PCYT1A

Summary

PCYT1A (phosphate cytidylyltransferase 1A, choline, HGNC:8754) is a protein-coding gene on chromosome 3q29, encoding Choline-phosphate cytidylyltransferase A (P49585). Catalyzes the key rate-limiting step in the CDP-choline pathway for phosphatidylcholine biosynthesis. It is a selective cancer dependency (DepMap: 51.2% of cell lines).

This gene belongs to the cytidylyltransferase family and is involved in the regulation of phosphatidylcholine biosynthesis. Mutations in this gene are associated with spondylometaphyseal dysplasia with cone-rod dystrophy. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 5130 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spondylometaphyseal dysplasia-cone-rod dystrophy syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 273 total — 5 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 97
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 51.2% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001312673

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8754
Approved symbol	PCYT1A
Name	phosphate cytidylyltransferase 1A, choline
Location	3q29
Locus type	gene with protein product
Status	Approved
Aliases	CT, CTPCT, CCTalpha
Ensembl gene	ENSG00000161217
Ensembl biotype	protein_coding
OMIM	123695
Entrez	5130

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 15 protein_coding, 4 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000292823, ENST00000411591, ENST00000412869, ENST00000419333, ENST00000430755, ENST00000431016, ENST00000433733, ENST00000438634, ENST00000441879, ENST00000443555, ENST00000444822, ENST00000460677, ENST00000460827, ENST00000473978, ENST00000488235, ENST00000491544, ENST00000875583, ENST00000875584, ENST00000875585, ENST00000875586, ENST00000875587, ENST00000928611

RefSeq mRNA: 2 — MANE Select: NM_001312673 NM_001312673, NM_005017

CCDS: CCDS3315

Canonical transcript exons

ENST00000431016 — 9 exons

Exon	Start	End
ENSE00001127573	196239547	196239735
ENSE00001127579	196241948	196242090
ENSE00001142503	196234368	196238894
ENSE00001637190	196287615	196287726
ENSE00003522855	196257788	196257887
ENSE00003537081	196247367	196247518
ENSE00003638206	196248207	196248323
ENSE00003676237	196270415	196270541
ENSE00003682469	196242562	196242640

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 96.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.5882 / max 287.1458, expressed in 1824 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
46337	37.5667	1824
46336	0.0175	4
46335	0.0040	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	96.10	gold quality
monocyte	CL:0000576	95.23	gold quality
skin of leg	UBERON:0001511	94.99	gold quality
mononuclear cell	CL:0000842	94.89	gold quality
leukocyte	CL:0000738	94.71	gold quality
skin of abdomen	UBERON:0001416	94.66	gold quality
tendon of biceps brachii	UBERON:0008188	94.46	gold quality
duodenum	UBERON:0002114	94.35	gold quality
granulocyte	CL:0000094	94.32	gold quality
tendon	UBERON:0000043	94.26	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.89	gold quality
blood	UBERON:0000178	93.74	gold quality
gingival epithelium	UBERON:0001949	93.73	gold quality
zone of skin	UBERON:0000014	93.71	gold quality
tibia	UBERON:0000979	93.58	gold quality
nipple	UBERON:0002030	93.53	gold quality
stromal cell of endometrium	CL:0002255	93.39	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.39	gold quality
muscle of leg	UBERON:0001383	93.38	gold quality
medial globus pallidus	UBERON:0002477	93.33	gold quality
jejunal mucosa	UBERON:0000399	93.24	gold quality
small intestine	UBERON:0002108	93.23	gold quality
gastrocnemius	UBERON:0001388	93.21	gold quality
jejunum	UBERON:0002115	93.02	gold quality
calcaneal tendon	UBERON:0003701	92.96	gold quality
esophagus squamous epithelium	UBERON:0006920	92.95	gold quality
adrenal tissue	UBERON:0018303	92.95	gold quality
gingiva	UBERON:0001828	92.82	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.80	gold quality
body of tongue	UBERON:0011876	92.62	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.28

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, ELK3, ETS1, ETS2, LHX2, MYC, SP1, SP2, SP3, SREBF1, SREBF2, TEAD2, ZNF143, ZNF76

miRNA regulators (miRDB)

47 targeting PCYT1A, 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-6748-5P	100.00	65.81	1057
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-1179	99.71	68.70	1040
HSA-MIR-4690-5P	99.65	66.24	813
HSA-MIR-6733-3P	99.54	67.80	1281
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-216A-5P	99.50	68.02	1288
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-122B-5P	99.46	70.81	1457
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-329-5P	99.27	68.11	1597
HSA-MIR-6815-3P	99.13	68.98	1530
HSA-MIR-1253	99.12	67.08	1688
HSA-MIR-3168	99.08	67.75	1384
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-4464	98.95	67.73	820
HSA-MIR-4748	98.95	67.53	810
HSA-MIR-421	98.90	67.04	1883
HSA-MIR-3124-3P	98.87	68.95	2123

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 51.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 16)

• Analyses showed genotype effects of PCYT1A genes on spina bifida risk, but did not show evidence of gene-nutrient. interactions. (PMID:17184542)
• N-Methylaspartate induced nitric oxide synthase activation and nuclear factor-kB subunit p65 nuclear translocation in A549 cells were responsible for decreased CTP:phosphocholine cytidylyltransferase A expression (PMID:20661636)
• We report loss-of-function mutations in PCYT1A as the cause of spondylometaphyseal dysplasia with cone-rod dystrophy. (PMID:24387990)
• Mutations in PCYT1A cause spondylometaphyseal dysplasia with cone-rod dystrophy (PMID:24387991)
• PCYT1A-generated phosphatidylcholine has a role in the normal function of white adipose tissue and insulin action (PMID:24889630)
• CCT contributes to phospholipid compositional homeostasis. [Review] (PMID:26165797)
• PCYT1A mutations were identified in patients with isolated retinal dystrophy without any skeletal involvement from two Italian families. (PMID:28272537)
• There is no correlation between single PCYT1A rs712012 and PCYT1A rs7639752 polymorphisms and the incidence of intrauterine fetal death. (PMID:28509322)
• Our study shows that choline intake in Polish pregnant women is inadequate and that polymorphisms of PEMT rs12325817 and PCYT1A rs7639752 are associated with betaine but not choline concentrations. (PMID:30055775)
• Mutations in PCYT1A gene is associated with impaired enzyme kinetics and folding resulting in lipodystrophy, spondylometaphyseal dysplasia with cone-rod dystrophy, and isolated retinal dystrophy (PMID:30559292)
• CCTA activation by membrane binding is sensitive to mutations in the alphaE and J segments, especially within or proximal to the alphaE hinge. (PMID:31488547)
• The membrane-adsorbed, folded allosteric linker of CCTA may partially cover the active site cleft and pull it close to the membrane surface. (PMID:31488548)
• De novo phosphatidylcholine synthesis is required for autophagosome membrane formation and maintenance during autophagy. (PMID:31517566)
• Differential dephosphorylation of CTP:phosphocholine cytidylyltransferase upon translocation to nuclear membranes and lipid droplets. (PMID:32186954)
• PCYT1A suppresses proliferation and migration via inhibiting mTORC1 pathway in lung adenocarcinoma. (PMID:32703435)
• Methylome and transcriptome profiling revealed epigenetic silencing of LPCAT1 and PCYT1A associated with lipidome alterations in polycystic ovary syndrome. (PMID:33521992)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	pcyt1ab	ENSDARG00000004492
danio_rerio	pcyt1aa	ENSDARG00000011233
mus_musculus	Pcyt1a	ENSMUSG00000005615
rattus_norvegicus	Pcyt1a	ENSRNOG00000001762
drosophila_melanogaster	Pcyt2	FBGN0035231
drosophila_melanogaster	Pcyt1	FBGN0041342
caenorhabditis_elegans		WBGENE00017241
caenorhabditis_elegans	Y18H1A.11	WBGENE00021215

Paralogs (2): PCYT1B (ENSG00000102230), PCYT2 (ENSG00000185813)

Protein

Protein identifiers

Choline-phosphate cytidylyltransferase A — P49585 (reviewed: P49585)

Alternative names: CCT-alpha, CTP:phosphocholine cytidylyltransferase A, Phosphorylcholine transferase A

All UniProt accessions (10): C9J050, C9J2E1, C9JEJ2, C9JPY0, C9JVS0, P49585, F8WAZ5, F8WBU2, H7BZN1, H7C1T3

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the key rate-limiting step in the CDP-choline pathway for phosphatidylcholine biosynthesis.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm. Cytosol. Membrane. Endoplasmic reticulum membrane. Nucleus.

Tissue specificity. Brain, placenta, liver, fetal and adult lung.

Post-translational modifications. The serine residues of the C-terminus are phosphorylated. The inactive soluble form is stabilized by phosphorylation, the active membrane bound form is promoted by anionic lipids or diacylglycerol, and is stabilized by dephosphorylation. Monoubiquitinated by the SCF(FBXL2) complex, leading to proteasomal degradation.

Disease relevance. Spondylometaphyseal dysplasia with cone-rod dystrophy (SMDCRD) [MIM:608940] An autosomal recessive disorder characterized by postnatal growth deficiency resulting in profound short stature, rhizomelia with bowing of the lower extremities, platyspondyly with anterior vertebral protrusions, progressive metaphyseal irregularity and cupping with shortened tubular bones, and early-onset progressive visual impairment associated with a pigmentary maculopathy and electroretinographic evidence of cone-rod dysfunction. The disease is caused by variants affecting the gene represented in this entry. Lipodystrophy, congenital generalized, 5 (CGL5) [MIM:620680] A form of congenital generalized lipodystrophy, a metabolic disorder characterized by a near complete absence of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis and diabetes mellitus. CGL5 is an autosomal recessive form with onset in early childhood. Affected individuals also have short stature. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Interconverts between an inactive cytosolic form and an active membrane-bound form. Activation involves disruption of an inhibitory interaction between helices at the base of the active site and the autoinhibitory (AI) region. Activated by anionic lipid vesicles and by oleic acid or diacylglycerol-containing phosphatidylcholine vesicles.

Pathway. Phospholipid metabolism; phosphatidylcholine biosynthesis; phosphatidylcholine from phosphocholine: step 1/2.

Similarity. Belongs to the cytidylyltransferase family.

RefSeq proteins (2): NP_001299602, NP_005008 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004821	Cyt_trans-like	Domain
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR041723	CCT	Domain
IPR045049	Pcy1-like	Family

Pfam: PF01467

Enzyme classification (BRENDA):

• EC 2.7.7.15 — choline-phosphate cytidylyltransferase (BRENDA: 15 organisms, 42 substrates, 64 inhibitors, 106 Km, 14 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
CTP	0.133–35.7	53
PHOSPHOCHOLINE	0.083–212	25
CHOLINE PHOSPHATE	0.167–3.2	14
CDPCHOLINE	0.21–0.64	3
DIPHOSPHATE	0.004–0.007	3
PHOSPHORYLCHOLINE	0.14–2.1	3
PHOSPHOETHANOLAMINE	1.43–69.4	2
PHOSPHODIMETHYLETHANOLAMINE	4	1
PHOSPHOMONOMETHYLETHANOLAMINE	6.9	1

Catalyzed reactions (Rhea), 1 shown:

• phosphocholine + CTP + H(+) = CDP-choline + diphosphate (RHEA:18997)

UniProt features (52 total): modified residue 17, binding site 13, sequence variant 8, region of interest 5, repeat 3, mutagenesis site 3, chain 1, sequence conflict 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49585-F1	76.82	0.51

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 (13): 84; 85; 92; 122; 122; 151; 168; 169; 173; 195; 196; 197 …

Post-translational modifications (17): 1, 8, 233, 315, 319, 321, 322, 323, 325, 329, 331, 333, 342, 343, 347, 352, 362

Mutagenesis-validated functional residues (3):

Position	Phenotype
37	abolishes formation of the interchain disulfide that can be observed when the enzyme is treated with copper phenanthrole
93	decreased solubility. decreased lipid vesicle-dependent choline-phosphate cytidylyltransferase activity. 4-fold decrease
240	decreased solubility.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1483191	Synthesis of PC

MSigDB gene sets: 448 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLCHOLINE_METABOLIC_PROCESS, GOBP_B_CELL_ACTIVATION, GOBP_PHOSPHATIDYLCHOLINE_BIOSYNTHETIC_PROCESS, GOBP_B_CELL_PROLIFERATION, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLUE_UP, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, EFC_Q6, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_B_CELL_MEDIATED_IMMUNITY, GOBP_GLYCEROLIPID_METABOLIC_PROCESS

GO Biological Process (9): phosphatidylcholine biosynthetic process (GO:0006656), CDP-choline pathway (GO:0006657), B cell proliferation (GO:0042100), isotype switching (GO:0045190), lipid metabolic process (GO:0006629), phospholipid biosynthetic process (GO:0008654), biosynthetic process (GO:0009058), phosphatidylcholine metabolic process (GO:0046470), organophosphate biosynthetic process (GO:0090407)

GO Molecular Function (11): choline-phosphate cytidylyltransferase activity (GO:0004105), calmodulin binding (GO:0005516), phosphatidylcholine binding (GO:0031210), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), molecular function inhibitor activity (GO:0140678), catalytic activity (GO:0003824), protein binding (GO:0005515), lipid binding (GO:0008289), transferase activity (GO:0016740), nucleotidyltransferase activity (GO:0016779)

GO Cellular Component (8): nucleus (GO:0005634), nuclear envelope (GO:0005635), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), glycogen granule (GO:0042587), cytoplasm (GO:0005737), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Glycerophospholipid biosynthesis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
protein binding	2
binding	2
intracellular membrane-bounded organelle	2
endomembrane system	2
phosphatidylcholine metabolic process	1
glycerophospholipid biosynthetic process	1
choline kinase activity	1
diacylglycerol cholinephosphotransferase activity	1
phosphatidylcholine biosynthetic process	1
B cell activation	1
lymphocyte proliferation	1
somatic recombination of immunoglobulin genes involved in immune response	1
B cell activation involved in immune response	1
primary metabolic process	1
phospholipid metabolic process	1
lipid biosynthetic process	1
organophosphate biosynthetic process	1
metabolic process	1
glycerophospholipid metabolic process	1
biosynthetic process	1
organophosphate metabolic process	1
cytidylyltransferase activity	1
phospholipid binding	1
cation binding	1
quaternary ammonium group binding	1
identical protein binding	1
protein dimerization activity	1
molecular function regulator activity	1
molecular_function	1
catalytic activity	1
transferase activity, transferring phosphorus-containing groups	1
nucleus	1
organelle envelope	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1814 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PCYT1A	CHKA	P35790	942
PCYT1A	CEPT1	Q9Y6K0	789
PCYT1A	CHPT1	Q8WUD6	770
PCYT1A	PEMT	Q9UBM1	683
PCYT1A	CHKB	Q9Y259	669
PCYT1A	WDR53	Q7Z5U6	626
PCYT1A	SELENOI	Q9C0D9	614
PCYT1A	SST	P01166	587
PCYT1A	ZDHHC19	Q8WVZ1	575
PCYT1A	FBXO45	P0C2W1	538
PCYT1A	UBXN7	O94888	534
PCYT1A	SMCO1	Q147U7	531
PCYT1A	PISD	Q9UG56	519
PCYT1A	CEP19	Q96LK0	503
PCYT1A	PTDSS1	P48651	495
PCYT1A	ETNK2	Q9NVF9	495

IntAct

93 interactions, top by confidence:

A	B	Type	Score
LSM3	LSM1	psi-mi:“MI:0914”(association)	0.950
PCYT1A	VKORC1L1	psi-mi:“MI:0915”(physical association)	0.740
VKORC1L1	PCYT1A	psi-mi:“MI:0914”(association)	0.740
NMNAT1	PCYT1A	psi-mi:“MI:0915”(physical association)	0.640
SPG11	AP5Z1	psi-mi:“MI:0914”(association)	0.620
RNF8	PCYT1A	psi-mi:“MI:0915”(physical association)	0.560
MAGEA3	PCYT1A	psi-mi:“MI:0915”(physical association)	0.560
PCYT1A	AGTRAP	psi-mi:“MI:0915”(physical association)	0.560
PCYT1A	MOB3C	psi-mi:“MI:0915”(physical association)	0.560
GYS1	PCYT1A	psi-mi:“MI:0915”(physical association)	0.560
PCYT1A	PCYT1B	psi-mi:“MI:0915”(physical association)	0.560
PCYT1A	MOB1A	psi-mi:“MI:0915”(physical association)	0.560
SDCBP	PCYT1A	psi-mi:“MI:0915”(physical association)	0.560
PCYT1A	PCYT1A	psi-mi:“MI:0915”(physical association)	0.560
SCAMP1	PCYT1A	psi-mi:“MI:0915”(physical association)	0.560
SNAPIN	PCYT1A	psi-mi:“MI:0915”(physical association)	0.560
PCYT1A	TNFRSF10D	psi-mi:“MI:0915”(physical association)	0.560
PCYT1A	FKBP7	psi-mi:“MI:0915”(physical association)	0.560
CEP170	DAPK3	psi-mi:“MI:0914”(association)	0.530
Cep170	WDR62	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
PLEKHA7	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
RRP1B	ZNF785	psi-mi:“MI:0914”(association)	0.350
PACC1	DEGS1	psi-mi:“MI:0914”(association)	0.350
STX11	GOSR1	psi-mi:“MI:0914”(association)	0.350
GPRC5C	NMT2	psi-mi:“MI:0914”(association)	0.350
IP6K3	PROZ	psi-mi:“MI:0914”(association)	0.350
DIPK2A	C11orf98	psi-mi:“MI:0914”(association)	0.350

BioGRID (97): PCYT1A (Affinity Capture-MS), PCYT1A (Affinity Capture-MS), PCYT1A (Affinity Capture-MS), PCYT1A (Affinity Capture-MS), PCYT1A (Affinity Capture-MS), PCYT1A (Affinity Capture-MS), PCYT1A (Affinity Capture-MS), PCYT1A (Affinity Capture-MS), PCYT1A (Affinity Capture-MS), PCYT1A (Affinity Capture-MS), PCYT1A (Proximity Label-MS), PCYT1A (Affinity Capture-RNA), PCYT1A (Affinity Capture-MS), PCYT1A (Affinity Capture-MS), PCYT1A (Two-hybrid)

ESM2 similar proteins: A0A097I2D0, A0A1W2PP81, A0A1W2PPE2, A0A1W2PPH5, A0A1W2PPL8, A0A1W2PPW3, A0A1W2PQ09, A0A1W2PR64, A0A1W2PRV1, A6NLC8, F4HR03, O54825, O75461, P0C1H6, P0CV38, P0DMV1, P0DMV2, P0DW11, P0DW12, P0DW13, P0DW14, P40914, P49585, P49906, P81195, Q0MTC0, Q13895, Q15544, Q2N2K6, Q3SZB8, Q5DJT8, Q5RA91, Q5U1X0, Q6CER9, Q6RG77, Q6XL73, Q75DE4, Q7XHR2, Q7Z2G1, Q80WL2

Diamond homologs: A1W0D6, A7H2L7, A8FMK8, C5A1S7, D3RZA9, D5EBS7, F4JJE0, O58466, O74975, O88637, P13259, P19836, P27623, P33412, P49583, P49584, P49585, P49586, P49587, Q55BZ4, Q5EA75, Q5HTW1, Q6TG09, Q811Q9, Q8RKI6, Q8SQW6, Q8TXT2, Q8U1T9, Q922E4, Q99447, Q9QZC4, Q9UTI6, Q9UZ37, Q9Y5K3, Q9ZV56, Q9ZVI9, B5I9H4, B6YXC8, C6A439, D3DZ18

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
MAPK1	down-regulates	PCYT1A	phosphorylation
MAPK3	down-regulates	PCYT1A	phosphorylation
Gbeta	down-regulates	PCYT1A	phosphorylation
ERK1/2	down-regulates	PCYT1A	phosphorylation
SP2	“down-regulates quantity by repression”	PCYT1A	“transcriptional regulation”
SP1	“up-regulates quantity by expression”	PCYT1A	“transcriptional regulation”
SP3	“up-regulates quantity by expression”	PCYT1A	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	3
Uncertain significance	123
Likely benign	110
Benign	13

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
101057	NM_001312673.2(PCYT1A):c.296C>T (p.Ala99Val)	Pathogenic
101059	NM_001312673.2(PCYT1A):c.295G>A (p.Ala99Thr)	Pathogenic
101064	NM_001312673.2(PCYT1A):c.571T>C (p.Phe191Leu)	Pathogenic
1032965	NM_001312673.2(PCYT1A):c.850G>T (p.Glu284Ter)	Pathogenic
1069192	NM_001312673.2(PCYT1A):c.223C>T (p.Arg75Ter)	Pathogenic
2431393	NM_001312673.2(PCYT1A):c.935dup (p.Ala313fs)	Likely pathogenic
373771	NM_001312673.2(PCYT1A):c.955_956dup (p.Ser319fs)	Likely pathogenic
450601	NM_001312673.2(PCYT1A):c.60dup (p.Pro21fs)	Likely pathogenic

SpliceAI

4324 predictions. Top by Δscore:

Variant	Effect	Δscore
3:196216746:CCCAG:C	donor_gain	1.0000
3:196216749:AGG:A	donor_loss	1.0000
3:196216751:G:GG	donor_gain	1.0000
3:196216751:GTAA:G	donor_loss	1.0000
3:196226963:A:AG	acceptor_gain	1.0000
3:196226963:AGCC:A	acceptor_loss	1.0000
3:196226964:G:GG	acceptor_gain	1.0000
3:196226964:GCCC:G	acceptor_gain	1.0000
3:196226964:GCCCT:G	acceptor_gain	1.0000
3:196227101:G:GT	donor_gain	1.0000
3:196228918:GAC:G	donor_gain	1.0000
3:196228921:G:GG	donor_gain	1.0000
3:196228928:GGGA:G	donor_gain	1.0000
3:196228929:GGA:G	donor_gain	1.0000
3:196228929:GGAG:G	donor_gain	1.0000
3:196228930:GA:G	donor_gain	1.0000
3:196228930:GAG:G	donor_gain	1.0000
3:196228932:G:GG	donor_gain	1.0000
3:196228938:G:T	donor_gain	1.0000
3:196239540:AACAT:A	donor_loss	1.0000
3:196239541:ACAT:A	donor_loss	1.0000
3:196239542:CATA:C	donor_loss	1.0000
3:196239543:ATAC:A	donor_loss	1.0000
3:196239544:TACC:T	donor_loss	1.0000
3:196239545:A:AC	donor_gain	1.0000
3:196239545:A:T	donor_loss	1.0000
3:196239546:C:CC	donor_gain	1.0000
3:196239557:T:TA	donor_gain	1.0000
3:196239557:TCCGG:T	donor_gain	1.0000
3:196239583:T:TA	donor_gain	1.0000

AlphaMissense

2437 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:196239577:A:C	F289L	1.000
3:196239577:A:T	F289L	1.000
3:196239579:A:G	F289L	1.000
3:196239610:C:A	W278C	1.000
3:196239610:C:G	W278C	1.000
3:196239612:A:G	W278R	1.000
3:196239612:A:T	W278R	1.000
3:196239623:A:G	L274P	1.000
3:196239707:A:T	V246D	1.000
3:196241961:A:T	V232D	1.000
3:196241967:A:G	L230P	1.000
3:196241967:A:T	L230H	1.000
3:196241985:C:A	G224V	1.000
3:196241985:C:T	G224D	1.000
3:196241986:C:G	G224R	1.000
3:196241987:C:A	R223S	1.000
3:196241987:C:G	R223S	1.000
3:196241988:C:A	R223M	1.000
3:196241988:C:G	R223T	1.000
3:196241994:A:G	L221P	1.000
3:196241996:G:C	N220K	1.000
3:196241996:G:T	N220K	1.000
3:196241998:T:C	N220D	1.000
3:196242000:C:G	R219P	1.000
3:196242001:G:C	R219G	1.000
3:196242010:A:C	Y216D	1.000
3:196242010:A:G	Y216H	1.000
3:196242024:C:G	R211P	1.000
3:196242027:A:T	V210E	1.000
3:196242030:A:T	I209N	1.000

dbSNP variants (sampled 300 via entrez): RS1000002360 (3:196248611 A>C,T), RS1000040292 (3:196238610 G>A,T), RS1000068741 (3:196286335 C>T), RS1000094844 (3:196262847 T>C,G), RS1000112593 (3:196237547 A>G), RS1000162447 (3:196275652 G>A,C,T), RS1000234154 (3:196276161 G>A), RS1000256928 (3:196265605 T>C), RS1000387504 (3:196255928 G>A), RS1000400176 (3:196281979 T>G), RS1000417099 (3:196286623 T>C), RS1000442951 (3:196269070 G>A), RS1000472185 (3:196272487 T>A,C), RS1000547835 (3:196245143 C>A,T), RS1000596639 (3:196251220 C>A,T)

Disease associations

OMIM: gene MIM:123695 | disease phenotypes: MIM:620680, MIM:608940

GenCC curated gene-disease

Disease	Classification	Inheritance
spondylometaphyseal dysplasia-cone-rod dystrophy syndrome	Definitive	Autosomal recessive
Leber congenital amaurosis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
spondylometaphyseal dysplasia-cone-rod dystrophy syndrome	Definitive	AR

Mondo (4): lipodystrophy, congenital generalized, type 5 (MONDO:0958023), spondylometaphyseal dysplasia-cone-rod dystrophy syndrome (MONDO:0012160), inherited retinal dystrophy (MONDO:0019118), Leber congenital amaurosis (MONDO:0018998)

Orphanet (2): Spondylometaphyseal dysplasia-cone-rod dystrophy syndrome (Orphanet:85167), OBSOLETE: Inherited retinal disorder (Orphanet:71862)

HPO phenotypes

97 total (30 of 97 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000403	Recurrent otitis media
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000512	Abnormal electroretinogram
HP:0000518	Cataract
HP:0000529	Progressive visual loss
HP:0000539	Abnormality of refraction
HP:0000540	Hypermetropia
HP:0000543	Optic disc pallor
HP:0000545	Myopia
HP:0000548	Cone/cone-rod dystrophy
HP:0000550	Undetectable electroretinogram
HP:0000563	Keratoconus
HP:0000568	Microphthalmia
HP:0000588	Optic disc coloboma
HP:0000589	Coloboma
HP:0000602	Ophthalmoplegia
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000689	Dental malocclusion
HP:0000729	Autistic behavior
HP:0000842	Hyperinsulinemia
HP:0000855	Insulin resistance
HP:0000887	Cupped ribs
HP:0000926	Platyspondyly
HP:0000946	Hypoplastic ilia
HP:0001105	Retinal atrophy
HP:0001132	Lens subluxation

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002395_558	Mean platelet volume	8.000000e-13

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D057130	Leber Congenital Amaurosis	C11.270.516; C11.768.364
D058499	Retinal Dystrophies	C11.768.585.658
C563825	Spondylometaphyseal Dysplasia with Cone-Rod Dystrophy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105855 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 4,624 (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
CHEMBL3301612	ENCORAFENIB	4	4,624

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.39	Kd	41	nM	ENCORAFENIB

PubChem BioAssay actives

1 with measured affinity, of 112 total; 1 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
Encorafenib	1425103: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0410	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Bortezomib	increases response to substance, increases expression	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Estradiol	increases expression, affects phosphorylation	2
Nickel	increases expression	2
Valproic Acid	increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
sodium arsenite	increases abundance, increases expression, affects cotreatment	1
cobaltous chloride	increases expression	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
U 0126	affects expression, affects reaction	1
torcetrapib	increases expression	1
bisphenol B	increases expression	1
1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone	decreases phosphorylation	1
bisphenol S	increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Vehicle Emissions	decreases expression, increases abundance	1
Cadmium	increases abundance, increases expression	1
Caffeine	affects phosphorylation	1
Carmustine	decreases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ivermectin	decreases expression	1
Manganese	increases expression, affects cotreatment, increases abundance	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
CHEMBL3991816	Binding	Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by ma	The target landscape of clinical kinase drugs. — Science

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00999609	PHASE3	ACTIVE_NOT_RECRUITING	Safety and Efficacy Study in Subjects With Leber Congenital Amaurosis
NCT06891443	PHASE3	RECRUITING	Study to Evaluate Sepofarsen in Subjects With Leber Congenital Amaurosis (LCA) Type 10 (HYPERION)
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT00516477	PHASE1	COMPLETED	Safety Study in Subjects With Leber Congenital Amaurosis
NCT00821340	PHASE1	COMPLETED	Clinical Trial of Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT03913143	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate Efficacy, Safety, Tolerability and Exposure After a Repeat-dose of Sepofarsen (QR-110) in LCA10 (ILLUMINATE)
NCT04855045	PHASE2/PHASE3	UNKNOWN	An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.
NCT00749957	PHASE1/PHASE2	COMPLETED	Phase 1/2 Safety and Efficacy Study of AAV-RPE65 Vector to Treat Leber Congenital Amaurosis
NCT01208389	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Phase 1 Follow-on Study of AAV2-hRPE65v2 Vector in Subjects With Leber Congenital Amaurosis (LCA) 2
NCT01496040	PHASE1/PHASE2	COMPLETED	Clinical Gene Therapy Protocol for the Treatment of Retinal Dystrophy Caused by Defects in RPE65
NCT02781480	PHASE1/PHASE2	COMPLETED	Clinical Trial of Gene Therapy for the Treatment of Leber Congenital Amaurosis (LCA)
NCT03913130	PHASE1/PHASE2	TERMINATED	Extension Study to Study PQ-110-001 (NCT03140969)
NCT03920007	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Study of Subretinally Injected ATSN-101 Administered in Patients With Leber Congenital Amaurosis Caused by Biallelic Mutations in GUCY2D
NCT05203939	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Study to Assess the Safety and Efficacy of OCU400 for Retinitis Pigmentosa and Leber Congenital Amaurosis
NCT05906953	PHASE1/PHASE2	RECRUITING	Safety and Efficacy Trial of HG004 for Leber Congenital Amaurosis Related to Rpe65 Gene Mutations (STAR)
NCT06088992	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Leber Congenital Amaurosis Inherited Blindness of Gene Therapy Trial(LIGHT)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT02575430	Not specified	COMPLETED	Natural History Study in Inherited Retinal Disease Subjects Caused by Mutations in RPE65 or LRAT
NCT02714816	Not specified	COMPLETED	Natural History Study of Patients With Leber Congenital Amaurosis Associated With Mutations in RPE65
NCT02946879	Not specified	COMPLETED	Long-Term Follow-Up Gene Therapy Study for Leber Congenital Amaurosis OPTIRPE65 (Retinal Dystrophy Associated With Defects in RPE65)
NCT02970266	Not specified	COMPLETED	Genetic Decryption of Leber Congenital Amaurosis (LCA) in a Large Cohort of Independent Families.
NCT07026565	Not specified	NOT_YET_RECRUITING	Psychotherapy Group for Parents of Children With LCA
NCT03872479	PHASE1/PHASE2	UNKNOWN	Single Ascending Dose Study in Participants With LCA10
NCT04123626	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Safety and Tolerability of QR-1123 in Subjects With Autosomal Dominant Retinitis Pigmentosa Due to the P23H Mutation in the RHO Gene
NCT04545736	PHASE1/PHASE2	RECRUITING	Oral Metformin for Treatment of ABCA4 Retinopathy
NCT06212297	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Fellow-eye Study (FE) of LX101 in Subjects With Inherited Retinal Dystrophy
NCT06852963	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Repeat-Dose, Open-Label, Two Arm Safety and Efficacy Study of Two Doses of VP-001 Administered Intravitreally in Participants With Confirmed PRPF31 Mutation-Associated Retinal Dystrophy, Including Participants Previously Treated With VP001
NCT07177196	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Personalized Antisense Oligonucleotide Therapy for a Single Participant With PRPH2 Mutation Associated With Retinal Dystrophy
NCT07063030	EARLY_PHASE1	RECRUITING	A Study of LX107 Gene Therapy in AIPL1-IRD Patients
NCT01546181	Not specified	COMPLETED	Retinal Imaging by Adaptive Optics in Healthy Eyes and During Retinal and General Diseases
NCT01876147	Not specified	COMPLETED	Visual and Functional Assessment in Low Vision Patients
NCT01920867	Not specified	UNKNOWN	Stem Cell Ophthalmology Treatment Study