HDHD2

Summary

HDHD2 (haloacid dehalogenase like hydrolase domain containing 2, HGNC:25364) is a protein-coding gene on chromosome 18q21.1, encoding Haloacid dehalogenase-like hydrolase domain-containing protein 2 (Q9H0R4).

Enables enzyme binding activity. Located in extracellular exosome.

Source: NCBI Gene 84064 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 47 total
• MANE Select transcript: NM_032124

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25364
Approved symbol	HDHD2
Name	haloacid dehalogenase like hydrolase domain containing 2
Location	18q21.1
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP564D1378
Ensembl gene	ENSG00000167220
Ensembl biotype	protein_coding
Entrez	84064

Gene structure

Transcript identifiers

Ensembl transcripts: 46 — 39 protein_coding, 3 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000300605, ENST00000586546, ENST00000587388, ENST00000587841, ENST00000588183, ENST00000588861, ENST00000588940, ENST00000590481, ENST00000590815, ENST00000591268, ENST00000591480, ENST00000591671, ENST00000592591, ENST00000592747, ENST00000851063, ENST00000884163, ENST00000884165, ENST00000884166, ENST00000884167, ENST00000884168, ENST00000884169, ENST00000884170, ENST00000884171, ENST00000884172, ENST00000884173, ENST00000884174, ENST00000884175, ENST00000884176, ENST00000884177, ENST00000884178, ENST00000927329, ENST00000927330, ENST00000927331, ENST00000927332, ENST00000927333, ENST00000927334, ENST00000927335, ENST00000927336, ENST00000964284, ENST00000964285, ENST00000964286, ENST00000964287, ENST00000964288, ENST00000964289, ENST00000964290, ENST00000964291

RefSeq mRNA: 2 — MANE Select: NM_032124 NM_001318765, NM_032124

CCDS: CCDS32829

Canonical transcript exons

ENST00000300605 — 7 exons

Exon	Start	End
ENSE00002853504	47107410	47108785
ENSE00003606246	47115132	47115348
ENSE00003610048	47134496	47134704
ENSE00003681413	47136339	47136449
ENSE00003690137	47112977	47113040
ENSE00003789674	47130244	47130328
ENSE00004283608	47150378	47150500

Expression profiles

Bgee: expression breadth ubiquitous, 140 present calls, max score 95.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.2959 / max 331.8308, expressed in 1813 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
171834	25.2959	1813

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
substantia nigra	UBERON:0002038	95.46	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.42	gold quality
prefrontal cortex	UBERON:0000451	95.15	gold quality
hypothalamus	UBERON:0001898	94.98	gold quality
amygdala	UBERON:0001876	94.86	gold quality
temporal lobe	UBERON:0001871	94.82	gold quality
superior frontal gyrus	UBERON:0002661	94.76	gold quality
cerebellar cortex	UBERON:0002129	94.73	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.73	gold quality
cerebellar hemisphere	UBERON:0002245	94.70	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.69	gold quality
cerebellum	UBERON:0002037	94.66	gold quality
cerebral cortex	UBERON:0000956	94.41	gold quality
primary visual cortex	UBERON:0002436	94.41	gold quality
anterior cingulate cortex	UBERON:0009835	94.38	gold quality
frontal cortex	UBERON:0001870	94.36	gold quality
telencephalon	UBERON:0001893	94.29	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.20	gold quality
caudate nucleus	UBERON:0001873	94.18	gold quality
ventricular zone	UBERON:0003053	94.17	gold quality
Ammon’s horn	UBERON:0001954	94.10	gold quality
brain	UBERON:0000955	94.07	gold quality
putamen	UBERON:0001874	93.99	gold quality
nucleus accumbens	UBERON:0001882	93.81	gold quality
islet of Langerhans	UBERON:0000006	93.61	gold quality
ganglionic eminence	UBERON:0004023	93.34	gold quality
embryo	UBERON:0000922	93.33	gold quality
right frontal lobe	UBERON:0002810	93.21	gold quality
right adrenal gland cortex	UBERON:0035827	93.19	gold quality
right adrenal gland	UBERON:0001233	92.92	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.50
E-CURD-112	no	3.67

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

115 targeting HDHD2, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-548BB-3P	99.86	70.58	4354

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hdhd2	ENSDARG00000024728
mus_musculus	Hdhd2	ENSMUSG00000025421
rattus_norvegicus	Ier3ip1	ENSRNOG00000043171
drosophila_melanogaster	CG17294	FBGN0032032
caenorhabditis_elegans		WBGENE00019522

Paralogs (3): LHPP (ENSG00000107902), PGP (ENSG00000184207), PDXP (ENSG00000241360)

Protein

Protein identifiers

Haloacid dehalogenase-like hydrolase domain-containing protein 2 — Q9H0R4 (reviewed: Q9H0R4)

All UniProt accessions (8): A0A1B0GXB1, Q9H0R4, K7EJQ8, K7EKX8, K7EMY7, K7EQD2, K7ER15, V9HW73

UniProt curated annotations — full annotation on UniProt →

Cofactor. Binds 1 Mg(2+) ion per subunit.

