HACD3

Summary

HACD3 (3-hydroxyacyl-CoA dehydratase 3, HGNC:24175) is a protein-coding gene on chromosome 15q22.31, encoding Very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase 3 (Q9P035). 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 biosynthetic process; positive regulation by virus of viral protein levels in host cell; and positive regulation of viral genome replication. Located in endoplasmic reticulum and nuclear membrane.

Source: NCBI Gene 51495 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 73 total
• Druggable target: yes
• MANE Select transcript: NM_016395

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24175
Approved symbol	HACD3
Name	3-hydroxyacyl-CoA dehydratase 3
Location	15q22.31
Locus type	gene with protein product
Status	Approved
Aliases	B-ind1, HSPC121
Ensembl gene	ENSG00000074696
Ensembl biotype	protein_coding
OMIM	615940
Entrez	51495

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 15 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron, 1 TEC

ENST00000261875, ENST00000442729, ENST00000561763, ENST00000562832, ENST00000562901, ENST00000565299, ENST00000566074, ENST00000566239, ENST00000566511, ENST00000568793, ENST00000569894, ENST00000624437, ENST00000855354, ENST00000921086, ENST00000921087, ENST00000921088, ENST00000955868, ENST00000955869

RefSeq mRNA: 2 — MANE Select: NM_016395 NM_001411136, NM_016395

CCDS: CCDS45282, CCDS92019

Canonical transcript exons

ENST00000261875 — 11 exons

Exon	Start	End
ENSE00000694389	65562774	65562884
ENSE00000694393	65564215	65564342
ENSE00000885245	65558680	65558731
ENSE00000885248	65570091	65570203
ENSE00000885249	65571548	65571654
ENSE00000942976	65572235	65572366
ENSE00001200603	65576303	65578349
ENSE00002594068	65530463	65530718
ENSE00003500561	65554887	65554960
ENSE00003561608	65551676	65551718
ENSE00003615976	65556739	65556903

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 99.14.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 52.5890 / max 542.7415, expressed in 1809 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147224	51.0152	1808
147225	1.1725	570
147226	0.1423	48
147227	0.1285	38
147228	0.1069	28
147229	0.0153	5
147230	0.0083	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pons	UBERON:0000988	99.14	gold quality
substantia nigra pars compacta	UBERON:0001965	99.04	gold quality
pigmented layer of retina	UBERON:0001782	99.03	gold quality
renal medulla	UBERON:0000362	99.02	gold quality
superior vestibular nucleus	UBERON:0007227	99.01	gold quality
retina	UBERON:0000966	99.00	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.96	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.96	gold quality
ventral tegmental area	UBERON:0002691	98.92	gold quality
middle temporal gyrus	UBERON:0002771	98.87	gold quality
inferior vagus X ganglion	UBERON:0005363	98.73	gold quality
subthalamic nucleus	UBERON:0001906	98.72	gold quality
entorhinal cortex	UBERON:0002728	98.70	gold quality
lateral globus pallidus	UBERON:0002476	98.68	gold quality
adrenal tissue	UBERON:0018303	98.63	gold quality
cerebellar vermis	UBERON:0004720	98.62	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.61	gold quality
postcentral gyrus	UBERON:0002581	98.57	gold quality
parietal lobe	UBERON:0001872	98.48	gold quality
caput epididymis	UBERON:0004358	98.46	gold quality
corpus epididymis	UBERON:0004359	98.43	gold quality
adult organism	UBERON:0007023	98.35	gold quality
tibia	UBERON:0000979	98.25	gold quality
globus pallidus	UBERON:0001875	98.04	gold quality
medial globus pallidus	UBERON:0002477	97.88	gold quality
superior frontal gyrus	UBERON:0002661	97.85	gold quality
bronchial epithelial cell	CL:0002328	97.61	gold quality
ventricular zone	UBERON:0003053	97.57	gold quality
dorsal root ganglion	UBERON:0000044	97.38	gold quality
visceral pleura	UBERON:0002401	97.24	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-114	yes	11.65
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB

miRNA regulators (miRDB)

117 targeting HACD3, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-12121	99.99	66.64	255
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-548AG	99.77	69.25	1492
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107

Literature-anchored findings (GeneRIF, showing 8)

• The structure of the B-IND1 gene promoter region was determined. (PMID:16516406)
• results suggest that hB-ind1 plays a crucial role in HCV RNA replication and the propagation of JFH1 virus through interaction with viral and host proteins (PMID:18160438)
• These results suggest that an Hsp90-dependent chaperone pathway incorporating hB-ind1 is involved in protein folding in the membranous web for the circumvention of the UPR and that it facilitates HCV replication (PMID:19656872)
• Genes in the erythroid differentiation and cell cycle regulation pathways influence interindividual variation in RBC indices. Our results provide insights into the molecular basis underlying variation in RBC traits. (PMID:22560525)
• Our results indicate that PTPLAD1 (HACD3) is in complex with insulin receptor (IR) in rat’s liver and in human HEK293 cells. SiRNA-mediated partial knockdown of PTPLAD1 increased level of IR tyrosine phosphorylation and affect IR endocytosis. PTPLAD1 depletion strongly enhanced insulin effect on Glut2 translocation in HEK293 cells similar to the increase in AKT-ser473 phosphorylation. [PTPLAD1] (PMID:25687571)
• HACD3 (PTPLAD1) is a new candidate gene for type-2 diabetes risk. HACD3 deletion decreases the autophosphorylation of insulin receptor in vitro. HACD3 may regulate the activity of CDK2 and RAB5C.Overexpression of HACD3 inhibits the tyrosine phosphorylation of CDK2 and RAB5C. HACD3 stimulates the physical association of insulin receptor with RAB11A and may regulate the recycling of insulin receptor to the plasma membrane. (PMID:30300385)
• PTPLAD1 Regulates PHB-Raf Interaction to Orchestrate Epithelial-Mesenchymal and Mitofusion-Fission Transitions in Colorectal Cancer. (PMID:38617530)
• HACD3 Prevents PB1 from Autophagic Degradation to Facilitate the Replication of Influenza A Virus. (PMID:38793585)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hacd3	ENSDARG00000016038
mus_musculus	Hacd3	ENSMUSG00000033629
rattus_norvegicus	Hacd3	ENSRNOG00000030232
drosophila_melanogaster	Hacd2	FBGN0032524
caenorhabditis_elegans		WBGENE00011205

Paralogs (3): HACD1 (ENSG00000165996), HACD4 (ENSG00000188921), HACD2 (ENSG00000206527)

Protein

Protein identifiers

Very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase 3 — Q9P035 (reviewed: Q9P035)

Alternative names: 3-hydroxyacyl-CoA dehydratase 3, Butyrate-induced protein 1, Protein-tyrosine phosphatase-like A domain-containing protein 1

All UniProt accessions (5): Q9P035, H3BMZ1, H3BPZ1, H3BRL8, H3BS72

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. May be involved in Rac1-signaling pathways leading to the modulation of gene expression. Promotes insulin receptor/INSR autophosphorylation and is involved in INSR internalization.

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. Interacts with RAC1. Associates with internalized insulin receptor/INSR complexes on Golgi/endosomal membranes; HACD3/PTPLAD1 together with ATIC and PRKAA2/AMPK2 is proposed to be part of a signaling network regulating INSR autophosphorylation and endocytosis.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Highly expressed in testis, kidney, brain, liver and weakly in skeletal muscle, spleen and heart. No expression detected in leukocytes.

Induction. By AKAP12 and histone deacetylase inhibitors such as sodium butyrate.

Pathway. Lipid metabolism; fatty acid biosynthesis.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q9P035-1	1	yes
Q9P035-2	2

RefSeq proteins (2): NP_001398065, NP_057479* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007052	CS_dom	Domain
IPR007482	Tyr_Pase-like_PTPLA	Family
IPR008978	HSP20-like_chaperone	Homologous_superfamily

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 (31 total): topological domain 7, transmembrane region 6, sequence conflict 6, modified residue 4, active site 2, sequence variant 2, chain 1, domain 1, coiled-coil region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P035-F1	88.71	0.64

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): 286; 293

Post-translational modifications (4): 1, 7, 114, 135

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: 270 (showing top): REACTOME_SYNTHESIS_OF_VERY_LONG_CHAIN_FATTY_ACYL_COAS, TGCGCANK_UNKNOWN, GOBP_REGULATION_BY_VIRUS_OF_VIRAL_PROTEIN_LEVELS_IN_HOST_CELL, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_VIRAL_GENOME_REPLICATION, RIZKI_TUMOR_INVASIVENESS_3D_DN, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, PATIL_LIVER_CANCER, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, MARTINEZ_RB1_TARGETS_UP, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, GOBP_JNK_CASCADE

GO Biological Process (14): canonical NF-kappaB signal transduction (GO:0007249), JNK cascade (GO:0007254), small GTPase-mediated signal transduction (GO:0007264), Rho protein signal transduction (GO:0007266), Rac protein signal transduction (GO:0016601), sphingolipid biosynthetic process (GO:0030148), fatty acid elongation (GO:0030497), very long-chain fatty acid biosynthetic process (GO:0042761), positive regulation of viral genome replication (GO:0045070), positive regulation by virus of viral protein levels in host cell (GO:0046726), negative regulation of intracellular signal transduction (GO:1902532), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631), fatty acid biosynthetic process (GO:0006633)

GO Molecular Function (6): GTPase activator activity (GO:0005096), 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 (5): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), focal adhesion (GO:0005925), nuclear membrane (GO:0031965), 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
intracellular signaling cassette	2
small GTPase-mediated signal transduction	2
lipid biosynthetic process	2
fatty acid biosynthetic process	2
positive regulation of viral process	2
organelle membrane	2
MAPK cascade	1
sphingolipid metabolic process	1
very long-chain fatty acid metabolic process	1
viral genome replication	1
regulation of viral genome replication	1
regulation by virus of viral protein levels in host cell	1
negative regulation of signal transduction	1
intracellular signal transduction	1
regulation of intracellular signal transduction	1
primary metabolic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
fatty acid metabolic process	1
monocarboxylic acid biosynthetic process	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	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
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cell-substrate junction	1
nucleus	1
nuclear envelope	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1408 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HACD3	HSD17B12	Q53GQ0	626
HACD3	TECR	Q9NZ01	581
HACD3	INTS14	Q96SY0	513
HACD3	NCLN	Q969V3	442
HACD3	ELOVL1	Q9BW60	426
HACD3	PLEKHG1	Q9ULL1	419
HACD3	DENND4A	Q7Z401	418
HACD3	ZNF668	Q96K58	418
HACD3	SMPD4	Q9NXE4	418
HACD3	CD2AP	Q9Y5K6	417
HACD3	SASH1	O94885	413
HACD3	ZBTB1	Q9Y2K1	410
HACD3	SH3KBP1	Q96B97	407
HACD3	ELOVL7	A1L3X0	403
HACD3	STT3B	Q8TCJ2	399

IntAct

213 interactions, top by confidence:

A	B	Type	Score
CFTR	HACD3	psi-mi:“MI:0403”(colocalization)	0.740
CFTR	HACD3	psi-mi:“MI:0914”(association)	0.740
CKAP4	FBXO28	psi-mi:“MI:0914”(association)	0.730
	PI4KA	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
WDR5	MEN1	psi-mi:“MI:0914”(association)	0.710
GABARAPL2	IPO5	psi-mi:“MI:0914”(association)	0.690
CFTR	TRIM21	psi-mi:“MI:0914”(association)	0.680
	DDX3X	psi-mi:“MI:0914”(association)	0.630
PPP5C	IRS4	psi-mi:“MI:0914”(association)	0.570
INSR	ACTB	psi-mi:“MI:0914”(association)	0.530
	XPO1	psi-mi:“MI:0914”(association)	0.530
GRB2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
FLVCR1	TNFRSF10B	psi-mi:“MI:0914”(association)	0.530
UNC93B1	GPR89A	psi-mi:“MI:0914”(association)	0.530
ERBB2	NDUFA4	psi-mi:“MI:0914”(association)	0.530
	HACD3	psi-mi:“MI:0915”(physical association)	0.510
	SCD	psi-mi:“MI:0914”(association)	0.500
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
ESR1		psi-mi:“MI:0914”(association)	0.460

BioGRID (333): PTPLAD1 (Affinity Capture-MS), PTPLAD1 (Affinity Capture-MS), PTPLAD1 (Affinity Capture-MS), PTPLAD1 (Affinity Capture-Western), PTPLAD1 (Affinity Capture-MS), PTPLAD1 (Affinity Capture-MS), PTPLAD1 (Affinity Capture-MS), PTPLAD1 (Proximity Label-MS), PTPLAD1 (Proximity Label-MS), PTPLAD1 (Affinity Capture-MS), PTPLAD1 (Affinity Capture-MS), PTPLAD1 (Affinity Capture-MS), PTPLAD1 (Affinity Capture-RNA), PTPLAD1 (Affinity Capture-MS), PTPLAD1 (Affinity Capture-MS)

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, B0YJ81, O14346, O17040, P40857, Q4W1W1, Q5ZEJ0, Q7XSZ4, Q8VZB2, Q9N1R5, Q9QY80, G1TGF1, P0C8Z0, P28707, P83868, Q15185, Q3ZBF7, Q5NVM4, Q6ID70, Q6PWL5, Q6YYB0, Q90955, Q9R0Q7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
HACD3	“up-regulates activity”	FASN	“chemical activation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 206 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signalling to RAS	5	22.7×	2e-04
Insulin receptor signalling cascade	5	22.7×	2e-04
Signaling by ERBB2 ECD mutants	5	22.7×	2e-04
GRB2 events in ERBB2 signaling	5	21.4×	2e-04
SHC1 events in ERBB2 signaling	5	16.1×	6e-04
Signaling by ERBB2 TMD/JMD mutants	5	16.1×	6e-04
Signaling by ERBB2 KD Mutants	5	14.3×	9e-04
FCERI mediated MAPK activation	5	11.7×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
autophagosome maturation	6	12.5×	6e-03
mitophagy	6	11.3×	7e-03
Ras protein signal transduction	7	8.5×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	52
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1622 predictions. Top by Δscore:

Variant	Effect	Δscore
15:65530704:C:G	donor_gain	1.0000
15:65530714:TACAG:T	donor_loss	1.0000
15:65530715:ACAG:A	donor_loss	1.0000
15:65530717:AGG:A	donor_loss	1.0000
15:65530719:GT:G	donor_loss	1.0000
15:65530720:T:G	donor_loss	1.0000
15:65551716:AAGG:A	donor_loss	1.0000
15:65551719:G:GC	donor_loss	1.0000
15:65551720:T:G	donor_loss	1.0000
15:65554884:TAG:T	acceptor_loss	1.0000
15:65554884:TAGC:T	acceptor_gain	1.0000
15:65554885:A:AG	acceptor_gain	1.0000
15:65554886:G:GA	acceptor_gain	1.0000
15:65554886:GCTC:G	acceptor_gain	1.0000
15:65554957:AGAGG:A	donor_loss	1.0000
15:65554958:GAG:G	donor_gain	1.0000
15:65554961:G:GC	donor_loss	1.0000
15:65554961:G:GG	donor_gain	1.0000
15:65554962:T:G	donor_loss	1.0000
15:65558732:G:GG	donor_gain	1.0000
15:65562889:G:GG	donor_gain	1.0000
15:65564214:GA:G	acceptor_gain	1.0000
15:65564339:CCAG:C	donor_loss	1.0000
15:65564340:CAG:C	donor_loss	1.0000
15:65564342:GGT:G	donor_loss	1.0000
15:65564343:G:GA	donor_loss	1.0000
15:65564344:T:G	donor_loss	1.0000
15:65570075:T:TA	acceptor_gain	1.0000
15:65570076:G:A	acceptor_gain	1.0000
15:65572230:TTCA:T	acceptor_loss	1.0000

AlphaMissense

2387 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:65530660:T:A	V10D	0.999
15:65530665:T:A	W12R	0.999
15:65530665:T:C	W12R	0.999
15:65530693:T:C	L21P	0.999
15:65556802:T:A	W90R	0.999
15:65556802:T:C	W90R	0.999
15:65556853:T:C	F107L	0.999
15:65556855:T:A	F107L	0.999
15:65556855:T:G	F107L	0.999
15:65556860:G:C	R109P	0.999
15:65530654:C:A	P8Q	0.998
15:65530673:G:C	Q14H	0.998
15:65530673:G:T	Q14H	0.998
15:65530705:T:C	L25P	0.998
15:65554892:G:A	G46R	0.998
15:65554892:G:C	G46R	0.998
15:65554893:G:A	G46E	0.998
15:65554938:T:C	F61S	0.998
15:65556804:G:C	W90C	0.998
15:65556804:G:T	W90C	0.998
15:65556838:T:C	F102L	0.998
15:65556840:T:A	F102L	0.998
15:65556840:T:G	F102L	0.998
15:65556862:T:A	W110R	0.998
15:65556862:T:C	W110R	0.998
15:65570184:A:C	S252R	0.998
15:65570186:T:A	S252R	0.998
15:65570186:T:G	S252R	0.998
15:65530667:G:C	W12C	0.997
15:65530667:G:T	W12C	0.997

dbSNP variants (sampled 300 via entrez): RS1000106249 (15:65541971 C>T), RS1000130740 (15:65575399 G>A,C), RS1000224602 (15:65536378 C>T), RS1000344699 (15:65564927 A>G), RS1000445438 (15:65558315 A>C), RS1000476814 (15:65558575 G>A), RS1000527931 (15:65570953 T>G), RS1000560392 (15:65537944 AAAAAAAAAAAAAAAATATATATATATATATATATAT>A), RS1000724107 (15:65552616 G>A,C), RS1000748397 (15:65565986 C>G), RS1000782275 (15:65573819 A>G,T), RS1001004942 (15:65547338 A>G), RS1001007251 (15:65564554 G>C), RS1001036198 (15:65547598 A>G), RS1001174398 (15:65560269 T>C)

Disease associations

OMIM: gene MIM:615940 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000587_7	Mean corpuscular hemoglobin	3.000000e-09
GCST001765_17	Red blood cell traits	3.000000e-09
GCST004605_4	Mean corpuscular hemoglobin concentration	9.000000e-10
GCST005316_496	Intelligence (MTAG)	2.000000e-08
GCST010083_124	Hemoglobin levels	3.000000e-11

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004509	hemoglobin measurement
EFO:0004527	mean corpuscular hemoglobin
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0004337	intelligence

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067427 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.76	Kd	17.3	nM	CHEMBL5653589
7.76	ED50	17.3	nM	CHEMBL5653589
6.68	Kd	210.3	nM	CHEMBL3752910
6.68	ED50	210.3	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148481: Binding affinity to human HACD3 incubated for 45 mins by Kinobead based pull down assay	kd	0.0173	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148481: Binding affinity to human HACD3 incubated for 45 mins by Kinobead based pull down assay	kd	0.2103	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cadmium Chloride	increases palmitoylation, decreases expression, increases expression, decreases reaction, increases abundance	3
Acetaminophen	decreases expression	2
Air Pollutants	increases abundance, increases oxidation, decreases expression, affects cotreatment	2
Cadmium	decreases reaction, increases abundance, increases palmitoylation, decreases expression	2
Cyclosporine	decreases expression	2
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
bisphenol A	increases expression	1
beta-lapachone	increases expression	1
sodium arsenite	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Benztropine	increases expression	1
Cannabidiol	increases expression	1
Cisplatin	increases expression	1
Clozapine	increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Emodin	decreases expression	1
Isoniazid	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651523	Binding	Binding affinity to human HACD3 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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