CPT1C

Summary

CPT1C (carnitine palmitoyltransferase 1C, HGNC:18540) is a protein-coding gene on chromosome 19q13.33, encoding Palmitoyl thioesterase CPT1C (Q8TCG5). Palmitoyl thioesterase specifically expressed in the endoplasmic reticulum of neurons.

This gene encodes a member of the carnitine/choline acetyltransferase family. The encoded protein regulates the beta-oxidation and transport of long-chain fatty acids into mitochondria, and may play a role in the regulation of feeding behavior and whole-body energy homeostasis. Alternatively spliced transcript variants encoding multiple protein isoforms have been observed for this gene.

Source: NCBI Gene 126129 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary spastic paraplegia 73 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 434 total — 8 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 28
• MANE Select transcript: NM_001199753

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18540
Approved symbol	CPT1C
Name	carnitine palmitoyltransferase 1C
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Aliases	FLJ23809, CPTIC, CPT1P, CATL1
Ensembl gene	ENSG00000169169
Ensembl biotype	protein_coding
OMIM	608846
Entrez	126129

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 26 protein_coding, 9 retained_intron, 4 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000295404, ENST00000323446, ENST00000392518, ENST00000405931, ENST00000594038, ENST00000594431, ENST00000594587, ENST00000595031, ENST00000595568, ENST00000595901, ENST00000595969, ENST00000596701, ENST00000596922, ENST00000597099, ENST00000598072, ENST00000598259, ENST00000598293, ENST00000598396, ENST00000598647, ENST00000598714, ENST00000599023, ENST00000599937, ENST00000600944, ENST00000602019, ENST00000878761, ENST00000878762, ENST00000878763, ENST00000878764, ENST00000878765, ENST00000878766, ENST00000878767, ENST00000929711, ENST00000929712, ENST00000929713, ENST00000929714, ENST00000929715, ENST00000929716, ENST00000941223, ENST00000941224, ENST00000941225

RefSeq mRNA: 11 — MANE Select: NM_001199753 NM_001136052, NM_001199752, NM_001199753, NM_001378482, NM_001378483, NM_001378484, NM_001378485, NM_001378486, NM_001378487, NM_001378488, NM_152359

CCDS: CCDS12779, CCDS46147

Canonical transcript exons

ENST00000598293 — 20 exons

Exon	Start	End
ENSE00001562845	49691821	49691889
ENSE00002239677	49691116	49691340
ENSE00003505449	49712736	49712849
ENSE00003505743	49705214	49705298
ENSE00003511311	49710723	49710857
ENSE00003518975	49711809	49711961
ENSE00003522309	49697326	49697465
ENSE00003529173	49692239	49692393
ENSE00003531375	49701317	49701418
ENSE00003537784	49713420	49713731
ENSE00003558982	49710320	49710484
ENSE00003571079	49701497	49701634
ENSE00003603964	49705007	49705114
ENSE00003606574	49700684	49700855
ENSE00003640621	49705909	49706104
ENSE00003658385	49707518	49707623
ENSE00003659007	49712972	49713064
ENSE00003678121	49708723	49708839
ENSE00003694003	49706231	49706413
ENSE00003788171	49704710	49704787

Expression profiles

Bgee: expression breadth ubiquitous, 190 present calls, max score 97.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.5996 / max 178.9283, expressed in 1063 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
177052	6.4804	1062
177053	0.1192	58

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	97.81	gold quality
cerebellar hemisphere	UBERON:0002245	97.47	gold quality
cerebellar cortex	UBERON:0002129	97.36	gold quality
right frontal lobe	UBERON:0002810	96.76	gold quality
adenohypophysis	UBERON:0002196	96.37	gold quality
cerebellum	UBERON:0002037	96.11	gold quality
cortical plate	UBERON:0005343	95.89	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.86	gold quality
anterior cingulate cortex	UBERON:0009835	95.75	gold quality
caudate nucleus	UBERON:0001873	95.22	gold quality
pituitary gland	UBERON:0000007	94.89	gold quality
nucleus accumbens	UBERON:0001882	94.64	gold quality
putamen	UBERON:0001874	94.51	gold quality
ganglionic eminence	UBERON:0004023	94.47	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.24	gold quality
amygdala	UBERON:0001876	93.86	gold quality
hypothalamus	UBERON:0001898	93.75	gold quality
prefrontal cortex	UBERON:0000451	93.61	gold quality
neocortex	UBERON:0001950	93.47	gold quality
frontal cortex	UBERON:0001870	92.96	gold quality
cerebral cortex	UBERON:0000956	92.84	gold quality
forebrain	UBERON:0001890	92.68	gold quality
primary visual cortex	UBERON:0002436	92.57	gold quality
brain	UBERON:0000955	92.55	gold quality
ventricular zone	UBERON:0003053	92.46	gold quality
Ammon’s horn	UBERON:0001954	92.29	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	91.58	gold quality
middle temporal gyrus	UBERON:0002771	91.56	gold quality
temporal lobe	UBERON:0001871	90.56	gold quality
stromal cell of endometrium	CL:0002255	89.83	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.69

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PRKAA1

Literature-anchored findings (GeneRIF, showing 21)

• CPT1c is localized in endoplasmic reticulum of neurons and has carnitine palmitoyltransferase activity (PMID:18192268)
• Accumulation of 3-hydroxylated intermediates of long-chain fatty acids may contribute to the pathogenesis of retinopathy in MTP deficiencies. (PMID:18385088)
• cells can use a novel mechanism involving CPT1C and fatty acid metabolism to protect against metabolic stress (PMID:21576264)
• Data suggest that an involvement of CPT1C in cellular energy-sensing pathways and provide evidence for a role of CPT1C in hypothalamic regulation of energy homeostasis. (PMID:21961029)
• High grade glioblastoma is associated with increased level of ZFP57, a protein involved in gene imprinting, and aberrant expression of CPT1A and CPT1C. (PMID:24618825)
• CPT1C mutation associated with novel form of pure autosomal dominant hereditary spastic paraplegia. (PMID:25751282)
• CPT1c is found in brain regions that are related to food intake and neuropsychiatric disease. CPT1c affects ceramide levels, endocannabionoids, and oxidative processes and may play an important role in various brain functions such as learning. (PMID:26041663)
• CPT1C binds malonyl-CoA and long-chain acyl-CoA suggest that it is a sensor of lipid metabolism in neurons, where it appears to impact ceramide and triacylglycerol metabolism. [review] (PMID:26708865)
• Depletion of PPARalpha resulted in low CPT1C expression. (PMID:28334197)
• This study identifies CPT1C as a novel biomarker and key regulator of cancer cell senescence through mitochondria-associated metabolic reprograming, and suggests that inhibition of CPT1C may represent a new therapeutic strategy for cancer treatment through induction of tumor senescence. (PMID:29317762)
• These results indicate that CPT1C-mediated autophagy enhancement in glucose deprivation conditions allows a greater availability of lipids to be used as fuel substrate for ATP generation, revealing a new role of CPT1C in stem cell adaptation to low nutrient environments. (PMID:29725060)
• CPT1C exerts the most significant effect on mitochondrial dysfunction-associated tumor cellular senescence among the members of the carnitine palmitoyltransferases family. (PMID:30070697)
• We demonstrate in HeLa cells that carnitine palmitoyltransferase 1C (CPT1C) senses malonyl-CoA and enhances LE/Lys anterograde transport by interacting with the endoplasmic reticulum protein protrudin and facilitating the transfer of Kinesin-1 from protrudin to LE/Lys (PMID:31868590)
• Carnitine palmitoyltransferase 1C contributes to progressive cellular senescence. (PMID:32289751)
• Carnitine palmitoyltransferase 1C reverses cellular senescence of MRC-5 fibroblasts via regulating lipid accumulation and mitochondrial function. (PMID:32632982)
• A novel miR-1291-ERRalpha-CPT1C axis modulates tumor cell proliferation, metabolism and tumorigenesis. (PMID:32641987)
• Cpt1c Downregulation Causes Plasma Membrane Remodelling and Anthracycline Resistance in Breast Cancer. (PMID:36674468)
• To be or not to be a fat burner, that is the question for cpt1c in cancer cells. (PMID:36693836)
• Metabolic Flux Analysis Reveals the Roles of Stearate and Oleate on CPT1C-mediated Tumor Cell Senescence. (PMID:37151873)
• APC/C-regulated CPT1C promotes tumor progression by upregulating the energy supply and accelerating the G1/S transition. (PMID:38783346)
• The YY1-CPT1C signaling axis modulates the proliferation and metabolism of pancreatic tumor cells under hypoxia. (PMID:38996932)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cpt1c	ENSMUSG00000007783
rattus_norvegicus	Cpt1c	ENSRNOG00000026163
drosophila_melanogaster	whd	FBGN0261862
caenorhabditis_elegans		WBGENE00012907
caenorhabditis_elegans		WBGENE00021002

Paralogs (6): CROT (ENSG00000005469), CHAT (ENSG00000070748), CRAT (ENSG00000095321), CPT1A (ENSG00000110090), CPT2 (ENSG00000157184), CPT1B (ENSG00000205560)

Protein

Protein identifiers

Palmitoyl thioesterase CPT1C — Q8TCG5 (reviewed: Q8TCG5)

Alternative names: Carnitine O-palmitoyltransferase 1, brain isoform, Carnitine palmitoyltransferase 1C, Carnitine palmitoyltransferase I

All UniProt accessions (9): Q8TCG5, M0QZ13, M0R0D3, M0R115, M0R1F9, M0R2B9, M0R2H6, M0R2V3, M0R399

UniProt curated annotations — full annotation on UniProt →

Function. Palmitoyl thioesterase specifically expressed in the endoplasmic reticulum of neurons. Modulates the trafficking of the glutamate receptor, AMPAR, to plasma membrane through depalmitoylation of GRIA1. Also regulates AMPR trafficking through the regulation of SACM1L phosphatidylinositol-3-phosphatase activity by interaction in a malonyl-CoA dependent manner. Binds malonyl-CoA and couples malonyl-CoA to ceramide levels, necessary for proper spine maturation and contributing to systemic energy homeostasis and appetite control. Binds to palmitoyl-CoA, but does not have carnitine palmitoyltransferase 1 catalytic activity or at very low levels.

Subunit / interactions. Peripherally associated with AMPAR complex. AMPAR complex consists of an inner core made of 4 pore-forming GluA/GRIA proteins (GRIA1, GRIA2, GRIA3 and GRIA4) and 4 major auxiliary subunits arranged in a twofold symmetry. One of the two pairs of distinct binding sites is occupied either by CNIH2, CNIH3 or CACNG2, CACNG3. The other harbors CACNG2, CACNG3, CACNG4, CACNG8 or GSG1L. This inner core of AMPAR complex is complemented by outer core constituents binding directly to the GluA/GRIA proteins at sites distinct from the interaction sites of the inner core constituents. Outer core constituents include at least PRRT1, PRRT2, CKAMP44/SHISA9, FRRS1L and NRN1. The proteins of the inner and outer core serve as a platform for other, more peripherally associated AMPAR constituents, including CPT1C. Alone or in combination, these auxiliary subunits control the gating and pharmacology of the AMPAR complex and profoundly impact their biogenesis and protein processing. Interacts with SACM1L; the interaction regulates SACM1L phosphatidylinositol-3-phosphatase activity and translocation to endoplasmic reticulum/trans Golgi network in a malonyl-CoA dependent manner. Interacts with ATL1.

Subcellular location. Cell projection. Dendrite. Axon. Endoplasmic reticulum membrane.

Tissue specificity. Expressed predominantly in brain and testis. Expressed in motor neurons.

Disease relevance. Spastic paraplegia 73, autosomal dominant (SPG73) [MIM:616282] 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. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. CPT1 enzymes are comprised of an N-terminal regulatory domain and a C-terminal catalytic domain that are separated by two transmembrane helices. In CPT1A, the regulatory domain, termed N, adopts a malonyl-CoA inhibitory and non-inhibitory state, Nalpha and Nbeta, respectively, which differ in their association with the catalytic domain. In CPT1C, the inhibitory Nalpha state is structurally homolog whereas the non-inhibitory Nbeta state is severely destabilized which probably contributes to the low catalytic activity of CPT1C relative to CPT1A and makes its association with the catalytic domain unlikely.

Similarity. Belongs to the carnitine/choline acetyltransferase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8TCG5-1	1	yes
Q8TCG5-2	2
Q8TCG5-3	3

RefSeq proteins (11): NP_001129524, NP_001186681, NP_001186682, NP_001365411, NP_001365412, NP_001365413, NP_001365414, NP_001365415, NP_001365416, NP_001365417, NP_689572 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000542	Carn_acyl_trans	Family
IPR023213	CAT-like_dom_sf	Homologous_superfamily
IPR032476	CPT_N	Domain
IPR039551	Cho/carn_acyl_trans_1_2	Domain
IPR042231	Cho/carn_acyl_trans_2	Homologous_superfamily

Pfam: PF00755, PF16484

Enzyme classification (BRENDA):

• EC 2.3.1.21 — carnitine O-palmitoyltransferase (BRENDA: 24 organisms, 112 substrates, 138 inhibitors, 206 Km, 16 kcat entries)

Substrate kinetics (BRENDA)

15 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-CARNITINE	0.0017–127	100
PALMITOYL-COA	0.0008–25.35	67
BUTYRYL-COA	0.0051–0.03	2
DECANOYL-COA	0.0009–0.017	2
HEXANOYL-COA	0.0018–0.152	2
L-PALMITOYLCARNITINE	0.123–0.14	2
LAUROYL-COA	0.011–0.013	2
MYRISTOYL-COA	0.0012–0.031	2
OCTANOYL-COA	0.0085–0.023	2
STEAROYL-COA	0.0017–0.018	2
ACETYL-COA	0.022	1
COA	0.0055	1
DODECANOYL-COA	0.004	1
L-OCTANOYLCARNITINE	1.139	1
TRANS-2-HEXADECENOYL-COA	0.0081	1

Catalyzed reactions (Rhea), 1 shown:

• S-hexadecanoyl-L-cysteinyl-[protein] + H2O = L-cysteinyl-[protein] + hexadecanoate + H(+) (RHEA:19233)

UniProt features (25 total): binding site 4, topological domain 3, mutagenesis site 3, sequence conflict 3, splice variant 2, transmembrane region 2, region of interest 2, chain 1, sequence variant 1, turn 1, helix 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2M76	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TCG5-F1	88.81	0.73

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 (1): 470 (proton acceptor)

Ligand- & substrate-binding residues (4): 552–564; 586; 588; 599

Mutagenesis-validated functional residues (3):

Position	Phenotype
252	loss of palmitoyl thioesterase activity.
470	loss of palmitoyl thioesterase activity. no effect on carnitine o-palmitoyltransferase inactivity.
474	loss of palmitoyl thioesterase activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 162 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, PID_HNF3B_PATHWAY, GOBP_MACROMOLECULE_DEACYLATION, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, KEGG_PPAR_SIGNALING_PATHWAY, GOBP_LIPID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_AMINO_ACID_BETAINE_METABOLIC_PROCESS, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOCC_NEURON_PROJECTION, HAN_SATB1_TARGETS_DN, MARTORIATI_MDM4_TARGETS_FETAL_LIVER_UP

GO Biological Process (6): fatty acid metabolic process (GO:0006631), carnitine metabolic process (GO:0009437), regulation of postsynaptic membrane neurotransmitter receptor levels (GO:0099072), lipid metabolic process (GO:0006629), fatty acid beta-oxidation (GO:0006635), macromolecule depalmitoylation (GO:0098734)

GO Molecular Function (7): palmitoyl-(protein) hydrolase activity (GO:0008474), acyltransferase activity (GO:0016746), catalytic activity (GO:0003824), carnitine O-palmitoyltransferase activity (GO:0004095), protein binding (GO:0005515), transferase activity (GO:0016740), hydrolase activity (GO:0016787)

GO Cellular Component (9): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), axon (GO:0030424), dendrite (GO:0030425), AMPA glutamate receptor complex (GO:0032281), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), membrane (GO:0016020), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
catalytic activity	2
neuron projection	2
synapse	2
lipid metabolic process	1
monocarboxylic acid metabolic process	1
amino-acid betaine metabolic process	1
regulation of biological quality	1
primary metabolic process	1
fatty acid catabolic process	1
fatty acid ligase activity	1
fatty acid oxidation	1
macromolecule deacylation	1
thiolester hydrolase activity	1
palmitoyl hydrolase activity	1
catalytic activity, acting on a protein	1
transferase activity	1
molecular_function	1
carnitine O-acyltransferase activity	1
O-palmitoyltransferase activity	1
binding	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
dendritic tree	1
ionotropic glutamate receptor complex	1

Protein interactions and networks

STRING

1442 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CPT1C	SLC25A20	O43772	924
CPT1C	CHKB	Q9Y259	901
CPT1C	AASDH	Q4L235	831
CPT1C	UCP3	P55916	807
CPT1C	FRRS1L	Q9P0K9	779
CPT1C	PPARD	Q03181	734
CPT1C	UCP2	P55851	716
CPT1C	KLF5	Q13887	698
CPT1C	ACADM	P11310	688
CPT1C	UCP1	P25874	681
CPT1C	PPARA	Q07869	678
CPT1C	PPARGC1A	Q9UBK2	674
CPT1C	ACADL	P28330	672
CPT1C	PDK4	Q16654	637
CPT1C	FASN	P49327	637

IntAct

2 interactions, top by confidence:

A	B	Type	Score
CPT1C	PPM1F	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (4): PPM1F (Affinity Capture-MS), CPT1C (Affinity Capture-MS), CPT1C (Co-localization), CPT1C (Affinity Capture-MS)

ESM2 similar proteins: A2RTX5, A2Z8S0, B2ZGJ1, F1LN46, O19094, P07668, P11035, P11466, P13222, P17569, P18886, P23786, P28329, P32198, P32738, P32756, P32796, P36859, P43155, P47934, P49696, P50416, P52825, P52826, P56523, P80235, P97742, Q03059, Q0V9S0, Q2KJB7, Q58DK1, Q5U3U3, Q60HG9, Q63704, Q68Y62, Q6P4X5, Q704S8, Q75G68, Q7ZXE1, Q80VY9

Diamond homologs: F1LN46, P28329, P32198, P50416, P97742, Q03059, Q58DK1, Q60HG9, Q63704, Q68Y62, Q8BGD5, Q8HY46, Q8TCG5, Q924X2, Q92523, B2ZGJ1, P11466, P13222, P32738, P43155, P52826, Q704S8, Q90YJ9, Q9DC50, Q9UKG9, O19094, P07668, P18886, P23786, P32756, P32796, P47934, P52825, Q00614, Q2KJB7, Q6P4X5, Q7ZXE1, Q5U3U3

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
PRKAA1	“up-regulates quantity by expression”	CPT1C	“transcriptional regulation”
malonyl-CoA	“down-regulates activity”	CPT1C	binding
CPT1C	“down-regulates quantity”	(R)-carnitine	“chemical modification”
CPT1C	“down-regulates quantity”	palmitoyl-CoA(4-)	“chemical modification”
CPT1C	“up-regulates quantity”	O-palmitoyl-L-carnitine	“chemical modification”
CPT1C	“up-regulates quantity”	“coenzyme A(4-)”	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	8
Uncertain significance	225
Likely benign	151
Benign	16

