CYP2U1

Summary

CYP2U1 (cytochrome P450 family 2 subfamily U member 1, HGNC:20582) is a protein-coding gene on chromosome 4q25, encoding Cytochrome P450 2U1 (Q7Z449). A cytochrome P450 monooxygenase involved in the metabolism of arachidonic acid and its conjugates.

This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This enzyme is a hydroxylase that metabolizes arachidonic acid, docosahexaenoic acid, and other long chain fatty acids.

Source: NCBI Gene 113612 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary spastic paraplegia (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 349 total — 31 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 23
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_183075

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20582
Approved symbol	CYP2U1
Name	cytochrome P450 family 2 subfamily U member 1
Location	4q25
Locus type	gene with protein product
Status	Approved
Aliases	SPG49
Ensembl gene	ENSG00000155016
Ensembl biotype	protein_coding
OMIM	610670
Entrez	113612

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000332884, ENST00000508453, ENST00000513302, ENST00000908818, ENST00000908819, ENST00000908820, ENST00000917361

RefSeq mRNA: 1 — MANE Select: NM_183075 NM_183075

CCDS: CCDS34047

Canonical transcript exons

ENST00000332884 — 5 exons

Exon	Start	End
ENSE00001297668	107949350	107949517
ENSE00001339864	107950245	107953461
ENSE00001504467	107947376	107947537
ENSE00002045215	107931549	107932133
ENSE00003536840	107944970	107945605

Expression profiles

Bgee: expression breadth ubiquitous, 241 present calls, max score 96.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.9256 / max 312.0635, expressed in 1577 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
49196	7.8245	1576
203308	0.1011	25

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
thymus	UBERON:0002370	96.26	gold quality
germinal epithelium of ovary	UBERON:0001304	92.19	gold quality
epithelial cell of pancreas	CL:0000083	89.10	silver quality
parietal pleura	UBERON:0002400	88.69	gold quality
tibialis anterior	UBERON:0001385	87.21	gold quality
islet of Langerhans	UBERON:0000006	87.01	gold quality
cardiac muscle of right atrium	UBERON:0003379	86.96	silver quality
pancreatic ductal cell	CL:0002079	86.52	gold quality
calcaneal tendon	UBERON:0003701	85.98	gold quality
ileal mucosa	UBERON:0000331	84.97	gold quality
visceral pleura	UBERON:0002401	84.64	gold quality
dorsal root ganglion	UBERON:0000044	84.47	gold quality
trigeminal ganglion	UBERON:0001675	83.90	gold quality
tibia	UBERON:0000979	83.89	gold quality
secondary oocyte	CL:0000655	83.82	gold quality
smooth muscle tissue	UBERON:0001135	83.21	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.01	gold quality
endothelial cell	CL:0000115	82.85	silver quality
tibial nerve	UBERON:0001323	82.36	gold quality
superficial temporal artery	UBERON:0001614	82.02	silver quality
pigmented layer of retina	UBERON:0001782	81.72	gold quality
Brodmann (1909) area 23	UBERON:0013554	81.23	gold quality
descending thoracic aorta	UBERON:0002345	81.06	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.88	gold quality
thoracic aorta	UBERON:0001515	80.68	gold quality
ascending aorta	UBERON:0001496	80.55	gold quality
ventricular zone	UBERON:0003053	80.53	gold quality
layer of synovial tissue	UBERON:0007616	80.21	gold quality
tendon	UBERON:0000043	80.01	gold quality
aorta	UBERON:0000947	80.01	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-83139	yes	8.16
E-MTAB-5061	yes	5.61
E-ANND-3	yes	4.92

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

165 targeting CYP2U1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-6845-3P	99.94	66.88	1439
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

Literature-anchored findings (GeneRIF, showing 20)

• CYP2U1 plays an important physiological role in fatty acid signaling processes in both cerebellum and thymus (PMID:14660610)
• Genetic polymorphism of CYP2U1, a cytochrome P450 involved in fatty acids hydroxylation. (PMID:20630735)
• CYP1B1 and CYP2U1 were the only quantifiable CYPs in in freshly isolated human brain microvessels. (PMID:21707071)
• The CYP2U1 gene shows a low mutation frequency in a general population of complicated hereditary spastic paraparesis (PMID:24337409)
• human cytochrome P450 2U1 oxidizes endogenous N-arachidonoylserotonin (PMID:24563460)
• Data suggest that the 3D model could be useful to identify other substrates of cytochrome P450 2U1 (CYP2U1) and help in understanding its physiologic roles. (PMID:25857771)
• This is the first report of CYP2E1 and CYP2U1 protein expression in human Amygdala. (PMID:25872594)
• This is the first formal report of pigmentary degenerative maculopathy associated with a CYP2U1 homozygous mutation (PMID:26914923)
• we identified two novel mutations in CYP2U1 in two unrelated Hereditary spastic paraplegia patients by whole exome sequencing (PMID:27292318)
• the mode of interaction of several Fe(III)-heme ligands and substrates with the active site of CYP2U1 on the basis of spectroscopic and molecular docking data.[CYP2U1] (PMID:27456766)
• The results suggested that SPG46 and SPG56 are rare causes of hereditary spastic paraplegia in China. (PMID:27553021)
• Cytochrome P450 2U1 (CYP2U1) exhibits several distinctive characteristics among the 57 human CYPs, such as its presence in almost all living organisms with a highly conserved sequence, its particular gene organization with only five exons, its major location in thymus and brain, and its protein sequence involving an unusually long N-terminal region containing 8 proline residues. [review] (PMID:28083596)
• we report a patient with SPG56 with novel compound heterozygous mutations in CYP2U1 which were identified by whole exome sequencing. Our patient exhibited complex features together with delayed myelination, broadening the phenotypic spectrum of SPG56, and implying that CYP2U1 should be screened in HSP with delayed myelination (PMID:28725025)
• protein sequence of CYP2U1 displayed two unique characteristics when compared to those of the human CYPs, the presence of a longer N-terminal region upstream of the putative trans-membrane helix (TMH) containing 8 proline residues, and of an insert of about 20 amino acids containing 5 arginine residues between helices A’ and A (PMID:28743672)
• Most CYP2U1 missense mutations in hereditary spastic paraplegia 56 lead to an inhibition of enzymatic activity that can be explained by the loss of proper heme binding to the protein or modification in protein structure. (PMID:29034544)
• we report a novel variant (CYP2U1:c.604G>A) in a consanguineous Pakistani family manifesting features of hereditary spastic paraplegia (PMID:31281085)
• Rare novel CYP2U1 and ZFYVE26 variants identified in two Pakistani families with spastic paraplegia. (PMID:32006740)
• Implication of folate deficiency in CYP2U1 loss of function. (PMID:34546337)
• Generation of iPSC lines from hereditary spastic paraplegia 56 (SPG56) patients and family members carrying CYP2U1 mutations. (PMID:36166872)
• Human Orphan Cytochrome P450 2U1 Catalyzes the omega-Hydroxylation of Leukotriene B4. (PMID:36498943)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cyp2u1	ENSDARG00000026548
mus_musculus	Cyp2u1	ENSMUSG00000027983
rattus_norvegicus	Cyp2u1	ENSRNOG00000011053

Paralogs (15): CYP2W1 (ENSG00000073067), CYP2D6 (ENSG00000100197), CYP2C18 (ENSG00000108242), CYP2E1 (ENSG00000130649), CYP2J2 (ENSG00000134716), CYP2C9 (ENSG00000138109), CYP2C8 (ENSG00000138115), CYP2C19 (ENSG00000165841), CYP2S1 (ENSG00000167600), CYP2R1 (ENSG00000186104), CYP2B6 (ENSG00000197408), CYP2F1 (ENSG00000197446), CYP2A13 (ENSG00000197838), CYP2A7 (ENSG00000198077), CYP2A6 (ENSG00000255974)

Protein

Protein identifiers

Cytochrome P450 2U1 — Q7Z449 (reviewed: Q7Z449)

Alternative names: Long-chain fatty acid omega-monooxygenase

All UniProt accessions (2): Q7Z449, E9PGH5

UniProt curated annotations — full annotation on UniProt →

Function. A cytochrome P450 monooxygenase involved in the metabolism of arachidonic acid and its conjugates. Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase). Acts as an omega and omega-1 hydroxylase for arachidonic acid and possibly for other long chain fatty acids. May modulate the arachidonic acid signaling pathway and play a role in other fatty acid signaling processes. May down-regulate the biological activities of N-arachidonoyl-serotonin, an endocannabinoid that has anti-nociceptive effects through inhibition of fatty acid amide hydrolase FAAH, TRPV1 receptor and T-type calcium channels. Catalyzes C-2 oxidation of the indole ring of N-arachidonoyl-serotonin forming a less active product 2-oxo-N-arachidonoyl-serotonin.

Subcellular location. Endoplasmic reticulum membrane. Microsome membrane. Mitochondrion inner membrane.

Tissue specificity. Widely expressed with stronger expression in thymus, heart and cerebellum.

Disease relevance. Spastic paraplegia 56, autosomal recessive, with or without pseudoxanthoma elasticum (SPG56) [MIM:615030] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. Complicated forms are recognized by additional variable features including spastic quadriparesis, seizures, dementia, amyotrophy, extrapyramidal disturbance, cerebral or cerebellar atrophy, optic atrophy, and peripheral neuropathy, as well as by extra neurological manifestations. In SPG56, upper limbs are often also affected. Some SPG56 patients may have a subclinical axonal neuropathy; others also have pseudoxanthoma elasticum. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Lipid metabolism; arachidonate metabolism.

Similarity. Belongs to the cytochrome P450 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q7Z449-1	1	yes
Q7Z449-2	2

RefSeq proteins (1): NP_898898* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001128	Cyt_P450	Family
IPR002401	Cyt_P450_E_grp-I	Family
IPR008069	Cyt_P450_E_grp-I_CYP2D-like	Family
IPR017972	Cyt_P450_CS	Conserved_site
IPR036396	Cyt_P450_sf	Homologous_superfamily
IPR050182	Cytochrome_P450_fam2	Family

Pfam: PF00067

Catalyzed reactions (Rhea), 4 shown:

• (5Z,8Z,11Z,14Z)-eicosatetraenoate + reduced [NADPH–hemoprotein reductase] + O2 = 20-hydroxy-(5Z,8Z,11Z,14Z)-eicosatetraenoate + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:39755)
• (5Z,8Z,11Z,14Z)-eicosatetraenoate + reduced [NADPH–hemoprotein reductase] + O2 = 19-hydroxy-(5Z,8Z,11Z,14Z)-eicosatetraenoate + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:39759)
• N-[(5Z,8Z,11Z,14Z)-eicosatetraenoyl]-serotonin + reduced [NADPH–hemoprotein reductase] + O2 = 2-oxo-N-[(5Z,8Z,11Z,14Z)-eicosatetraenoyl]-serotonin + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:50296)
• an omega-methyl-long-chain fatty acid + reduced [NADPH–hemoprotein reductase] + O2 = an omega-hydroxy-long-chain fatty acid + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:56748)

UniProt features (13 total): transmembrane region 5, sequence variant 4, splice variant 2, chain 1, binding site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z449-F1	88.45	0.74

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 (1): 490 (axial binding residue)

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-211958	Miscellaneous substrates
R-HSA-2142816	Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE)
R-HSA-5579011	Defective CYP2U1 causes SPG56

MSigDB gene sets: 164 (showing top): chr4q25, REACTOME_BIOLOGICAL_OXIDATIONS, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_LONG_CHAIN_FATTY_ACID_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, WANG_LMO4_TARGETS_DN, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_LIPID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_UNSATURATED_FATTY_ACID_METABOLIC_PROCESS, GOBP_ARACHIDONATE_METABOLIC_PROCESS, GOBP_STEROID_METABOLIC_PROCESS, GOCC_ORGANELLE_INNER_MEMBRANE, GOCC_NUCLEAR_OUTER_MEMBRANE_ENDOPLASMIC_RETICULUM_MEMBRANE_NETWORK, LEE_DOUBLE_POLAR_THYMOCYTE

GO Biological Process (7): obsolete organic acid metabolic process (GO:0006082), xenobiotic metabolic process (GO:0006805), steroid metabolic process (GO:0008202), omega-hydroxylase P450 pathway (GO:0097267), cytochrome metabolic process (GO:1903604), lipid metabolic process (GO:0006629), arachidonate metabolic process (GO:0019369)

GO Molecular Function (10): monooxygenase activity (GO:0004497), iron ion binding (GO:0005506), steroid hydroxylase activity (GO:0008395), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen (GO:0016712), heme binding (GO:0020037), arachidonate omega-hydroxylase activity (GO:0052869), long-chain fatty acid omega-hydroxylase activity (GO:0102033), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen (GO:0016705), metal ion binding (GO:0046872)

GO Cellular Component (6): cytoplasm (GO:0005737), mitochondrial inner membrane (GO:0005743), endoplasmic reticulum membrane (GO:0005789), mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Cytochrome P450 - arranged by substrate type	1
Arachidonate metabolism	1
Metabolic disorders of biological oxidation enzymes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
oxidoreductase activity	2
monooxygenase activity	2
cellular anatomical structure	2
cytoplasm	2
intracellular membrane-bounded organelle	2
metabolic process	1
cellular response to xenobiotic stimulus	1
lipid metabolic process	1
arachidonate metabolic process	1
protein metabolic process	1
primary metabolic process	1
long-chain fatty acid metabolic process	1
icosanoid metabolic process	1
unsaturated fatty acid metabolic process	1
olefinic compound metabolic process	1
transition metal ion binding	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen	1
tetrapyrrole binding	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen	1
fatty acid omega-hydroxylase activity	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
organelle inner membrane	1
mitochondrial membrane	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
endomembrane system	1

Protein interactions and networks

STRING

1736 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CYP2U1	AP5Z1	O43299	680
CYP2U1	MTRFR	Q9H3J6	653
CYP2U1	DDHD2	O94830	629
CYP2U1	B4GALNT1	Q00973	621
CYP2U1	DDHD1	Q8NEL9	603
CYP2U1	GBA2	Q9HCG7	571
CYP2U1	FA2H	Q7L5A8	569
CYP2U1	ZFYVE26	Q68DK2	545
CYP2U1	SPG7	Q9UQ90	541
CYP2U1	AP4S1	Q9Y587	532
CYP2U1	PNPLA6	Q8IY17	530
CYP2U1	AP4B1	Q9Y6B7	527
CYP2U1	PLA2G6	O60733	525
CYP2U1	SPG21	Q9NZD8	514
CYP2U1	TECPR2	O15040	505

IntAct

6 interactions, top by confidence:

A	B	Type	Score
BMI1	MEIS3P1	psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
LGR4	POLRMT	psi-mi:“MI:0914”(association)	0.350
SLC27A6	NBAS	psi-mi:“MI:0914”(association)	0.350
SLC9A3	ESYT3	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): CYP2U1 (Affinity Capture-MS), CYP2U1 (Affinity Capture-MS), CYP2U1 (Affinity Capture-MS), CYP2U1 (Affinity Capture-MS), CYP2U1 (Affinity Capture-MS), CYP2U1 (Affinity Capture-MS)

ESM2 similar proteins: A0A087X1C5, E9Q816, O18992, O46658, P00191, P03940, P08686, P10633, P10634, P10635, P11714, P12394, P12938, P12939, P15540, P24456, P24457, P30437, P51589, P51590, P52786, P70085, P78329, Q01361, Q0IIF9, Q29473, Q29488, Q2LA59, Q2LA60, Q2LCM1, Q2XNC8, Q2XNC9, Q4V8D1, Q64403, Q64562, Q64680, Q6GUQ4, Q6VVW9, Q6VVX0, Q7Z449

Diamond homologs: A0A087X1C5, E9Q5K4, F1Q8C3, O18809, O18992, O35293, O46658, O54749, O54750, O55071, O62671, O93297, P00176, P00178, P00179, P00180, P00181, P00182, P04167, P05178, P05179, P05180, P05181, P08682, P08683, P10610, P10632, P10633, P10634, P10635, P11371, P11712, P11714, P12789, P12790, P12791, P12938, P12939, P15123, P17666

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	31
Likely pathogenic	13
Uncertain significance	163
Likely benign	89
Benign	18

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1073573	NM_183075.3(CYP2U1):c.947_948del (p.Asp316fs)	Pathogenic
1344268	NM_183075.3(CYP2U1):c.1288+1G>A	Pathogenic
1686868	NM_183075.3(CYP2U1):c.1391C>G (p.Pro464Arg)	Pathogenic
1686869	NM_183075.3(CYP2U1):c.41del (p.Pro14fs)	Pathogenic
1686870	NM_183075.3(CYP2U1):c.808dup (p.Val270fs)	Pathogenic
1951827	NM_183075.3(CYP2U1):c.543_544del (p.His182fs)	Pathogenic
2427619	NC_000004.11:g.(?108852800)(108866781_?)del	Pathogenic
2826361	NM_183075.3(CYP2U1):c.1091del (p.Cys364fs)	Pathogenic
2844974	NM_183075.3(CYP2U1):c.654_661del (p.Cys219fs)	Pathogenic
3255488	NM_183075.3(CYP2U1):c.913C>T (p.His305Tyr)	Pathogenic
3381975	NM_183075.3(CYP2U1):c.1084_1088del (p.Leu362fs)	Pathogenic
3674787	NM_183075.3(CYP2U1):c.890del (p.Phe297fs)	Pathogenic
3690830	NM_183075.3(CYP2U1):c.48G>A (p.Trp16Ter)	Pathogenic
3704381	NM_183075.3(CYP2U1):c.651del (p.Phe218fs)	Pathogenic
374541	NM_183075.3(CYP2U1):c.1396C>T (p.Arg466Ter)	Pathogenic
3768835	NM_183075.3(CYP2U1):c.1001del (p.Asn334fs)	Pathogenic
3778669	NM_183075.3(CYP2U1):c.1307T>C (p.Ile436Thr)	Pathogenic
39501	NM_183075.3(CYP2U1):c.1139A>G (p.Glu380Gly)	Pathogenic
39502	NM_183075.3(CYP2U1):c.61_73del (p.Leu21fs)	Pathogenic
429249	NM_183075.3(CYP2U1):c.1210_1211del (p.Glu404fs)	Pathogenic
433183	NM_183075.3(CYP2U1):c.943C>T (p.Gln315Ter)	Pathogenic
4681551	NM_183075.3(CYP2U1):c.704T>A (p.Leu235Ter)	Pathogenic
489169	NM_183075.3(CYP2U1):c.342C>A (p.Tyr114Ter)	Pathogenic
595276	NM_183075.3(CYP2U1):c.786_789del (p.Ile261_Cys262insTer)	Pathogenic
659414	NM_183075.3(CYP2U1):c.1033_1034del (p.Ile345fs)	Pathogenic
970169	NM_183075.3(CYP2U1):c.854del (p.Lys285fs)	Pathogenic
979170	NM_183075.3(CYP2U1):c.604G>A (p.Glu202Lys)	Pathogenic
987449	NM_183075.3(CYP2U1):c.901dup (p.Ile301fs)	Pathogenic
989059	NM_183075.3(CYP2U1):c.1A>C (p.Met1Leu)	Pathogenic
989061	NM_183075.3(CYP2U1):c.1469G>A (p.Cys490Tyr)	Pathogenic

SpliceAI

1033 predictions. Top by Δscore:

Variant	Effect	Δscore
4:107932132:GG:G	donor_gain	1.0000
4:107932133:GG:G	donor_gain	1.0000
4:107944968:AGG:A	acceptor_gain	1.0000
4:107944969:GGG:G	acceptor_gain	1.0000
4:107947370:A:AG	acceptor_gain	1.0000
4:107947371:C:G	acceptor_gain	1.0000
4:107947372:A:AG	acceptor_gain	1.0000
4:107947373:T:G	acceptor_gain	1.0000
4:107947374:A:AG	acceptor_gain	1.0000
4:107947375:G:GG	acceptor_gain	1.0000
4:107947375:GAA:G	acceptor_gain	1.0000
4:107947375:GAAAA:G	acceptor_gain	1.0000
4:107947474:G:GT	donor_gain	1.0000
4:107947497:G:GA	donor_gain	1.0000
4:107949345:TTTA:T	acceptor_loss	1.0000
4:107949346:TTA:T	acceptor_loss	1.0000
4:107949347:TA:T	acceptor_loss	1.0000
4:107949348:A:AG	acceptor_gain	1.0000
4:107949349:G:GG	acceptor_gain	1.0000
4:107949349:GT:G	acceptor_gain	1.0000
4:107949476:G:GT	donor_gain	1.0000
4:107949512:GGA:G	donor_gain	1.0000
4:107949513:GA:G	donor_gain	1.0000
4:107949514:A:G	donor_gain	1.0000
4:107949514:ATAGG:A	donor_loss	1.0000
4:107949515:TAGGT:T	donor_loss	1.0000
4:107949518:G:GA	donor_loss	1.0000
4:107949519:T:A	donor_loss	1.0000
4:107932129:GAAGG:G	donor_gain	0.9900
4:107944964:TTGCA:T	acceptor_loss	0.9900

AlphaMissense

3574 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:107945013:G:C	R178S	0.998
4:107945013:G:T	R178S	0.998
4:107947484:G:C	R412T	0.998
4:107949508:T:C	F483L	0.998
4:107949510:T:A	F483L	0.998
4:107949510:T:G	F483L	0.998
4:107932091:C:A	R150S	0.997
4:107945012:G:C	R178T	0.997
4:107947462:G:C	A405P	0.997
4:107947484:G:T	R412M	0.997
4:107947485:G:C	R412S	0.997
4:107947485:G:T	R412S	0.997
4:107950245:G:A	G486E	0.997
4:107949460:T:C	F467L	0.996
4:107949462:T:A	F467L	0.996
4:107949462:T:G	F467L	0.996
4:107945536:G:T	G353W	0.995
4:107945566:T:A	W363R	0.995
4:107945566:T:C	W363R	0.995
4:107949427:T:A	W456R	0.995
4:107949427:T:C	W456R	0.995
4:107950245:G:T	G486V	0.995
4:107950256:T:C	C490R	0.995
4:107944999:T:A	W174R	0.994
4:107944999:T:C	W174R	0.994
4:107945546:C:T	T356I	0.994
4:107949508:T:A	F483I	0.994
4:107932091:C:G	R150G	0.993
4:107945012:G:T	R178M	0.993
4:107945036:G:C	R186P	0.993

dbSNP variants (sampled 300 via entrez): RS10002671 (4:107944902 G>A,C,T), RS1000504287 (4:107931148 T>C), RS10006005 (4:107945940 G>A), RS10006604 (4:107937609 T>A,C), RS1000680665 (4:107936334 A>G), RS1000683169 (4:107936097 GTCT>G), RS1000974357 (4:107930706 T>C,G), RS10012561 (4:107939149 T>A,C), RS1001712858 (4:107951499 G>A), RS1001748293 (4:107953253 C>T), RS1001781686 (4:107951159 A>G,T), RS10018413 (4:107946636 T>A,C,G), RS1002182557 (4:107940672 C>T), RS1002254591 (4:107940039 T>C), RS1002262367 (4:107947805 T>A)

Disease associations

OMIM: gene MIM:610670 | disease phenotypes: MIM:615030, MIM:303350, MIM:231530, MIM:270800

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary spastic paraplegia 56	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hereditary spastic paraplegia	Definitive	AR

Mondo (7): hereditary spastic paraplegia 56 (MONDO:0014015), hereditary spastic paraplegia (MONDO:0019064), congenital nervous system disorder (MONDO:0002320), 3-hydroxyacyl-CoA dehydrogenase deficiency (MONDO:0017715), neurodegenerative disease (MONDO:0005559), hereditary spastic paraplegia 5A (MONDO:0010047), intellectual disability (MONDO:0001071)

Orphanet (6): Autosomal recessive spastic paraplegia type 56 (Orphanet:320411), Hereditary spastic paraplegia (Orphanet:685), 3-hydroxyacyl-CoA dehydrogenase deficiency (Orphanet:309127), Hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency (Orphanet:71212), Autosomal recessive spastic paraplegia type 5A (Orphanet:100986), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001249	Intellectual disability
HP:0001258	Spastic paraplegia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001332	Dystonia
HP:0002064	Spastic gait
HP:0002079	Hypoplasia of the corpus callosum
HP:0002135	Basal ganglia calcification
HP:0002317	Unsteady gait
HP:0002395	Lower limb hyperreflexia
HP:0002453	Abnormal globus pallidus morphology
HP:0002500	Abnormal cerebral white matter morphology
HP:0003477	Peripheral axonal neuropathy
HP:0003487	Babinski sign
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0007350	Upper limb hyperreflexia
HP:0011463	Childhood onset
HP:0030051	Tip-toe gait
HP:0031936	Delayed ability to walk
HP:0100543	Cognitive impairment

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90000025_279	Appendicular lean mass	3.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004980	appendicular lean mass

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D019636	Neurodegenerative Diseases	C10.574
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C535310	3-Hydroxyacyl-CoA Dehydrogenase Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523986 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 15,540 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL477772	PAZOPANIB	4	15,540

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — CYP2 family: physiological enzymes subset

ChEMBL bioactivities

16 potent at pChembl≥5 of 17 total, top 16 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.60	IC50	251.2	nM	CHEMBL601428
6.16	IC50	700	nM	CHEMBL3330409
6.05	IC50	900	nM	CHEMBL3330410
5.96	IC50	1100	nM	CHEMBL2130955
5.72	IC50	1900	nM	CHEMBL2130955
5.60	IC50	2500	nM	CHEMBL5612347
5.55	IC50	2800	nM	CHEMBL2130955
5.43	IC50	3700	nM	CHEMBL5406721
5.43	IC50	3700	nM	CHEMBL46909
5.42	IC50	3800	nM	CHEMBL5418617
5.41	IC50	3900	nM	CHEMBL5429178
5.31	IC50	4900	nM	CHEMBL2130955
5.23	IC50	5900	nM	CHEMBL5406218
5.22	IC50	6053	nM	CHEMBL65590
5.10	IC50	7900	nM	PAZOPANIB
5.00	IC50	1e+04	nM	CHEMBL5395150

PubChem BioAssay actives

18 with measured affinity, of 466 total; 15 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
8-imidazol-1-yl-5,6,7,8-tetrahydroquinoline	2022035: Inhibition of CYP450 (unknown origin)	ic50	0.0335	uM
N-(4-chlorophenyl)-5-ethyl-N-methyl-3-phenyl-1,2-oxazole-4-carboxamide	2108148: Inhibition of CYP450 (unknown origin)	ic50	0.2512	uM
2-(dimethylamino)-2-(2-ethylphenyl)-N-[3-(3-sulfamoylphenyl)-1H-indazol-5-yl]acetamide	2119433: Inhibition of CYP450 (unknown origin)	ic50	0.7000	uM
2-pyrrolidin-1-yl-N-[3-(3-sulfamoylphenyl)-1H-indazol-5-yl]-2-thiophen-3-ylacetamide	2119433: Inhibition of CYP450 (unknown origin)	ic50	0.9000	uM
2-[4-(trifluoromethyl)phenyl]chromen-4-one	1860369: Inhibition of CYP450 in human HCT-116 cells assessed as 20-HETE formation in presence of arachidonic acid incubated for 15 mins by multi-enzyme assay based LC-MS/MS analysis	ic50	1.1000	uM
4-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-4-N-[[(7R)-5,6,7,8-tetrahydro-1,6-naphthyridin-7-yl]methyl]cyclohexane-1,4-diamine	2124397: Inhibition of CYP450 (unknown origin)	ic50	2.5000	uM
1-[3-(2,4-dimethoxyphenyl)phenyl]-2,4-dimethoxybenzene	1973305: Inhibition of CYP450 in pooled human liver microsomes in presence of NADPH measured every 3 mins for 120 mins by fluorescence based analysis	ic50	3.7000	uM
1-[(E)-2-(2,4-dimethoxyphenyl)ethenyl]-3,5-dimethoxybenzene	1973305: Inhibition of CYP450 in pooled human liver microsomes in presence of NADPH measured every 3 mins for 120 mins by fluorescence based analysis	ic50	3.7000	uM
2,4-bis(3,5-dimethoxyphenyl)pyrimidine	1973305: Inhibition of CYP450 in pooled human liver microsomes in presence of NADPH measured every 3 mins for 120 mins by fluorescence based analysis	ic50	3.8000	uM
2,5-bis(3,5-dimethoxyphenyl)thiophene	1973305: Inhibition of CYP450 in pooled human liver microsomes in presence of NADPH measured every 3 mins for 120 mins by fluorescence based analysis	ic50	3.9000	uM
4-[2-(2,4-dimethoxyphenyl)-1,3-thiazol-4-yl]phenol	1973305: Inhibition of CYP450 in pooled human liver microsomes in presence of NADPH measured every 3 mins for 120 mins by fluorescence based analysis	ic50	5.9000	uM
1-pyridin-4-yl-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-4-ol	2022025: Inhibition of CYP450 in human liver microsomes	ic50	6.0534	uM
(5R)-3-[1-(1H-indol-2-ylmethyl)piperidin-4-yl]-5-(6-methoxyquinolin-4-yl)-1,3-oxazolidin-2-one	306257: Inhibition of CYP450	ic50	7.9433	uM
3-[1-[(3,4-dimethylphenyl)methyl]piperidin-4-yl]-5-(6-methoxyquinolin-4-yl)-1,3-oxazolidin-2-one	306257: Inhibition of CYP450	ic50	10.0000	uM
1-[3-(3,5-dimethoxyphenyl)phenyl]-3,5-dimethoxybenzene	1973305: Inhibition of CYP450 in pooled human liver microsomes in presence of NADPH measured every 3 mins for 120 mins by fluorescence based analysis	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	7
Benzo(a)pyrene	increases methylation, increases expression	3
bisphenol A	decreases methylation, increases expression	2
Arsenic	increases expression, affects methylation, decreases methylation	2
Cyclosporine	decreases expression	2
FR900359	decreases phosphorylation	1
urushiol	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
trichostatin A	increases expression	1
sodium arsenite	decreases expression	1
nickel sulfate	decreases expression	1
prochloraz	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
arachidonoylserotonin	increases oxidation	1
obeticholic acid	increases expression	1
abrine	decreases expression	1
(+)-JQ1 compound	increases expression	1
Bortezomib	increases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Arbutin	increases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Calcitriol	increases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Formaldehyde	increases expression	1
Mercury	increases expression	1
Nickel	decreases expression	1
Dihydrotestosterone	increases expression	1
Testosterone	affects cotreatment, increases expression	1

ChEMBL screening assays

183 unique, capped per target: 181 admet, 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2060324	ADMET	Inhibition of CYP450	Rapid identification of ETP-46992, orally bioavailable PI3K inhibitor, selective versus mTOR. — Bioorg Med Chem Lett
CHEMBL4614611	Binding	Drug metabolism in human liver microsomes assessed as Cytochrome P450-mediated formation of 12-OHNVP by measuring Kcat/Km ratio in presence of NADPH regenerating reagents by uHPLC-MS/MS analysis	Twelfth-Position Deuteration of Nevirapine Reduces 12-Hydroxy-Nevirapine Formation and Nevirapine-Induced Hepatocyte Death. — J Med Chem

Cellosaurus cell lines

4 cell lines: 4 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C1SK	AIBNi015-A	Induced pluripotent stem cell	Female
CVCL_C1SL	AIBNi016-A	Induced pluripotent stem cell	Female
CVCL_C1SM	AIBNi017-A	Induced pluripotent stem cell	Female
CVCL_C1SN	AIBNi018-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT01662414	PHASE4	COMPLETED	Effect of Undenatured Cysteine-Rich Whey Protein Isolate (HMS 90®) in Patients With Parkinson’s Disease
NCT04871464	PHASE4	UNKNOWN	Role and Mechanism of Probiotics in Improving Motor Symptoms in Mild to Moderate Parkinson’s Disease
NCT05357612	PHASE4	RECRUITING	Characterization of the Serotonin 2A Receptor Selective PET Tracer [18F]MH.MZ in Patients With Neurodegenerative Diseases
NCT05508789	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Donanemab (LY3002813) in Participants With Early Symptomatic Alzheimer’s Disease (TRAILBLAZER-ALZ 5)
NCT05738486	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Different Donanemab (LY3002813) Dosing Regimens in Adults With Early Alzheimer’s Disease (TRAILBLAZER-ALZ 6)
NCT06111014	PHASE3	TERMINATED	Continuation Study for Latozinemab
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT00001365	PHASE2	COMPLETED	Dextromethorphan for the Treatment of Parkinson’s Disease and Similar Conditions of the Nervous System
NCT00406029	PHASE2	COMPLETED	Dyskinesia in Parkinson’s Disease (Study P04501)
NCT00537017	PHASE2	COMPLETED	Follow Up Safety Study of SCH 420814 in Subjects With Parkinson’s Disease (P05175)
NCT00907283	PHASE2	UNKNOWN	Ferrochelating Treatment in Patients Affected by Neurodegeneration With Brain Iron Accumulation (NBIA)
NCT01518374	PHASE2	COMPLETED	Clinical Evaluation of Florbetapir F 18 (18F-AV-45)
NCT02656498	PHASE2	COMPLETED	[18F]THK-5351 Positron Emission Computed Tomography Study of Normal, Mild Cognitive Impairment, Alzheimer’s Disease and Other Neurodegenerative Disease
NCT03127514	PHASE2	COMPLETED	AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT03538522	PHASE2	COMPLETED	A Double-Blind, Placebo-Controlled Safety and Efficacy Study of NA-831
NCT04838301	PHASE2	RECRUITING	Allopregnanolone Regenerative Therapeutic for Mild Alzheimer’s Disease
NCT04937452	PHASE2	COMPLETED	Dopaminergic Therapy for Frontotemporal Dementia Patients
NCT05318976	PHASE2	COMPLETED	A Study of XPro1595 in Patients With Early Alzheimer’s Disease With Biomarkers of Inflammation
NCT05321498	PHASE2	WITHDRAWN	Study to Assess the Efficacy of XPro1595 in Patients With Mild Cognitive Impairment With Biomarkers of Inflammation
NCT05479981	PHASE2	COMPLETED	Extension of AOC 1001-CS1 (MARINA) Study in Adult Myotonic Dystrophy Type 1 (DM1) Patients
NCT05522387	PHASE2	TERMINATED	An Open-Label Extension of XPro1595 in Patients With Alzheimer’s Disease
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT00316797	PHASE1	COMPLETED	Biodistribution and Safety of a Radiopharmaceutical in Healthy Subjects
NCT01758510	PHASE1	COMPLETED	Safety Study of HLA-haplo Matched Allogenic Bone Marrow Derived Stem Cell Treatment in Amyotrophic Lateral Sclerosis
NCT02267434	PHASE1	COMPLETED	Study Assessing Tolerability and Safety of AFFITOPE® PD03A in Patients With Early Parkinson’s Disease
NCT02270489	PHASE1	COMPLETED	Study Assessing Safety and Therapeutic Activity of AFFITOPE® PD01A and PD03A in Patients With Early MSA
NCT03065192	PHASE1	COMPLETED	Safety and Efficacy Study of VY-AADC01 for Advanced Parkinson’s Disease
NCT04578028	PHASE1	COMPLETED	A First in Human Study to Assess the Safety, Tolerability and Pharmacokinetics of ONO-2808-01 in Healthy Participants
NCT05143463	PHASE1	COMPLETED	A FIH Study to Assess the Safety and Tolerability of NS Intravenous NS101 Infusion
NCT05490576	PHASE1	UNKNOWN	Tau And Connectomics In TES Study
NCT05792163	PHASE1	COMPLETED	A First Time in Human Study of SNP318 as a Treatment for Neurodegenerative Diseases Including Alzheimer’s Disease
NCT07232147	PHASE1	NOT_YET_RECRUITING	Clinical Research on Stem Cell Therapy for Parkinson’s Disease
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT06478238	EARLY_PHASE1	RECRUITING	Calcium Folinate Treatment of Spastic Paraplegia 56
NCT00023075	Not specified	COMPLETED	Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis