748:T:A	D122V	0.994
15:90931379:A:G	Y146H	0.993
15:90931735:A:C	N126K	0.992
15:90931735:A:T	N126K	0.992
15:90931748:T:G	D122A	0.991
15:90931751:G:T	A121E	0.991
15:90931879:A:C	F78L	0.991
15:90931879:A:T	F78L	0.991
15:90931881:A:G	F78L	0.991
15:90931929:C:G	D62H	0.991
15:90932437:T:C	H35R	0.991
15:90931733:A:G	L127P	0.990
15:90931737:T:C	N126D	0.990
15:90931749:C:G	D122H	0.990
15:90931810:C:A	K101N	0.990
15:90931810:C:G	K101N	0.990
15:90932438:G:T	H35N	0.990
15:90932486:G:C	H19D	0.990
15:90931915:G:C	D66E	0.989

dbSNP variants (sampled 300 via entrez): RS1001590636 (15:90930458 G>A), RS1002885222 (15:90931142 T>A,C), RS1003083414 (15:90933276 G>A), RS1004029773 (15:90932900 G>A,T), RS1005758079 (15:90934516 A>G), RS1006154540 (15:90929752 A>T), RS1006662851 (15:90930067 AT>A), RS1007057911 (15:90934324 C>A,T), RS1007329868 (15:90930140 A>T), RS1008060560 (15:90932932 C>A), RS1008111382 (15:90932694 G>A), RS1008841050 (15:90931208 T>C), RS1010086535 (15:90930076 C>G), RS1010225787 (15:90932411 C>T), RS1011005694 (15:90934399 C>G,T)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (1): breast ductal adenocarcinoma (MONDO:0005590)

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	2
Air Pollutants	increases abundance, increases expression, affects cotreatment	2
Cisplatin	affects expression, affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
bisphenol A	affects cotreatment, increases expression	1
sodium arsenate	decreases expression, increases abundance	1
cobaltous chloride	decreases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, increases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
ICG 001	increases expression	1
bisphenol S	affects cotreatment, increases expression	1
jinfukang	increases expression, affects cotreatment	1
Decitabine	affects expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, increases expression, increases abundance	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases methylation	1
Carbamazepine	affects expression	1
Coal	increases abundance, increases expression	1
Dexamethasone	increases expression, affects cotreatment	1
Diazinon	increases methylation	1
Estradiol	decreases expression, affects cotreatment	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Ozone	affects cotreatment, increases expression, increases abundance	1
Phthalic Acids	decreases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	EARLY_PHASE1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	EARLY_PHASE1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT01208974	Not specified	ACTIVE_NOT_RECRUITING	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery