CS

Summary

CS (citrate synthase, HGNC:2422) is a protein-coding gene on chromosome 12q13.3, encoding Citrate synthase, mitochondrial (O75390). Key enzyme of the Krebs tricarboxylic acid cycle which catalyzes the synthesis of citrate from acetyl coenzyme A and oxaloacetate. It is a selective cancer dependency (DepMap: 36.6% of cell lines).

The protein encoded by this gene is a Krebs tricarboxylic acid cycle enzyme that catalyzes the synthesis of citrate from oxaloacetate and acetyl coenzyme A. The enzyme is found in nearly all cells capable of oxidative metablism. This protein is nuclear encoded and transported into the mitochondrial matrix, where the mature form is found.

Source: NCBI Gene 1431 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 44 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 36.6% of screened cell lines
• MANE Select transcript: NM_004077

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2422
Approved symbol	CS
Name	citrate synthase
Location	12q13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000062485
Ensembl biotype	protein_coding
OMIM	118950
Entrez	1431

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 24 protein_coding, 11 retained_intron, 4 nonsense_mediated_decay

ENST00000351328, ENST00000542324, ENST00000546585, ENST00000546621, ENST00000546891, ENST00000546930, ENST00000547283, ENST00000547298, ENST00000547449, ENST00000547912, ENST00000548041, ENST00000548567, ENST00000548746, ENST00000548849, ENST00000549143, ENST00000549221, ENST00000550044, ENST00000550159, ENST00000550655, ENST00000550700, ENST00000550734, ENST00000550996, ENST00000551137, ENST00000551155, ENST00000551253, ENST00000551430, ENST00000551441, ENST00000551473, ENST00000551936, ENST00000551968, ENST00000552222, ENST00000552331, ENST00000552688, ENST00000904224, ENST00000904225, ENST00000921535, ENST00000921536, ENST00000947272, ENST00000947273

RefSeq mRNA: 1 — MANE Select: NM_004077 NM_004077

CCDS: CCDS8913

Canonical transcript exons

ENST00000351328 — 11 exons

Exon	Start	End
ENSE00003462969	56275002	56275131
ENSE00003480306	56275996	56276195
ENSE00003501837	56285916	56286023
ENSE00003501898	56273587	56273796
ENSE00003513078	56282420	56282608
ENSE00003533644	56283792	56283857
ENSE00003541640	56274777	56274878
ENSE00003562168	56300160	56300330
ENSE00003629831	56286595	56286645
ENSE00003656673	56282860	56282991
ENSE00003841381	56271699	56273254

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 99.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 132.1132 / max 1009.6120, expressed in 1828 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
131504	106.7404	1827
131505	23.4241	1815
131503	1.9487	1043

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	99.45	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.17	gold quality
heart right ventricle	UBERON:0002080	99.06	gold quality
gastrocnemius	UBERON:0001388	99.03	gold quality
vastus lateralis	UBERON:0001379	99.02	gold quality
myocardium	UBERON:0002349	98.99	gold quality
body of tongue	UBERON:0011876	98.95	gold quality
diaphragm	UBERON:0001103	98.94	gold quality
cardiac ventricle	UBERON:0002082	98.92	gold quality
heart left ventricle	UBERON:0002084	98.92	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.86	gold quality
skeletal muscle tissue	UBERON:0001134	98.83	gold quality
triceps brachii	UBERON:0001509	98.83	gold quality
biceps brachii	UBERON:0001507	98.81	gold quality
cardiac atrium	UBERON:0002081	98.80	gold quality
gluteal muscle	UBERON:0002000	98.79	gold quality
quadriceps femoris	UBERON:0001377	98.77	gold quality
apex of heart	UBERON:0002098	98.77	gold quality
muscle tissue	UBERON:0002385	98.77	gold quality
right atrium auricular region	UBERON:0006631	98.76	gold quality
deltoid	UBERON:0001476	98.72	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.72	gold quality
muscle organ	UBERON:0001630	98.67	gold quality
muscle of leg	UBERON:0001383	98.62	gold quality
heart	UBERON:0000948	98.60	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.58	gold quality
tibialis anterior	UBERON:0001385	98.43	gold quality
right adrenal gland	UBERON:0001233	98.36	gold quality
right adrenal gland cortex	UBERON:0035827	98.36	gold quality
rectum	UBERON:0001052	98.35	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	15.89
E-MTAB-9801	no	2.84

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FEZF2, MAF, MYB, POU1F1, RORA, SP1, TBR1, TEAD1

miRNA regulators (miRDB)

108 targeting CS, 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-4692	100.00	67.32	2066
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548J-3P	99.94	72.61	4881
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

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 36.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 19)

• Responses of skeletal and cardiac muscles in CS activity and gene expression at 1 and 48 h after endurance training. Acute effect of exercise on training-induced elevation in CS activity in rat soleus but not ventricle muscles. (PMID:12531911)
• possible role of CS-specific autoantibodies in the pathomechanism of allograft vasculopathy (PMID:15711981)
• It is likely that enhanced citrate synthase activity contributes to the conversion of glucose to lipids in pancreatic cancer providing substrate for membrane lipids synthesis. (PMID:15714131)
• These results provide an important basis for the study of mitochondrial dysfunction due to aberrant CSa trafficking. (PMID:19479947)
• Citrate synthase (CS) is a direct RORalpha target gene and one mechanism by which RORalpha regulates lipid metabolism is via regulation of CS expression. (PMID:22485150)
• The citrate synthase knockdown cells exhibited severe defects in respiratory activity and marked decreases in ATP production, but great increases in glycolytic metabolism. (PMID:23139858)
• Paretic muscle in hemiparetic stroke survivors had lower CS concentration. (PMID:26361074)
• Citrate synthase activity was lower in patients with heart failure with preserved ejection fraction compared to controls. (PMID:27179829)
• citrate synthase and ACSS1 have tumorigenic functions in hepatocellular carcinoma (PMID:27363021)
• mir-122 and its targets G6PC3, ALDOA and CS play roles in the hypoxia responses that regulate glucose and energy metabolism and can serve as hypoxia biomarkers. (PMID:27793029)
• Hence, we conclude that SIRT3 exhibits neuroprotection via deacetylating and increasing mitochondrial enzyme activities. (PMID:28161643)
• Data suggest that downregulation of citrate synthase (CS) expression in 293T cells leads to low level of ATP production, excessive superoxide formation and cell apoptosis, which implies a possible mechanism for hearing loss in A/J mice. (PMID:28216161)
• Data suggest that METTL12, localized in mitochondrial matrix, modifies/methylates Lys368 of citrate synthase in external surface region close to its catalytic site; addition/removal of methylation has no effect on citrate synthase activity; Lys368 occurs in highly conserved sequence of amino acid residues of citrate synthase. (METTL12 = methyltransferase-like protein 12) (PMID:28391595)
• METTL12 methylates CS on Lys-395, which is localized in the CS active site. Interestingly, the METTL12-mediated methylation inhibited CS activity and was blocked by the CS substrate oxaloacetate. (PMID:28887308)
• The active sites of the citrate synthase is almost identical, the differences in reactions catalyzed by citrate synthase are caused by residues that are in the vicinity of the active site and influence conformational changes of the citrate synthase. (PMID:31141475)
• Rethinking the Citric Acid Cycle: Connecting Pyruvate Carboxylase and Citrate Synthase to the Flow of Energy and Material. (PMID:33435350)
• The left-lateralisation of citrate synthase activity in the anterior cingulate cortex of male violent suicide victims. (PMID:36350374)
• The Novel Role of Mitochondrial Citrate Synthase and Citrate in the Pathophysiology of Alzheimer’s Disease. (PMID:37393492)
• Citrate synthase lysine K215 hypoacetylation contributes to microglial citrate accumulation and pro-inflammatory functions after traumatic brain injury. (PMID:38421106)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	cs	ENSDARG00000103364
mus_musculus	Cs	ENSMUSG00000005683
mus_musculus	Csl	ENSMUSG00000046934
rattus_norvegicus	Cs	ENSRNOG00000023520
drosophila_melanogaster	CG14740	FBGN0037988
drosophila_melanogaster	kdn	FBGN0261955
caenorhabditis_elegans		WBGENE00000833

Protein

Protein identifiers

Citrate synthase, mitochondrial — O75390 (reviewed: O75390)

Alternative names: Citrate (Si)-synthase

All UniProt accessions (21): O75390, A0A0C4DGI3, B4DJV2, F8VPA1, F8VPF9, F8VR34, F8VRI6, F8VRP1, F8VTT8, F8VU34, F8VVY4, F8VWQ5, F8VX07, F8VX68, F8VZK9, F8W0J2, F8W1S4, F8W4S1, F8W642, H0YH82, H0YIC4

UniProt curated annotations — full annotation on UniProt →

Function. Key enzyme of the Krebs tricarboxylic acid cycle which catalyzes the synthesis of citrate from acetyl coenzyme A and oxaloacetate.

Subunit / interactions. Homodimer.

Subcellular location. Mitochondrion matrix.

Post-translational modifications. Methylated. Trimethylation at Lys-395 by CSKMT decreases citrate synthase activity. In response to mitochondrial stress, the precursor protein is ubiquitinated by the SIFI complex in the cytoplasm before mitochondrial import, leading to its degradation. Within the SIFI complex, UBR4 initiates ubiquitin chain that are further elongated or branched by KCMF1.

Pathway. Carbohydrate metabolism; tricarboxylic acid cycle; isocitrate from oxaloacetate: step 1/2.

Miscellaneous. Citrate synthase is found in nearly all cells capable of oxidative metabolism.

Similarity. Belongs to the citrate synthase family.

RefSeq proteins (1): NP_004068* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002020	Citrate_synthase	Family
IPR010109	Citrate_synthase_euk	Family
IPR016142	Citrate_synth-like_lrg_a-sub	Homologous_superfamily
IPR016143	Citrate_synth-like_sm_a-sub	Homologous_superfamily
IPR019810	Citrate_synthase_AS	Active_site
IPR036969	Citrate_synthase_sf	Homologous_superfamily

Pfam: PF00285

Enzyme classification (BRENDA):

• EC 2.3.3.1 — citrate (Si)-synthase (BRENDA: 15 organisms, 9 substrates, 48 inhibitors, 28 Km, 18 kcat entries)
• EC 2.3.3.16 — citrate synthase (unknown stereospecificity) (BRENDA: 100 organisms, 82 substrates, 183 inhibitors, 214 Km, 98 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ACETYL-COA	0.0007–125	101
OXALOACETATE	0.0011–90.3	93
ACETYL-COA	0.005–10	14
OXALOACETATE	0.0036–5	14
PROPIONYL-COA	0.0017–0.016	5
CITRATE	0.0005–0.001	4

Catalyzed reactions (Rhea), 1 shown:

• oxaloacetate + acetyl-CoA + H2O = citrate + CoA + H(+) (RHEA:16845)

UniProt features (72 total): helix 25, modified residue 18, sequence conflict 8, strand 7, active site 3, turn 3, binding site 3, mutagenesis site 2, transit peptide 1, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
8ZVV	X-RAY DIFFRACTION	1.59
8ZVU	X-RAY DIFFRACTION	1.78
8ZVR	X-RAY DIFFRACTION	1.8
8ZVW	X-RAY DIFFRACTION	1.82
8ZVL	X-RAY DIFFRACTION	2.05
8ZVT	X-RAY DIFFRACTION	2.05
8ZW1	X-RAY DIFFRACTION	2.1
5UZQ	X-RAY DIFFRACTION	2.16
8ZVM	X-RAY DIFFRACTION	2.27
5UZP	X-RAY DIFFRACTION	2.29
5UZR	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75390-F1	94.56	0.93

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 (3): 301; 347; 402

Ligand- & substrate-binding residues (3): 356 (in chain a); 428 (in chain a); 448 (in chain b)

Post-translational modifications (18): 76, 76, 103, 193, 321, 321, 327, 327, 375, 375, 382, 393, 393, 395, 450, 459, 459, 57

Mutagenesis-validated functional residues (2):

Position	Phenotype
393	does not inhibit methylation.
395	inhibits methylation.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1268020	Mitochondrial protein import
R-HSA-71403	Citric acid cycle (TCA cycle)
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-9854311	Maturation of TCA enzymes and regulation of TCA cycle

MSigDB gene sets: 304 (showing top): MORF_MTA1, MORF_DNMT1, MORF_ESPL1, WWTAAGGC_UNKNOWN, GCM_GSPT1, MORF_UBE2I, MORF_RRM1, MORF_HDAC1, MORF_CDK2, TGACCTY_ERR1_Q2, MORF_HDAC2, HNF1_Q6, CHX10_01, GGGTGGRR_PAX4_03, GCM_BCL2L1

GO Biological Process (3): carbohydrate metabolic process (GO:0005975), tricarboxylic acid cycle (GO:0006099), citrate metabolic process (GO:0006101)

GO Molecular Function (6): RNA binding (GO:0003723), citrate synthase activity (GO:0036440), identical protein binding (GO:0042802), obsolete citrate (Si)-synthase activity (GO:0004108), transferase activity (GO:0016740), acyltransferase activity, acyl groups converted into alkyl on transfer (GO:0046912)

GO Cellular Component (5): nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), extracellular exosome (GO:0070062), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Protein localization	1
Aerobic respiration and respiratory electron transport	1
Metabolism of proteins	1
Citric acid cycle (TCA cycle)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
primary metabolic process	2
intracellular membrane-bounded organelle	2
aerobic respiration	1
tricarboxylic acid metabolic process	1
nucleic acid binding	1
acyltransferase activity, acyl groups converted into alkyl on transfer	1
protein binding	1
catalytic activity	1
acyltransferase activity	1
cytoplasm	1
mitochondrion	1
intracellular organelle lumen	1
extracellular vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

4880 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CS	IDH2	P48735	946
CS	FH	P07954	945
CS	IDH1	O75874	934
CS	ACO2	Q99798	905
CS	ACO1	P21399	897
CS	MDH2	P40926	854
CS	LDHC	P07864	830
CS	SLC25A16	P16260	819
CS	GAPDH	P00354	800
CS	PC	P11498	792
CS	PDIA6	Q15084	788
CS	VDAC3	Q9Y277	779
CS	ACLY	P53396	776
CS	OGDH	Q02218	775
CS	LDHA	P00338	766

IntAct

82 interactions, top by confidence:

A	B	Type	Score
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
NEK10	CS	psi-mi:“MI:2364”(proximity)	0.420
CS	HSPE1	psi-mi:“MI:0915”(physical association)	0.400
ATXN7L1	CS	psi-mi:“MI:0915”(physical association)	0.400
CS	PLEC	psi-mi:“MI:0915”(physical association)	0.400
	FER1L5	psi-mi:“MI:0915”(physical association)	0.400
	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
PHOSPHO1	DDX39A	psi-mi:“MI:0914”(association)	0.350
ORF10	NUP42	psi-mi:“MI:0914”(association)	0.350
METTL14	HMGB1P1	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
OPA3	CS	psi-mi:“MI:0914”(association)	0.350
COQ6	NDUFAB1	psi-mi:“MI:0914”(association)	0.350
OPA3	NDUFAB1	psi-mi:“MI:0914”(association)	0.350
DDR1		psi-mi:“MI:0914”(association)	0.350
	AP3B1	psi-mi:“MI:0914”(association)	0.350
USP11	PRRC2B	psi-mi:“MI:0914”(association)	0.350
CHM	POLR3A	psi-mi:“MI:0914”(association)	0.350
PRKD1	MYO1C	psi-mi:“MI:0914”(association)	0.350
SH2D3C	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
DOCK8	IPO5	psi-mi:“MI:0914”(association)	0.350
ARHGAP36	HAX1	psi-mi:“MI:0914”(association)	0.350
ZDHHC5	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
	NBAS	psi-mi:“MI:0914”(association)	0.350
TAGLN	LOC392647	psi-mi:“MI:0914”(association)	0.350
	CLIC1	psi-mi:“MI:0914”(association)	0.350
MAP3K7	ACOT7	psi-mi:“MI:0914”(association)	0.350

BioGRID (705): CS (Affinity Capture-MS), CS (Affinity Capture-RNA), CS (Affinity Capture-RNA), CS (Affinity Capture-RNA), CS (Affinity Capture-MS), CS (Co-fractionation), CS (Co-fractionation), IDH3A (Co-fractionation), PDHX (Co-fractionation), SDHA (Co-fractionation), SDHB (Co-fractionation), CS (Affinity Capture-MS), CS (Affinity Capture-MS), CS (Affinity Capture-MS), CS (Affinity Capture-MS)

ESM2 similar proteins: A0A0S3QTD0, A0A3G1DJJ8, A4H9H8, A4HXU4, C7C435, C7C436, O33915, O68883, O75390, O80433, P00889, P00890, P08679, P0ABH7, P0ABH8, P0C1Z2, P14165, P18789, P20115, P20902, P21553, P24118, P34085, P34575, P42457, P49298, P51036, P51037, P51038, P79024, Q0GNE0, Q0GNE1, Q0QHL3, Q10306, Q16P20, Q17GM7, Q1RGV8, Q28DK1, Q29RK1, Q2TXF1

Diamond homologs: A0A0S3QTD0, A4H9H8, A4HXU4, B0YD89, C7C435, C7C436, O00098, O75390, O80433, P00889, P00890, P08679, P0C1Z2, P20115, P23007, P24118, P34085, P34575, P43635, P49298, P51044, P79024, P83372, Q0GNE0, Q0GNE1, Q0QEL7, Q0QHL3, Q10306, Q16P20, Q17GM7, Q28DK1, Q29RK1, Q43175, Q4QDX3, Q4S5X1, Q50I20, Q553V1, Q61JF9, Q6C793, Q6S9V5

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
CS	“down-regulates quantity”	acetyl-CoA	“chemical modification”
CS	“down-regulates quantity”	oxaloacetate(2-)	“chemical modification”
CS	“up-regulates quantity”	citrate(3-)	“chemical modification”
CSKMT	“down-regulates activity”	CS	methylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 111 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
FCERI mediated NF-kB activation	5	10.4×	6e-03
CLEC7A (Dectin-1) signaling	5	9.5×	8e-03
SARS-CoV-2 activates/modulates innate and adaptive immune responses	6	7.1×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	33
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1808 predictions. Top by Δscore:

Variant	Effect	Δscore
12:56273253:TA:T	acceptor_gain	1.0000
12:56273255:C:CC	acceptor_gain	1.0000
12:56273582:CTTA:C	donor_loss	1.0000
12:56273583:TTACC:T	donor_loss	1.0000
12:56273584:TA:T	donor_loss	1.0000
12:56273585:A:AC	donor_gain	1.0000
12:56273585:A:C	donor_loss	1.0000
12:56273586:C:CC	donor_gain	1.0000
12:56273586:C:G	donor_loss	1.0000
12:56273792:ACAAC:A	acceptor_gain	1.0000
12:56273793:CAAC:C	acceptor_gain	1.0000
12:56273793:CAACC:C	acceptor_gain	1.0000
12:56273794:AAC:A	acceptor_gain	1.0000
12:56273795:AC:A	acceptor_gain	1.0000
12:56273796:CC:C	acceptor_gain	1.0000
12:56273797:C:CC	acceptor_gain	1.0000
12:56273799:G:C	acceptor_gain	1.0000
12:56273799:G:GC	acceptor_gain	1.0000
12:56273806:G:C	acceptor_gain	1.0000
12:56273806:G:GC	acceptor_gain	1.0000
12:56274771:GCTTA:G	donor_loss	1.0000
12:56274772:CTTAC:C	donor_loss	1.0000
12:56274773:TTA:T	donor_loss	1.0000
12:56274774:TA:T	donor_loss	1.0000
12:56274775:A:AC	donor_gain	1.0000
12:56274775:A:AG	donor_loss	1.0000
12:56274775:AC:A	donor_gain	1.0000
12:56274776:C:CC	donor_gain	1.0000
12:56274776:C:CG	donor_loss	1.0000
12:56274776:CC:C	donor_gain	1.0000

AlphaMissense

3028 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:56273213:A:C	F424L	1.000
12:56273213:A:T	F424L	1.000
12:56273215:A:G	F424L	1.000
12:56273612:T:A	D402V	1.000
12:56273612:T:C	D402G	1.000
12:56273617:A:C	N400K	1.000
12:56273617:A:T	N400K	1.000
12:56273776:A:C	H347Q	1.000
12:56273776:A:T	H347Q	1.000
12:56273778:G:C	H347D	1.000
12:56273780:C:T	G346D	1.000
12:56273786:C:T	G344D	1.000
12:56275015:C:T	G302E	1.000
12:56275016:C:G	G302R	1.000
12:56275016:C:T	G302R	1.000
12:56275027:C:T	G298E	1.000
12:56273141:C:A	R448S	0.999
12:56273141:C:G	R448S	0.999
12:56273142:C:A	R448M	0.999
12:56273142:C:G	R448T	0.999
12:56273214:A:C	F424C	0.999
12:56273215:A:C	F424V	0.999
12:56273215:A:T	F424I	0.999
12:56273600:C:T	G406E	0.999
12:56273601:C:A	G406W	0.999
12:56273602:A:C	S405R	0.999
12:56273602:A:T	S405R	0.999
12:56273604:T:G	S405R	0.999
12:56273611:A:C	D402E	0.999
12:56273611:A:T	D402E	0.999

dbSNP variants (sampled 300 via entrez): RS1000006386 (12:56291494 CAGG>C,CAGGAGG), RS1000066329 (12:56283441 C>T), RS1000131674 (12:56276382 C>A,T), RS1000322159 (12:56290768 G>A), RS1000330693 (12:56296926 C>T), RS1000625935 (12:56285707 A>C), RS1000930576 (12:56292858 C>T), RS1001099020 (12:56285748 C>T), RS1001287000 (12:56298652 G>GC), RS1001292010 (12:56289849 C>T), RS1001408143 (12:56290042 C>T), RS1001439315 (12:56292009 A>G), RS1001475440 (12:56282725 T>C), RS1001527647 (12:56292457 T>C), RS1001542559 (12:56271390 C>G)

Disease associations

OMIM: gene MIM:118950 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001885_1	Height	3.000000e-09
GCST002740_46	Inflammatory skin disease	3.000000e-12
GCST008839_427	Height	1.000000e-189
GCST010002_217	Refractive error	6.000000e-174
GCST90090967_22	Height	2.000000e-12

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295678 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Doxorubicin	decreases expression, decreases reaction	3
bisphenol A	increases expression, affects expression	2
bisphenol S	increases expression	2
Resveratrol	decreases expression, decreases reaction, increases activity	2
Dronabinol	decreases expression, increases expression	2
Zidovudine	affects expression, decreases expression	2
Particulate Matter	decreases expression, affects cotreatment, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression, decreases expression	1
6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid	decreases reaction, decreases activity	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	increases expression	1
ochratoxin A	decreases expression	1
acipimox	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation	1
ebselen	decreases activity, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
manganese(III)-tetrakis(4-benzoic acid)porphyrin	decreases activity, decreases reaction	1
nutlin 3	affects cotreatment, increases secretion	1
2,3-bis(4-hydroxyphenyl)-propionitrile	decreases reaction, increases activity	1
4,4’,4’’-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol	increases activity, decreases reaction	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118555	Binding	Binding affinity to CS in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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