HACD4

Summary

HACD4 (3-hydroxyacyl-CoA dehydratase 4, HGNC:20920) is a protein-coding gene on chromosome 9p21.3, encoding Very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase 4 (Q5VWC8). Catalyzes the third of the four reactions of the long-chain fatty acids elongation cycle.

Enables enzyme binding activity and very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase activity. Involved in fatty acid elongation and very long-chain fatty acid biosynthetic process. Located in endoplasmic reticulum.

Source: NCBI Gene 401494 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 52 total
• MANE Select transcript: NM_001010915

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20920
Approved symbol	HACD4
Name	3-hydroxyacyl-CoA dehydratase 4
Location	9p21.3
Locus type	gene with protein product
Status	Approved
Aliases	Em:AL662879.1, OTTHUMG00000021016
Ensembl gene	ENSG00000188921
Ensembl biotype	protein_coding
OMIM	615941
Entrez	401494

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000488436, ENST00000495827, ENST00000913433, ENST00000913434

RefSeq mRNA: 3 — MANE Select: NM_001010915 NM_001010915, NM_001321883, NM_001321903

CCDS: CCDS43791

Canonical transcript exons

ENST00000495827 — 7 exons

Exon	Start	End
ENSE00001372429	21015898	21016010
ENSE00001376908	21029295	21029398
ENSE00001377315	21011589	21011695
ENSE00001383973	21026596	21026723
ENSE00001385443	21008021	21008146
ENSE00001484211	21031553	21031640
ENSE00001864841	20999509	21007119

Expression profiles

Bgee: expression breadth ubiquitous, 211 present calls, max score 93.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.8033 / max 352.4561, expressed in 1416 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
100201	15.7255	1416
100200	0.0778	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	93.85	gold quality
monocyte	CL:0000576	92.46	gold quality
bronchus	UBERON:0002185	92.10	gold quality
leukocyte	CL:0000738	92.08	gold quality
bone marrow	UBERON:0002371	88.55	gold quality
trabecular bone tissue	UBERON:0002483	86.67	gold quality
blood	UBERON:0000178	85.23	gold quality
ileal mucosa	UBERON:0000331	84.65	gold quality
mucosa of paranasal sinus	UBERON:0005030	84.30	gold quality
oviduct epithelium	UBERON:0004804	84.06	gold quality
granulocyte	CL:0000094	83.64	gold quality
tibia	UBERON:0000979	83.36	gold quality
visceral pleura	UBERON:0002401	82.70	gold quality
bone marrow cell	CL:0002092	82.67	gold quality
germinal epithelium of ovary	UBERON:0001304	82.23	gold quality
epithelial cell of pancreas	CL:0000083	81.51	gold quality
calcaneal tendon	UBERON:0003701	81.45	gold quality
parietal pleura	UBERON:0002400	81.42	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.31	gold quality
amniotic fluid	UBERON:0000173	79.45	gold quality
superficial temporal artery	UBERON:0001614	78.37	silver quality
palpebral conjunctiva	UBERON:0001812	77.53	gold quality
layer of synovial tissue	UBERON:0007616	77.53	gold quality
lower lobe of lung	UBERON:0008949	77.10	gold quality
stromal cell of endometrium	CL:0002255	76.99	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	76.98	gold quality
lower esophagus muscularis layer	UBERON:0035833	76.80	gold quality
esophagus squamous epithelium	UBERON:0006920	76.76	gold quality
lower esophagus	UBERON:0013473	76.74	gold quality
smooth muscle tissue	UBERON:0001135	76.33	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	20.50
E-ANND-3	yes	6.63

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

160 targeting HACD4, 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-7110-3P	100.00	73.18	2486
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 3)

• PTPLAD2 is a potential tumor suppressor and prognostic indicator that reduces STAT3 phosphorylation. (PMID:24530685)
• association of HACD4 haplotypes with atherosclerotic phenotypes connotes a further validation and replication in larger cohorts as well as functional studies to enlighten the potential mechanism of its action in pathophysiology of atherosclerosis. (PMID:29031776)
• Inactivating Frameshift Mutations of HACD4 and TCP10L Tumor Suppressor Genes in Colorectal and Gastric Cancers. (PMID:29532408)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hacd4	ENSDARG00000102221
mus_musculus	Hacd4	ENSMUSG00000028497
rattus_norvegicus	Hacd4	ENSRNOG00000005772
drosophila_melanogaster	Hacd2	FBGN0032524
caenorhabditis_elegans		WBGENE00011205

Paralogs (3): HACD3 (ENSG00000074696), HACD1 (ENSG00000165996), HACD2 (ENSG00000206527)

Protein

Protein identifiers

Very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase 4 — Q5VWC8 (reviewed: Q5VWC8)

Alternative names: 3-hydroxyacyl-CoA dehydratase 4, Protein-tyrosine phosphatase-like A domain-containing protein 2

All UniProt accessions (1): Q5VWC8

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the third of the four reactions of the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process, allows the addition of two carbons to the chain of long- and very long-chain fatty acids/VLCFAs per cycle. This enzyme catalyzes the dehydration of the 3-hydroxyacyl-CoA intermediate into trans-2,3-enoyl-CoA, within each cycle of fatty acid elongation. Thereby, it participates in the production of VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators.