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
1431343	NM_001199753.2(CPT1C):c.2057_2061del (p.Ile686fs)	Pathogenic
1455162	NM_001199753.2(CPT1C):c.1018C>T (p.Arg340Ter)	Pathogenic
189198	NM_001199753.2(CPT1C):c.109C>T (p.Arg37Cys)	Pathogenic
2085835	NM_001199753.2(CPT1C):c.1669C>T (p.Arg557Ter)	Pathogenic
2190149	NM_001199753.2(CPT1C):c.652C>T (p.Gln218Ter)	Pathogenic
2722957	NM_001199753.2(CPT1C):c.558C>A (p.Tyr186Ter)	Pathogenic
2733165	NM_001199753.2(CPT1C):c.1735_1736del (p.Arg579fs)	Pathogenic
3668080	NM_001199753.2(CPT1C):c.1233dup (p.Ala412fs)	Pathogenic
2032169	NM_001199753.2(CPT1C):c.2019+1G>C	Likely pathogenic
2831950	NM_001199753.2(CPT1C):c.694-2A>G	Likely pathogenic
3027450	NM_001199753.2(CPT1C):c.1045C>T (p.Arg349Ter)	Likely pathogenic
3340522	NM_001199753.2(CPT1C):c.1081C>T (p.Gln361Ter)	Likely pathogenic
3700548	NM_001199753.2(CPT1C):c.1450-2A>C	Likely pathogenic
4537455	NM_001199753.2(CPT1C):c.733C>T (p.Arg245Ter)	Likely pathogenic
623959	NM_001199753.2(CPT1C):c.1655G>T (p.Gly552Val)	Likely pathogenic
978230	NM_001199753.2(CPT1C):c.2T>G (p.Met1Arg)	Likely pathogenic

SpliceAI

3002 predictions. Top by Δscore:

Variant	Effect	Δscore
19:49691338:GTG:G	donor_gain	1.0000
19:49691342:T:A	donor_loss	1.0000
19:49701415:CAAG:C	donor_loss	1.0000
19:49701416:AAGGT:A	donor_loss	1.0000
19:49701417:AGGTG:A	donor_loss	1.0000
19:49701493:TTAG:T	acceptor_loss	1.0000
19:49701495:A:AG	acceptor_gain	1.0000
19:49701495:AGT:A	acceptor_loss	1.0000
19:49701496:G:GC	acceptor_gain	1.0000
19:49701496:GT:G	acceptor_gain	1.0000
19:49701496:GTA:G	acceptor_gain	1.0000
19:49701496:GTAC:G	acceptor_gain	1.0000
19:49701496:GTACC:G	acceptor_gain	1.0000
19:49701630:ATTAT:A	donor_gain	1.0000
19:49701631:TTAT:T	donor_gain	1.0000
19:49701635:G:GG	donor_gain	1.0000
19:49701672:GGC:G	donor_gain	1.0000
19:49704707:CAG:C	acceptor_loss	1.0000
19:49704708:A:AC	acceptor_loss	1.0000
19:49704709:G:GT	acceptor_loss	1.0000
19:49704997:T:A	acceptor_gain	1.0000
19:49705111:CCCGG:C	donor_loss	1.0000
19:49705112:CCGG:C	donor_loss	1.0000
19:49705113:CGGTG:C	donor_loss	1.0000
19:49705115:G:GG	donor_gain	1.0000
19:49705115:GT:G	donor_loss	1.0000
19:49705116:T:G	donor_loss	1.0000
19:49705211:CAG:C	acceptor_loss	1.0000
19:49705212:A:AG	acceptor_gain	1.0000
19:49705212:AGACT:A	acceptor_loss	1.0000

AlphaMissense

5216 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:49705052:G:T	G273W	0.997
19:49707519:T:A	W449R	0.997
19:49707519:T:C	W449R	0.997
19:49710784:G:C	R598P	0.997
19:49705948:T:A	V335D	0.996
19:49710780:G:C	G597R	0.996
19:49701631:T:A	N230K	0.995
19:49701631:T:G	N230K	0.995
19:49705298:G:C	D322H	0.995
19:49705007:G:C	D258H	0.994
19:49705053:G:A	G273E	0.994
19:49705243:C:G	C303W	0.994
19:49705278:G:C	R315P	0.994
19:49708822:T:A	W517R	0.994
19:49708822:T:C	W517R	0.994
19:49710771:T:C	F594L	0.994
19:49710773:C:A	F594L	0.994
19:49710773:C:G	F594L	0.994
19:49705050:C:A	A272D	0.993
19:49706104:G:T	R387M	0.993
19:49707529:A:T	K452I	0.993
19:49707530:A:C	K452N	0.993
19:49707530:A:T	K452N	0.993
19:49710781:G:T	G597V	0.993
19:49705047:G:C	R271P	0.992
19:49705049:G:C	A272P	0.992
19:49705083:G:C	R283P	0.992
19:49705241:T:C	C303R	0.992
19:49705968:T:C	F342L	0.992
19:49705970:C:A	F342L	0.992

dbSNP variants (sampled 300 via entrez): RS1000151538 (19:49703421 C>T), RS1000231962 (19:49703785 C>T), RS1000388855 (19:49691481 C>A,T), RS1000880518 (19:49695729 G>A), RS1000953332 (19:49692116 G>C), RS1000973362 (19:49696032 A>G), RS1001318183 (19:49702964 C>G), RS1001444117 (19:49707928 G>A), RS1001474367 (19:49709689 G>A), RS1001492160 (19:49691150 G>A), RS1001561090 (19:49701483 C>T), RS1001590122 (19:49703731 C>G), RS1001695900 (19:49703376 A>G,T), RS1001716111 (19:49709139 C>G), RS1002073745 (19:49696600 A>G)

Disease associations

OMIM: gene MIM:608846 | disease phenotypes: MIM:616282, MIM:303350

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary spastic paraplegia 73	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hereditary spastic paraplegia	Limited	AD

Mondo (2): hereditary spastic paraplegia 73 (MONDO:0014568), hereditary spastic paraplegia (MONDO:0019064)

Orphanet (2): Autosomal dominant spastic paraplegia type 73 (Orphanet:444099), Hereditary spastic paraplegia (Orphanet:685)

HPO phenotypes

28 total (28 of 28 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000012	Urinary urgency
HP:0000020	Urinary incontinence
HP:0000726	Dementia
HP:0001250	Seizure
HP:0001258	Spastic paraplegia
HP:0001288	Gait disturbance
HP:0001347	Hyperreflexia
HP:0001761	Pes cavus
HP:0002061	Lower limb spasticity
HP:0002064	Spastic gait
HP:0002166	Impaired vibration sensation in the lower limbs
HP:0002314	Degeneration of the lateral corticospinal tracts
HP:0002921	Abnormal cerebrospinal fluid morphology
HP:0003202	Skeletal muscle atrophy
HP:0003457	EMG abnormality
HP:0003487	Babinski sign
HP:0003581	Adult onset
HP:0003677	Slowly progressive
HP:0003701	Proximal muscle weakness
HP:0006886	Impaired distal vibration sensation
HP:0007020	Progressive spastic paraplegia
HP:0007199	Progressive spastic paraparesis
HP:0008944	Distal lower limb amyotrophy
HP:0009053	Distal lower limb muscle weakness
HP:0012898	Abnormal lower-limb motor evoked potentials
HP:0034397	Claw toe deformity
HP:0034399	Prolonged central motor conduction time

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST006482_11	Lung function (FEV1/FVC)	3.000000e-08
GCST006803_99	Schizophrenia	4.000000e-11
GCST007932_17	Medication use (thyroid preparations)	5.000000e-11
GCST008971_16	Urate levels	1.000000e-15
GCST008972_199	Urate levels	2.000000e-15

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio
EFO:0009933	Thyroid preparation use measurement
EFO:0004531	urate measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Carnitine palmitoyltransferases

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression, affects expression	4
aristolochic acid I	increases expression	1
bufotalin	decreases expression	1
propionaldehyde	increases expression	1
bisphenol A	increases expression	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	decreases methylation	1
nickel sulfate	decreases 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	decreases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, decreases expression	1
MRK 003	decreases expression	1
Bortezomib	increases response to substance	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Methapyrilene	decreases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Tretinoin	decreases expression	1
Tunicamycin	increases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	decreases methylation	1
Thapsigargin	increases expression	1
Particulate Matter	increases abundance, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
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
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00677768	Not specified	COMPLETED	Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)
NCT01568658	Not specified	ACTIVE_NOT_RECRUITING	Genetic and Physical Study of Childhood Nerve and Muscle Disorders
NCT02327845	Not specified	ENROLLING_BY_INVITATION	Phenotype, Genotype & Biomarkers in ALS and Related Disorders
NCT02852278	Not specified	COMPLETED	A Patient Centric Motor Neuron Disease Activities of Daily Living Scale
NCT02859428	Not specified	TERMINATED	Disease Natural History and Biomarkers of SPG3A, SPG4A, and SPG31
NCT03104088	Not specified	COMPLETED	Studying Cognition in SPG4
NCT03206190	Not specified	RECRUITING	The preSPG4 Study - Studying the Prodromal and Early Phase of SPG4
NCT03627416	Not specified	COMPLETED	Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy
NCT03981276	Not specified	RECRUITING	Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders
NCT04006418	Not specified	RECRUITING	A Registered Cohort Study on Spastic Paraplegia
NCT04180098	Not specified	COMPLETED	Improving Gait Adaptability in Hereditary Spastic Paraplegia
NCT04256681	Not specified	COMPLETED	SNAP: Measurement of the Subjective Perception of the Symptom in Hereditary Spastic Paraparesis (HSP)
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia
NCT04875416	Not specified	ACTIVE_NOT_RECRUITING	Phenotype, Genotype and Biomarkers 2
NCT04912609	Not specified	COMPLETED	Trehalose Administration in Subjects With Spastic Paraplegia 11 (3AL-SPG11)
NCT05354622	Not specified	RECRUITING	Hereditary Spastic Paraplegia Genomic Sequencing Initiative (HSPseq)
NCT05373082	Not specified	COMPLETED	Identification of Modifying Factors in Hereditary Spastic Paraplegia
NCT05411627	Not specified	WITHDRAWN	A Pilot Study of Shockwave Therapy in HSP
NCT05432999	Not specified	COMPLETED	Extracorporeal Shockwave Therapy for Spasticity in People With Spinal Cord Injury
NCT05613114	Not specified	COMPLETED	Effect of Dalfampridine in Patients With Hereditary Spastic Paraplegia
NCT05767268	Not specified	COMPLETED	Assessment of the Psychophysical State During Rehabilitation Treatment With Lokomat
NCT05848271	Not specified	RECRUITING	Natural History Study of Patients with HPDL Mutations
NCT06156813	Not specified	RECRUITING	Turkish Lower-Extremity Motor Activity Log (LE-MAL)
NCT06229626	Not specified	RECRUITING	Evaluation of an Intensive Training Program for Patients with Hereditary Spastic Paraparesis SPG4/Spast
NCT06260982	Not specified	UNKNOWN	Cognitive Disorders in Hereditary Spastic Paraplegia Type 4
NCT06553976	Not specified	RECRUITING	Spastic Paraplegia - Centers of Excellence Research Network
NCT06572046	Not specified	RECRUITING	STOP-HSP.Net: a Registry for Hereditary Spastic Paraplegia as an Integration Tool for Future Therapeutic Strategies
NCT06573866	Not specified	RECRUITING	Enhancement of Quality of Work And Life
NCT06680063	Not specified	COMPLETED	Correlation Between Clinical Assessment and Neurophysiological Assessment in Spinal Cord Injury