Similarity. Belongs to the HAD-like hydrolase superfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H0R4-1	1	yes
Q9H0R4-2	2

RefSeq proteins (2): NP_001305694, NP_115500* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006355	LHPP/HDHD2	Family
IPR006357	HAD-SF_hydro_IIA	Family
IPR023214	HAD_sf	Homologous_superfamily
IPR036412	HAD-like_sf	Homologous_superfamily

Pfam: PF13242, PF13344

UniProt features (41 total): strand 13, helix 12, binding site 6, turn 5, chain 1, coiled-coil region 1, sequence variant 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3HLT	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H0R4-F1	95.33	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 (6): 13–15; 13; 15; 46–47; 179; 204

Post-translational modifications (1): 50

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 107 (showing top): TATTATA_MIR374, ATGTTAA_MIR302C, MODULE_239, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, ATAACCT_MIR154, IVANOVA_HEMATOPOIESIS_EARLY_PROGENITOR, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_ESTER_BONDS, GOMF_PHOSPHORIC_ESTER_HYDROLASE_ACTIVITY, ATACTGT_MIR144, CAGTATT_MIR200B_MIR200C_MIR429, chr18q21, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_DN, BRUINS_UVC_RESPONSE_LATE, LEE_BMP2_TARGETS_DN, KRIEG_KDM3A_TARGETS_NOT_HYPOXIA

GO Biological Process (1): dephosphorylation (GO:0016311)

GO Molecular Function (4): phosphatase activity (GO:0016791), enzyme binding (GO:0019899), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (2): cytoplasm (GO:0005737), extracellular exosome (GO:0070062)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phosphate-containing compound metabolic process	1
phosphoric ester hydrolase activity	1
protein binding	1
cation binding	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1
extracellular vesicle	1

Protein interactions and networks

STRING

994 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HDHD2	IER3IP1	Q9Y5U9	555
HDHD2	KATNAL2	Q8IYT4	510
HDHD2	A6NLF2	A6NLF2	475
HDHD2	WDR70	Q9NW82	460
HDHD2	TMEM267	Q0VDI3	457
HDHD2	Q8NG57	Q8NG57	446
HDHD2	TTC38	Q5R3I4	443
HDHD2	ST8SIA5	O15466	432
HDHD2	LMBRD2	Q68DH5	428
HDHD2	Q3MI93	Q3MI93	419
HDHD2	HNRNPR	O43390	411
HDHD2	PHYKPL	Q8IUZ5	411
HDHD2	ABHD14B	Q96IU4	409
HDHD2	SKOR2	Q2VWA4	404
HDHD2	RAPGEF5	Q92565	388

IntAct

16 interactions, top by confidence:

A	B	Type	Score
UQCRB	COX7A2L	psi-mi:“MI:0914”(association)	0.640
MEOX2	HDHD2	psi-mi:“MI:0915”(physical association)	0.560
HDHD2	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
FSD1	UBFD1	psi-mi:“MI:0914”(association)	0.530
HDHD2	LHPP	psi-mi:“MI:0915”(physical association)	0.400
PRNP	CARNS1	psi-mi:“MI:0914”(association)	0.350
PRNP	WDR91	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
SPANXN4	UBA6	psi-mi:“MI:0914”(association)	0.350
ZNF512B	KPNA3	psi-mi:“MI:0914”(association)	0.350
BCAS2	ISY1-RAB43	psi-mi:“MI:0914”(association)	0.350

BioGRID (21): HDHD2 (Two-hybrid), LHPP (Affinity Capture-MS), HIST1H1D (Affinity Capture-MS), HDLBP (Affinity Capture-MS), HDHD2 (Affinity Capture-MS), HRAS (Affinity Capture-MS), HDHD2 (Affinity Capture-MS), HDHD2 (Affinity Capture-MS), HDHD2 (Affinity Capture-MS), HDHD2 (Affinity Capture-MS), LHPP (Affinity Capture-MS), HDHD2 (Affinity Capture-MS), HDHD2 (Affinity Capture-MS), HDHD2 (Affinity Capture-MS), HDHD2 (Affinity Capture-MS)

ESM2 similar proteins: A0A6N3IN21, A3KCL7, A4IFH5, A7MBC0, A7MBI7, D3ZDK7, D3ZDM7, E1BNQ4, P09367, P10950, P11172, P13439, P17256, P20132, P24298, P25409, P31754, P46597, P50053, P97328, Q02974, Q03426, Q0VCW4, Q1JPD3, Q3B8E3, Q3TY86, Q3ZKN0, Q5BJJ5, Q5E9T8, Q5M7T9, Q5R514, Q5R824, Q5RD71, Q5RFE6, Q6PCB7, Q6SKR2, Q80W22, Q8CHP8, Q8CIM3, Q8HZJ0

Diamond homologs: A5PLK2, Q0VD18, Q3B8E3, Q3UGR5, Q3ZCH9, Q5BJJ5, Q5I0D5, Q5R4B4, Q6AYR6, Q6ZT62, Q9D7I5, Q9H008, Q9H0R4, Q9V1B3, A0RKU8, A9VQ75, B7HEG2, B7IPS5, B7JFI8, C1EZE2, C3LED0, C3P0C8, F8D9F4, O26311, O32125, O59346, P44755, P94512, Q2UEK4, Q4QMY0, Q58832, Q5E9D6, Q631J2, Q6HBC8, Q6HQY9, Q72H00, Q72XV8, Q815I8, Q8TWR2, Q8U040

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	38
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2098 predictions. Top by Δscore:

Variant	Effect	Δscore
18:47077459:GTG:G	donor_gain	1.0000
18:47077475:A:T	donor_gain	1.0000
18:47112971:ACAT:A	donor_loss	1.0000
18:47112972:CAT:C	donor_loss	1.0000
18:47112973:ATA:A	donor_loss	1.0000
18:47112974:TA:T	donor_loss	1.0000
18:47112975:A:AC	donor_gain	1.0000
18:47112975:A:T	donor_loss	1.0000
18:47112976:C:CC	donor_gain	1.0000
18:47112976:CCAGT:C	donor_gain	1.0000
18:47115127:CTT:C	donor_loss	1.0000
18:47115128:TTA:T	donor_loss	1.0000
18:47115129:TA:T	donor_loss	1.0000
18:47115130:A:AC	donor_gain	1.0000
18:47115130:A:AT	donor_loss	1.0000
18:47115130:ACAT:A	donor_gain	1.0000
18:47115131:C:CA	donor_loss	1.0000
18:47115131:C:CC	donor_gain	1.0000
18:47115131:CAT:C	donor_gain	1.0000
18:47115131:CATC:C	donor_gain	1.0000
18:47115131:CATCT:C	donor_gain	1.0000
18:47115184:T:TA	donor_gain	1.0000
18:47115345:TAAC:T	acceptor_gain	1.0000
18:47115347:ACCT:A	acceptor_loss	1.0000
18:47115348:CCTA:C	acceptor_loss	1.0000
18:47115349:C:CC	acceptor_gain	1.0000
18:47115349:CTAG:C	acceptor_loss	1.0000
18:47115350:T:A	acceptor_loss	1.0000
18:47136300:A:AC	donor_gain	1.0000
18:47136301:C:CC	donor_gain	1.0000

AlphaMissense

1680 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:47115133:T:A	D204V	0.998
18:47134665:A:C	N47K	0.997
18:47134665:A:T	N47K	0.997
18:47134669:G:A	T46I	0.997
18:47115132:A:C	D204E	0.996
18:47115132:A:T	D204E	0.996
18:47113026:A:C	D209E	0.995
18:47113026:A:T	D209E	0.995
18:47115133:T:G	D204A	0.995
18:47115134:C:G	D204H	0.995
18:47115207:T:A	K179N	0.995
18:47115207:T:G	K179N	0.995
18:47115208:T:G	K179T	0.995
18:47115209:T:C	K179E	0.995
18:47115209:T:G	K179Q	0.995
18:47113027:T:A	D209V	0.994
18:47113027:T:G	D209A	0.994
18:47113028:C:G	D209H	0.994
18:47115136:C:T	G203E	0.994
18:47115139:A:T	I202K	0.994
18:47115208:T:A	K179I	0.994
18:47115211:C:T	G178E	0.994
18:47130298:A:T	V114D	0.994
18:47115133:T:C	D204G	0.993
18:47115136:C:A	G203V	0.992
18:47115238:G:T	A169D	0.992
18:47134582:G:A	S75F	0.992
18:47134666:T:A	N47I	0.992
18:47136401:A:C	D13E	0.992
18:47136401:A:T	D13E	0.992

dbSNP variants (sampled 300 via entrez): RS1000057365 (18:47110224 T>G), RS1000079178 (18:47120108 C>T), RS1000104515 (18:47137806 A>C,G), RS1000132873 (18:47119866 T>C), RS1000185969 (18:47113644 G>T), RS1000289791 (18:47117238 G>A), RS1000304929 (18:47107020 A>G), RS1000309879 (18:47129479 A>C), RS1000343246 (18:47146121 C>A,G,T), RS1000360852 (18:47148328 G>A), RS1000362840 (18:47126328 T>C), RS1000513459 (18:47110576 G>A), RS1000515744 (18:47142711 AC>A), RS1000538213 (18:47135211 C>G,T), RS1000715118 (18:47141125 G>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

2 associations (top):

Study	Trait	p-value
GCST006585_1563	Blood protein levels	5.000000e-77
GCST010136_31	Fruit consumption	2.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008111	diet measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, decreases expression	5
Benzo(a)pyrene	increases expression, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	decreases expression, increases expression	2
Cadmium Chloride	increases abundance, increases expression	2
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Decitabine	affects expression, affects methylation	1
Air Pollutants	decreases expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Cadmium	increases abundance, increases expression	1
Nickel	decreases expression	1
Thiram	decreases expression	1
Urethane	decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
Lactic Acid	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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