Subunit / interactions. May interact with enzymes of the ELO family (including ELOVL1); with those enzymes that mediate condensation, the first of the four steps of the reaction cycle responsible for fatty acids elongation, may be part of a larger fatty acids elongase complex.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Highly expressed in leukocytes, and low expression in heart, spleen, kidney, and placenta.

Pathway. Lipid metabolism; fatty acid biosynthesis.

Similarity. Belongs to the very long-chain fatty acids dehydratase HACD family.

RefSeq proteins (3): NP_001010915, NP_001308812, NP_001308832 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007482	Tyr_Pase-like_PTPLA	Family

Pfam: PF04387

Catalyzed reactions (Rhea), 2 shown:

• (3R)-hydroxyhexadecanoyl-CoA = (2E)-hexadecenoyl-CoA + H2O (RHEA:39159)
• a very-long-chain (3R)-3-hydroxyacyl-CoA = a very-long-chain (2E)-enoyl-CoA + H2O (RHEA:45812)

UniProt features (18 total): topological domain 7, transmembrane region 6, active site 2, chain 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5VWC8-F1	85.73	0.57

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): 156; 163

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-75876	Synthesis of very long-chain fatty acyl-CoAs

MSigDB gene sets: 155 (showing top): REACTOME_SYNTHESIS_OF_VERY_LONG_CHAIN_FATTY_ACYL_COAS, CHUNG_BLISTER_CYTOTOXICITY_DN, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, MARTINEZ_RB1_TARGETS_DN, MCBRYAN_PUBERTAL_BREAST_3_4WK_UP, GOBP_VERY_LONG_CHAIN_FATTY_ACID_METABOLIC_PROCESS, GOBP_FATTY_ACID_BIOSYNTHETIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_LIPID_BIOSYNTHETIC_PROCESS, GOBP_SPHINGOLIPID_BIOSYNTHETIC_PROCESS

GO Biological Process (6): sphingolipid biosynthetic process (GO:0030148), fatty acid elongation (GO:0030497), very long-chain fatty acid biosynthetic process (GO:0042761), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631), fatty acid biosynthetic process (GO:0006633)

GO Molecular Function (5): 3-hydroxyacyl-CoA dehydratase activity (GO:0018812), enzyme binding (GO:0019899), very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase activity (GO:0102158), protein binding (GO:0005515), lyase activity (GO:0016829)

GO Cellular Component (3): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Fatty acyl-CoA biosynthesis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lipid biosynthetic process	2
fatty acid biosynthetic process	2
sphingolipid metabolic process	1
very long-chain fatty acid metabolic process	1
primary metabolic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
fatty acid metabolic process	1
monocarboxylic acid biosynthetic process	1
enoyl-CoA hydratase activity	1
protein binding	1
(2E)-enoyl-CoA hydratase activity	1
binding	1
catalytic activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1056 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HACD4	FOCAD	Q5VW36	601
HACD4	HSD17B12	Q53GQ0	600
HACD4	TECR	Q9NZ01	593
HACD4	ACSS3	Q9H6R3	491
HACD4	NLGN2	Q8NFZ4	451
HACD4	SDSL	Q96GA7	435
HACD4	ELOVL1	Q9BW60	428
HACD4	STRADB	Q9C0K7	427
HACD4	ATP5MK	Q96IX5	426
HACD4	LRRTM2	O43300	405
HACD4	PIK3AP1	Q6ZUJ8	401
HACD4	COASY	Q13057	400
HACD4	MDGA2	Q7Z553	399
HACD4	CLSTN3	Q9BQT9	396
HACD4	ZBTB38	Q8NAP3	394

IntAct

4 interactions, top by confidence:

A	B	Type	Score
CD79A	HACD4	psi-mi:“MI:0915”(physical association)	0.560
HACD4	CD79A	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (1): PTPLAD2 (Two-hybrid)

ESM2 similar proteins: A2AKM2, A4FUY9, A5D6V4, A7YY55, A8WGS4, Q01685, Q0P5C7, Q15629, Q3T124, Q4R8A8, Q4V8U5, Q5BJF2, Q5GH60, Q5GH61, Q5GH68, Q5HZE5, Q5ND56, Q5NVQ2, Q5R7Z3, Q5U2T1, Q5VWC8, Q5XI41, Q5ZM57, Q60457, Q6DED0, Q6GLX2, Q6GNB5, Q6P4N1, Q6PP77, Q6YWS8, Q7SY06, Q84QC0, Q86X19, Q8CGF5, Q8K0U3, Q8K2C9, Q8N609, Q8QZR0, Q8R000, Q8VZB2

Diamond homologs: A2AKM2, A7YY55, Q0P5C7, Q5NVQ2, Q5VWC8, Q5ZM57, Q6GNB5, Q7SY06, Q8K2C9, Q9P035, Q11118, Q23280, Q2KIP8, Q5RBK3, Q6Y1H2, Q8L7U4, Q9D3B1, Q9FR62, O14346, O17040, P40857, Q4W1W1, Q5ZEJ0, Q7XSZ4, Q8VZB2, Q9D9A7, Q9N1R5, P0C8Z0, Q6ID70, Q6YYB0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
HACD4	“up-regulates activity”	FASN	“chemical activation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	48
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1440 predictions. Top by Δscore:

Variant	Effect	Δscore
9:21006968:T:TA	donor_gain	1.0000
9:21006969:C:A	donor_gain	1.0000
9:21026732:C:T	acceptor_gain	1.0000
9:21026744:A:AC	acceptor_gain	1.0000
9:21026744:A:C	acceptor_gain	1.0000
9:21026752:A:C	acceptor_gain	1.0000
9:21029825:T:A	donor_gain	1.0000
9:21006984:CTGCA:C	donor_gain	0.9900
9:21014774:G:C	donor_gain	0.9900
9:21016008:GAGCT:G	acceptor_gain	0.9900
9:21016009:AGCT:A	acceptor_gain	0.9900
9:21026731:CCG:C	acceptor_gain	0.9900
9:21026732:C:CT	acceptor_gain	0.9900
9:21026738:T:TC	acceptor_gain	0.9900
9:21026747:C:CT	acceptor_gain	0.9900
9:21026750:A:AC	acceptor_gain	0.9900
9:21026750:A:C	acceptor_gain	0.9900
9:21026752:A:AC	acceptor_gain	0.9900
9:21031547:CCCTA:C	donor_loss	0.9900
9:21031548:CCTAC:C	donor_loss	0.9900
9:21031549:CTACC:C	donor_loss	0.9900
9:21031550:TA:T	donor_loss	0.9900
9:21031551:A:C	donor_loss	0.9900
9:21006983:A:AC	donor_gain	0.9800
9:21006984:C:CC	donor_gain	0.9800
9:21016007:TGAGC:T	acceptor_gain	0.9800
9:21016010:GCT:G	acceptor_gain	0.9800
9:21026730:CCCG:C	acceptor_gain	0.9800
9:21026733:G:C	acceptor_gain	0.9800
9:21026738:T:C	acceptor_gain	0.9800

AlphaMissense

1513 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:21026704:A:C	F54L	0.982
9:21026704:A:T	F54L	0.982
9:21026706:A:G	F54L	0.982
9:21015915:A:C	N122K	0.979
9:21015915:A:T	N122K	0.979
9:21029348:C:T	G30D	0.979
9:21026676:A:G	C64R	0.977
9:21029340:A:G	W33R	0.975
9:21029340:A:T	W33R	0.975
9:21029352:A:G	C29R	0.971
9:21029343:A:G	S32P	0.969
9:21008129:A:G	S170P	0.965
9:21029336:A:T	I34K	0.963
9:21008125:A:G	L171P	0.962
9:21015920:A:G	W121R	0.960
9:21015920:A:T	W121R	0.960
9:21029353:G:C	F28L	0.958
9:21029353:G:T	F28L	0.958
9:21029355:A:G	F28L	0.958
9:21029336:A:C	I34R	0.953
9:21026654:T:A	E71V	0.951
9:21008021:C:G	G206R	0.949
9:21029349:C:G	G30R	0.949
9:21008128:G:C	S170W	0.947
9:21015999:T:A	R94S	0.943
9:21015999:T:G	R94S	0.943
9:21007119:C:T	G206D	0.942
9:21011594:G:T	A162D	0.940
9:21011589:C:G	A164P	0.935
9:21008115:A:C	F174L	0.932

dbSNP variants (sampled 300 via entrez): RS1000039126 (9:21012995 A>T), RS1000053241 (9:21028961 A>G), RS1000151468 (9:21030608 A>T), RS1000170667 (9:21004776 T>TAAAG), RS1000220152 (9:21010631 G>T), RS1000229592 (9:21017056 A>C), RS1000322515 (9:21016717 G>A,T), RS1000323057 (9:20999018 G>A), RS1000672251 (9:20999205 G>T), RS1000715939 (9:21010462 C>A,G), RS1000769530 (9:21010735 A>C), RS1000865290 (9:20999772 G>A,C), RS1000904833 (9:21003671 A>T), RS1000959689 (9:21012040 C>T), RS1001022624 (9:21006372 C>G,T)

Disease associations

OMIM: gene MIM:615941 | 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
GCST002115_13	Axial length	9.000000e-06
GCST006956_16	Erectile dysfunction	7.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005318	axial length measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, increases expression	6
trichostatin A	increases expression, affects cotreatment	3
bisphenol A	increases expression, affects cotreatment	2
Air Pollutants	decreases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
methylmercuric chloride	decreases expression	1
arsenite	decreases expression	1
sodium arsenite	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
nickel sulfate	decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	affects expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Arsenic Trioxide	increases expression	1
Atrazine	decreases expression	1
Bilirubin	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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