PAICS

Summary

PAICS (phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthase, HGNC:8587) is a protein-coding gene on chromosome 4q12, encoding Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (P22234). Bifunctional phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazole succinocarboxamide synthetase catalyzing two reactions of the de novo purine biosynthetic pathway. It is a selective cancer dependency (DepMap: 47.4% of cell lines).

This gene encodes a bifunctional enzyme containing phosphoribosylaminoimidazole carboxylase activity in its N-terminal region and phosphoribosylaminoimidazole succinocarboxamide synthetase in its C-terminal region. It catalyzes steps 6 and 7 of purine biosynthesis. The gene is closely linked and divergently transcribed with a locus that encodes an enzyme in the same pathway, and transcription of the two genes is coordinately regulated. The human genome contains several pseudogenes of this gene. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10606 — RefSeq curated summary.

At a glance

• Gene–disease (curated): PAICS deficiency (Limited, GenCC)
• Clinical variants (ClinVar): 47 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 24
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 47.4% of screened cell lines
• MANE Select transcript: NM_001079524

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8587
Approved symbol	PAICS
Name	phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthase
Location	4q12
Locus type	gene with protein product
Status	Approved
Aliases	ADE2H1, AIRC
Ensembl gene	ENSG00000128050
Ensembl biotype	protein_coding
OMIM	172439
Entrez	10606

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 21 protein_coding, 3 retained_intron

ENST00000264221, ENST00000399688, ENST00000504188, ENST00000505164, ENST00000508554, ENST00000510584, ENST00000512576, ENST00000514888, ENST00000879753, ENST00000879754, ENST00000879755, ENST00000879756, ENST00000879757, ENST00000913768, ENST00000913769, ENST00000913770, ENST00000913771, ENST00000913772, ENST00000913773, ENST00000913774, ENST00000913775, ENST00000913776, ENST00000913777, ENST00000963017

RefSeq mRNA: 6 — MANE Select: NM_001079524 NM_001079524, NM_001079525, NM_001392010, NM_001392011, NM_001392012, NM_006452

CCDS: CCDS47060, CCDS47061

Canonical transcript exons

ENST00000512576 — 9 exons

Exon	Start	End
ENSE00000877958	56448418	56448597
ENSE00000877959	56448710	56448823
ENSE00000877960	56450619	56450702
ENSE00000877961	56451872	56452052
ENSE00000877962	56453603	56453761
ENSE00002057525	56436260	56436328
ENSE00002063899	56459372	56464578
ENSE00003469518	56441663	56441860
ENSE00003523494	56446695	56446873

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 98.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 97.9745 / max 2114.6077, expressed in 1817 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47728	77.6703	1790
47726	10.6728	1783
47724	3.3991	1265
47731	1.6361	733
47727	1.4561	983
47732	0.6973	387
47733	0.6445	347
47729	0.5870	328
47734	0.4632	224
47730	0.3788	154

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	98.45	gold quality
embryo	UBERON:0000922	97.65	gold quality
ganglionic eminence	UBERON:0004023	97.45	gold quality
rectum	UBERON:0001052	95.66	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.06	gold quality
lateral globus pallidus	UBERON:0002476	94.78	gold quality
islet of Langerhans	UBERON:0000006	94.62	gold quality
adrenal tissue	UBERON:0018303	94.39	gold quality
endometrium epithelium	UBERON:0004811	94.36	gold quality
cortical plate	UBERON:0005343	93.87	gold quality
endometrium	UBERON:0001295	93.79	gold quality
liver	UBERON:0002107	93.72	gold quality
colonic mucosa	UBERON:0000317	93.71	gold quality
vermiform appendix	UBERON:0001154	93.32	gold quality
stromal cell of endometrium	CL:0002255	92.90	gold quality
substantia nigra pars compacta	UBERON:0001965	92.77	gold quality
globus pallidus	UBERON:0001875	92.65	gold quality
caecum	UBERON:0001153	92.45	gold quality
medial globus pallidus	UBERON:0002477	92.44	gold quality
right lobe of liver	UBERON:0001114	92.43	gold quality
upper leg skin	UBERON:0004262	92.39	gold quality
adrenal gland	UBERON:0002369	92.35	gold quality
gingival epithelium	UBERON:0001949	92.34	gold quality
cranial nerve II	UBERON:0000941	92.33	gold quality
pigmented layer of retina	UBERON:0001782	92.30	gold quality
retina	UBERON:0000966	92.28	gold quality
substantia nigra pars reticulata	UBERON:0001966	92.25	gold quality
left adrenal gland	UBERON:0001234	92.18	gold quality
right adrenal gland	UBERON:0001233	92.15	gold quality
smooth muscle tissue	UBERON:0001135	92.04	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	136.62
E-HCAD-5	yes	37.95
E-MTAB-9067	yes	21.95
E-CURD-112	yes	20.11
E-CURD-122	yes	19.48
E-GEOD-93593	yes	15.56
E-MTAB-10042	yes	14.32
E-MTAB-6819	no	1629.72
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

101 targeting PAICS, 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-6129	100.00	66.46	2080
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 47.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 11)

• purine biosynthetic pathway enzymes PPAT and PAICS, as well as pyruvate kinase activity are increased in lung cancer (PMID:26140362)
• we show that PAICS, which catalyzes a critical step in purine biosynthetic pathway, is overexpressed and plays a role in BLCA cell proliferation, colony formation, and 3D spheroid invasion, suggesting a role in oncogenesis. (PMID:30121007)
• PAICS is hypomethylated in the lung adenocarcinoma tissues.PAICS is highly expressed in the lung adenocarcinoma tissues. (PMID:30641222)
• Combinatorial targeting of MTHFD2 and PAICS in purine synthesis as a novel therapeutic strategy. (PMID:31624245)
• Crystal structures of human PAICS reveal substrate and product binding of an emerging cancer target. (PMID:32571877)
• PAICS contributes to gastric carcinogenesis and participates in DNA damage response by interacting with histone deacetylase 1/2. (PMID:32632107)
• PAICS is related to glioma grade and can promote glioma growth and migration. (PMID:34173716)
• Regulating COX10-AS1 / miR-142-5p / PAICS axis inhibits the proliferation of non-small cell lung cancer. (PMID:34323174)
• Evidence Supporting Substrate Channeling between Domains of Human PAICS: A Time-Course Analysis of (13)C-Bicarbonate Incorporation. (PMID:35285625)
• Multienzyme interactions of the de novo purine biosynthetic protein PAICS facilitate purinosome formation and metabolic channeling. (PMID:35331738)
• PAICS ubiquitination recruits UBAP2 to trigger phase separation for purinosome assembly. (PMID:37848033)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	paics	ENSDARG00000033539
mus_musculus	Paics	ENSMUSG00000029247
rattus_norvegicus	Paics	ENSRNOG00000002101
drosophila_melanogaster	Paics	FBGN0020513
caenorhabditis_elegans		WBGENE00015116

Protein

Protein identifiers

Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase — P22234 (reviewed: P22234)

All UniProt accessions (3): P22234, D6RF62, E9PBS1

UniProt curated annotations — full annotation on UniProt →

Function. Bifunctional phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazole succinocarboxamide synthetase catalyzing two reactions of the de novo purine biosynthetic pathway.

Subunit / interactions. Homooctamer.

Disease relevance. Phosphoribosylaminoimidazole carboxylase deficiency (PAICSD) [MIM:619859] An autosomal recessive inborn error of purine metabolism, clinically characterized by multiple congenital anomalies and early neonatal death. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Purine metabolism; IMP biosynthesis via de novo pathway; 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide from 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxylate: step 1/2. Purine metabolism; IMP biosynthesis via de novo pathway; 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxylate from 5-amino-1-(5-phospho-D-ribosyl)imidazole (carboxylase route): step 1/1.

Similarity. In the N-terminal section; belongs to the SAICAR synthetase family. In the C-terminal section; belongs to the AIR carboxylase family. Class II subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P22234-1	1	yes
P22234-2	2

RefSeq proteins (6): NP_001072992, NP_001072993, NP_001378939, NP_001378940, NP_001378941, NP_006443 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000031	PurE_dom	Domain
IPR018236	SAICAR_synthetase_CS	Conserved_site
IPR028923	SAICAR_synt/ADE2_N	Domain
IPR033626	PurE_classII	Domain
IPR050089

Pfam: PF00731, PF01259

Catalyzed reactions (Rhea), 2 shown:

• 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxylate + H(+) = 5-amino-1-(5-phospho-beta-D-ribosyl)imidazole + CO2 (RHEA:10792)
• 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxylate + L-aspartate + ATP = (2S)-2-[5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamido]succinate + ADP + phosphate + 2 H(+) (RHEA:22628)

UniProt features (64 total): helix 18, strand 17, modified residue 8, turn 6, mutagenesis site 4, region of interest 3, sequence variant 2, sequence conflict 2, initiator methionine 1, chain 1, splice variant 1, binding site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
6YB8	X-RAY DIFFRACTION	2.36
6YB9	X-RAY DIFFRACTION	2.41
2H31	X-RAY DIFFRACTION	2.8
7ALE	X-RAY DIFFRACTION	2.95

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P22234-F1	95.96	0.95

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): 332

Post-translational modifications (8): 107, 238, 247, 274, 2, 22, 27, 36

Mutagenesis-validated functional residues (4):

Position	Phenotype
303	loss of phosphoribosylaminoimidazole carboxylase activity.
332	loss of phosphoribosylaminoimidazole carboxylase activity.
334	loss of phosphoribosylaminoimidazole carboxylase activity.
400	no effect on phosphoribosylaminoimidazole carboxylase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-73817	Purine ribonucleoside monophosphate biosynthesis

MSigDB gene sets: 414 (showing top): GNF2_CKS1B, MODULE_52, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, HORIUCHI_WTAP_TARGETS_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, BASSO_B_LYMPHOCYTE_NETWORK, MODULE_56, MATTIOLI_MGUS_VS_PCL, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_B_LYMPHOCYTE, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, MODULE_16, USF_C

GO Biological Process (6): GMP biosynthetic process (GO:0006177), ‘de novo’ IMP biosynthetic process (GO:0006189), purine nucleobase biosynthetic process (GO:0009113), ‘de novo’ AMP biosynthetic process (GO:0044208), ‘de novo’ XMP biosynthetic process (GO:0097294), purine nucleotide biosynthetic process (GO:0006164)

GO Molecular Function (11): phosphoribosylaminoimidazole carboxylase activity (GO:0004638), phosphoribosylaminoimidazolesuccinocarboxamide synthase activity (GO:0004639), ATP binding (GO:0005524), identical protein binding (GO:0042802), cadherin binding (GO:0045296), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), lyase activity (GO:0016829), carboxy-lyase activity (GO:0016831), ligase activity (GO:0016874)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Nucleotide biosynthesis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
purine-containing compound biosynthetic process	2
catalytic activity	2
purine ribonucleotide biosynthetic process	1
purine ribonucleoside monophosphate biosynthetic process	1
GMP metabolic process	1
IMP biosynthetic process	1
purine nucleobase metabolic process	1
nucleobase biosynthetic process	1
AMP biosynthetic process	1
XMP biosynthetic process	1
purine nucleotide metabolic process	1
nucleotide biosynthetic process	1
carboxy-lyase activity	1
acid-amino acid ligase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein binding	1
cell adhesion molecule binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
binding	1
carbon-carbon lyase activity	1
intracellular anatomical structure	1
cytoplasm	1
extracellular vesicle	1

Protein interactions and networks

STRING

4192 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PAICS	PPAT	Q06203	986
PAICS	CHD7	Q9P2D1	946
PAICS	GART	P22102	922
PAICS	LGALS4	P56470	791
PAICS	LGALS2	P05162	767
PAICS	PFAS	O15067	762
PAICS	ADSL	P30566	746
PAICS	ATIC	P31939	736
PAICS	RAD52	P43351	716
PAICS	PRDM16	Q9HAZ2	697
PAICS	LGALS7B	P47929	669
PAICS	GMPS	P49915	627
PAICS	ADSS2	P30520	605
PAICS	RAD51	Q06609	593
PAICS	ATR	Q13535	588

IntAct

184 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
PAICS	PAICS	psi-mi:“MI:0915”(physical association)	0.850
PAICS	L3MBTL2	psi-mi:“MI:0915”(physical association)	0.720
L3MBTL2	PAICS	psi-mi:“MI:0915”(physical association)	0.720
FXR2	PAICS	psi-mi:“MI:0915”(physical association)	0.710
PAICS	FXR2	psi-mi:“MI:0915”(physical association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PAICS	LNX1	psi-mi:“MI:0915”(physical association)	0.670
AP2S1	AP2A2	psi-mi:“MI:0914”(association)	0.640
PAICS	NUDT18	psi-mi:“MI:0915”(physical association)	0.620
PAICS	FAA2	psi-mi:“MI:0915”(physical association)	0.560
SRP1	PAICS	psi-mi:“MI:0915”(physical association)	0.560
PAICS	SRP1	psi-mi:“MI:0915”(physical association)	0.560
FAA2	PAICS	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (415): PAICS (Affinity Capture-MS), PAICS (Affinity Capture-MS), PAICS (Two-hybrid), L3MBTL2 (Two-hybrid), CEP76 (Two-hybrid), PAICS (Two-hybrid), PAICS (Two-hybrid), NUDT18 (Two-hybrid), LNX1 (Two-hybrid), ABCC1 (Co-fractionation), ASNS (Co-fractionation), ASS1 (Co-fractionation), ATIC (Co-fractionation), ETFA (Co-fractionation), GART (Co-fractionation)

ESM2 similar proteins: A0A2R8RWN9, A0JN27, E2R222, F1LTR1, O94925, P13264, P22234, P51583, P61201, P61202, P61203, P97834, Q07G17, Q13042, Q13888, Q15303, Q15645, Q28D01, Q2TBV1, Q2TBV5, Q2YDL1, Q3MHJ2, Q4R9A8, Q4VC33, Q5F398, Q5JUK3, Q5R532, Q5RB59, Q5RBN9, Q5RKJ1, Q5SP67, Q5TDH0, Q5XHZ9, Q61527, Q6GR10, Q6IQT4, Q6IR75, Q6P1K8, Q7L5Y9, Q7SXR3

Diamond homologs: A0AJM6, A1A0S2, A1U1A4, A2C4B2, A3CWL5, A3MXE4, A5GN71, A5IMW3, A5IRV3, A5UNH4, A5UWC5, A6Q3C7, A6QFS5, A6U0N4, A7GYK7, A7IAF5, A7NKB4, A7X0V7, A7ZD85, A8MCJ8, A8Z1K8, A9B302, A9WK38, B0CD47, B0S341, B1HTV1, B1LCA5, B1XNE9, B1YJ02, B2IWK4, B3DT37, B4RHH0, B5ELM2, B5Y714, B7GFT5, B7GU64, B7J6C1, B8DDY5, B8DTV0, B8GCM2

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
PAICS	“down-regulates quantity”	5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium	“chemical modification”
PAICS	“up-regulates quantity”	5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-)	“chemical modification”
PAICS	“down-regulates quantity”	L-aspartate(1-)	“chemical modification”
PAICS	“up-regulates quantity”	SAICAR(4-)	“chemical modification”
PAICS	“down-regulates quantity”	5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-)	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 173 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signalling to ERKs	5	22.9×	2e-04
Signaling by NTRK1 (TRKA)	10	15.0×	5e-07
Signaling by NTRKs	10	13.8×	7e-07
Signaling by high-kinase activity BRAF mutants	5	12.1×	3e-03
MAP2K and MAPK activation	5	10.9×	4e-03
Signaling by RAF1 mutants	5	10.6×	4e-03
Signaling by BRAF and RAF1 fusions	8	10.4×	1e-04
Signaling by moderate kinase activity BRAF mutants	5	9.7×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
mRNA transport	6	10.3×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	28
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1686821	NM_001079524.2(PAICS):c.158A>G (p.Lys53Arg)	Pathogenic
3242227	NM_001079524.2(PAICS):c.535T>C (p.Ser179Pro)	Likely pathogenic

SpliceAI

1496 predictions. Top by Δscore:

Variant	Effect	Δscore
4:56435344:GCTCA:G	donor_loss	1.0000
4:56435348:ACCGG:A	donor_loss	1.0000
4:56435415:T:A	donor_gain	1.0000
4:56435839:G:GT	donor_gain	1.0000
4:56441657:CCACA:C	acceptor_loss	1.0000
4:56441658:CACAG:C	acceptor_loss	1.0000
4:56441659:ACAGT:A	acceptor_loss	1.0000
4:56441660:CA:C	acceptor_loss	1.0000
4:56441661:A:AG	acceptor_gain	1.0000
4:56441662:G:GA	acceptor_gain	1.0000
4:56441662:G:T	acceptor_loss	1.0000
4:56441662:GTACT:G	acceptor_gain	1.0000
4:56446691:GTA:G	acceptor_loss	1.0000
4:56446693:A:AC	acceptor_loss	1.0000
4:56446833:GATA:G	donor_gain	1.0000
4:56448412:TCACA:T	acceptor_loss	1.0000
4:56448413:CACAG:C	acceptor_loss	1.0000
4:56448415:CA:C	acceptor_loss	1.0000
4:56448416:A:AG	acceptor_gain	1.0000
4:56448416:AG:A	acceptor_gain	1.0000
4:56448417:G:GG	acceptor_gain	1.0000
4:56448417:G:GT	acceptor_loss	1.0000
4:56448417:GG:G	acceptor_gain	1.0000
4:56448417:GGAT:G	acceptor_gain	1.0000
4:56448819:AACAG:A	donor_loss	1.0000
4:56448820:ACAGG:A	donor_loss	1.0000
4:56448821:CAGGT:C	donor_loss	1.0000
4:56448822:AGG:A	donor_loss	1.0000
4:56448823:G:GC	donor_loss	1.0000
4:56450617:A:AG	acceptor_gain	1.0000

AlphaMissense

2790 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:56446782:G:C	R101T	1.000
4:56448820:A:C	K228N	1.000
4:56448820:A:T	K228N	1.000
4:56441703:A:C	K19N	0.999
4:56441703:A:T	K19N	0.999
4:56446771:A:C	E97D	0.999
4:56446771:A:T	E97D	0.999
4:56446782:G:T	R101I	0.999
4:56446783:A:C	R101S	0.999
4:56446783:A:T	R101S	0.999
4:56446791:C:A	A104E	0.999
4:56446797:G:A	G106D	0.999
4:56446873:G:C	K131N	0.999
4:56446873:G:T	K131N	0.999
4:56448589:G:C	D189H	0.999
4:56448590:A:T	D189V	0.999
4:56448770:G:C	D212H	0.999
4:56448771:A:C	D212A	0.999
4:56448771:A:G	D212G	0.999
4:56448771:A:T	D212V	0.999
4:56448772:T:A	D212E	0.999
4:56448772:T:G	D212E	0.999
4:56448773:T:C	S213P	0.999
4:56448776:T:A	W214R	0.999
4:56448776:T:C	W214R	0.999
4:56448780:G:C	R215T	0.999
4:56448781:A:C	R215S	0.999
4:56448781:A:T	R215S	0.999
4:56448785:T:A	W217R	0.999
4:56448785:T:C	W217R	0.999

dbSNP variants (sampled 300 via entrez): RS1000020801 (4:56449705 C>T), RS1000028114 (4:56434461 C>T), RS1000127698 (4:56414252 T>C), RS10001639 (4:56454072 T>G), RS1000293209 (4:56464399 G>A), RS1000350256 (4:56439083 C>A,G,T), RS1000386892 (4:56420672 G>A,C), RS1000389708 (4:56413788 T>C), RS1000422030 (4:56439305 C>T), RS1000466178 (4:56416025 A>G,T), RS1000496571 (4:56459640 C>T), RS1000549232 (4:56434737 T>C), RS1000565835 (4:56458156 G>C), RS1000628532 (4:56448011 T>C), RS1000669384 (4:56422405 C>T)

Disease associations

OMIM: gene MIM:172439 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
PAICS deficiency	Limited	Autosomal recessive

Mondo (2): (MONDO:0859244), PAICS deficiency (MONDO:0859003)

Orphanet (0):

HPO phenotypes

24 total (24 of 24 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000248	Brachycephaly
HP:0000316	Hypertelorism
HP:0000369	Low-set ears
HP:0000452	Choanal stenosis
HP:0000453	Choanal atresia
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000921	Missing ribs
HP:0001561	Polyhydramnios
HP:0001762	Talipes equinovarus
HP:0002032	Esophageal atresia
HP:0002575	Tracheoesophageal fistula
HP:0003196	Short nose
HP:0003811	Neonatal death
HP:0004209	Clinodactyly of the 5th finger
HP:0004322	Short stature
HP:0004502	Bilateral choanal atresia
HP:0005280	Depressed nasal bridge
HP:0008439	Lumbar hemivertebrae
HP:0008689	Bilateral cryptorchidism
HP:0008743	Coronal hypospadias
HP:0011461	Fetal onset
HP:0012368	Flat face

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5922 (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: 2,395 (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
CHEMBL3301622	GILTERITINIB	4	2,395

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

ChEMBL bioactivities

43 potent at pChembl≥5 of 43 total, top 43 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.00	IC50	10	nM	CHEMBL4439335
8.00	IC50	10	nM	CHEMBL4586958
8.00	IC50	10	nM	CHEMBL4445327
8.00	IC50	10	nM	CHEMBL4516567
8.00	IC50	10	nM	CHEMBL4514185
8.00	IC50	10	nM	CHEMBL4551539
8.00	IC50	10	nM	CHEMBL4575613
8.00	IC50	10	nM	CHEMBL4466413
8.00	IC50	10	nM	CHEMBL4536252
8.00	IC50	10	nM	CHEMBL4442163
8.00	IC50	10	nM	CHEMBL4474352
8.00	IC50	10	nM	CHEMBL4468822
8.00	IC50	10	nM	CHEMBL4438093
8.00	IC50	10	nM	CHEMBL4459387
8.00	IC50	10	nM	CHEMBL4578668
8.00	IC50	10	nM	CHEMBL4455550
8.00	IC50	10	nM	CHEMBL4565482
8.00	IC50	10	nM	CHEMBL4546611
8.00	IC50	10	nM	CHEMBL4518584
8.00	IC50	10	nM	CHEMBL4593253
8.00	IC50	10	nM	CHEMBL4446674
7.69	Kd	20.52	nM	CHEMBL3752910
7.69	ED50	20.52	nM	CHEMBL3752910
7.60	IC50	25	nM	CHEMBL4451506
7.60	IC50	25	nM	CHEMBL4470155
7.60	IC50	25	nM	CHEMBL4462176
7.60	IC50	25	nM	CHEMBL4444329
7.60	IC50	25	nM	CHEMBL4445038
7.60	IC50	25	nM	CHEMBL4585820
7.60	IC50	25	nM	CHEMBL4516092
7.60	IC50	25	nM	CHEMBL4446513
7.60	IC50	25	nM	CHEMBL4454750
7.60	IC50	25	nM	CHEMBL4473997
7.60	IC50	25	nM	CHEMBL4476811
7.60	IC50	25	nM	CHEMBL4466767
7.60	IC50	25	nM	CHEMBL4538041
7.60	IC50	25	nM	CHEMBL4590239
7.60	IC50	25	nM	CHEMBL4458444
7.60	IC50	25	nM	CHEMBL4570990
7.60	IC50	25	nM	CHEMBL4578225
7.26	Kd	54.77	nM	CHEMBL5653589
7.26	ED50	54.77	nM	CHEMBL5653589
5.26	Kd	5481	nM	GILTERITINIB

PubChem BioAssay actives

3 with measured affinity, of 249 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148931: Binding affinity to human PAICS incubated for 45 mins by Kinobead based pull down assay	kd	0.0205	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148931: Binding affinity to human PAICS incubated for 45 mins by Kinobead based pull down assay	kd	0.0548	uM
Gilteritinib	1425098: 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	5.4810	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, affects cotreatment	4
Tretinoin	decreases expression	4
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	2
bisphenol S	increases expression	2
Acrolein	affects cotreatment, increases oxidation, increases abundance	2
Estradiol	increases expression	2
Nickel	decreases expression, increases expression	2
Ozone	affects cotreatment, increases oxidation, increases abundance	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	increases abundance, increases expression	1
ochratoxin A	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
coumarin	increases phosphorylation	1
hydroquinone	decreases expression	1
quinoline	increases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	decreases ADP-ribosylation	1
K 7174	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3991811	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

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1PJ	Abcam K-562 PAICS KO	Cancer cell line	Female
CVCL_D2L5	Abcam Raji PAICS KO	Cancer cell line	Male
CVCL_WQ20	Abcam Jurkat PAICS KO	Cancer cell line	Male

Clinical trials (associated diseases)

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