E4F1

Summary

E4F1 (E4F transcription factor 1, HGNC:3121) is a protein-coding gene on chromosome 16p13.3, encoding Transcription factor E4F1 (Q66K89). May function as a transcriptional repressor. It is a selective cancer dependency (DepMap: 41.8% of cell lines).

The zinc finger protein encoded by this gene is one of several cellular transcription factors whose DNA-binding activities are regulated through the action of adenovirus E1A. A 50-kDa amino-terminal product is generated from the full-length protein through proteolytic cleavage. The protein is differentially regulated by E1A-induced phosphorylation. The full-length gene product represses transcription from the E4 promoter in the absence of E1A, while the 50-kDa form acts as a transcriptional activator in its presence. Alternative splicing results in multiple transcripts encoding different proteins.

Source: NCBI Gene 1877 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 158 total — 2 likely-pathogenic
• Cancer dependency (DepMap): dependent in 41.8% of screened cell lines
• Transcription factor: yes — 10 downstream targets (CollecTRI)
• MANE Select transcript: NM_004424

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3121
Approved symbol	E4F1
Name	E4F transcription factor 1
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	E4F
Ensembl gene	ENSG00000167967
Ensembl biotype	protein_coding
OMIM	603022
Entrez	1877

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 20 protein_coding, 4 retained_intron, 1 nonsense_mediated_decay

ENST00000301727, ENST00000562589, ENST00000563643, ENST00000564139, ENST00000564930, ENST00000565090, ENST00000565413, ENST00000567111, ENST00000569796, ENST00000862875, ENST00000862876, ENST00000862877, ENST00000862878, ENST00000862879, ENST00000862880, ENST00000862881, ENST00000862882, ENST00000927663, ENST00000927664, ENST00000927665, ENST00000956543, ENST00000956544, ENST00000956545, ENST00000956546, ENST00000956547

RefSeq mRNA: 3 — MANE Select: NM_004424 NM_001288776, NM_001288778, NM_004424

CCDS: CCDS32370, CCDS73809, CCDS73810

Canonical transcript exons

ENST00000301727 — 14 exons

Exon	Start	End
ENSE00001118787	2234171	2234388
ENSE00001118794	2234859	2235001
ENSE00001118797	2233438	2233647
ENSE00001118799	2234583	2234781
ENSE00001118800	2233011	2233183
ENSE00001242895	2228372	2228523
ENSE00001297313	2223591	2223770
ENSE00003462673	2235216	2235742
ENSE00003480554	2229570	2229675
ENSE00003625565	2233882	2233990
ENSE00003656698	2232171	2232364
ENSE00003656726	2235081	2235143
ENSE00003662124	2232456	2232576
ENSE00003789479	2232756	2232908

Expression profiles

Bgee: expression breadth ubiquitous, 138 present calls, max score 91.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.5712 / max 196.0499, expressed in 1809 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
152215	10.5354	1797
152216	6.8374	1694
152217	0.1984	71

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	91.50	gold quality
lower esophagus mucosa	UBERON:0035834	91.32	gold quality
sural nerve	UBERON:0015488	90.90	gold quality
cerebellum	UBERON:0002037	90.72	gold quality
cerebellar hemisphere	UBERON:0002245	90.70	gold quality
cerebellar cortex	UBERON:0002129	90.66	gold quality
right lobe of thyroid gland	UBERON:0001119	90.26	gold quality
granulocyte	CL:0000094	89.68	gold quality
left lobe of thyroid gland	UBERON:0001120	89.52	gold quality
thyroid gland	UBERON:0002046	89.01	gold quality
pituitary gland	UBERON:0000007	88.96	gold quality
skin of leg	UBERON:0001511	88.91	gold quality
skin of abdomen	UBERON:0001416	88.73	gold quality
zone of skin	UBERON:0000014	88.66	gold quality
apex of heart	UBERON:0002098	88.62	gold quality
adenohypophysis	UBERON:0002196	88.62	gold quality
blood	UBERON:0000178	88.20	gold quality
prostate gland	UBERON:0002367	88.00	gold quality
mucosa of transverse colon	UBERON:0004991	87.94	gold quality
spleen	UBERON:0002106	87.79	gold quality
body of uterus	UBERON:0009853	87.71	gold quality
metanephros cortex	UBERON:0010533	87.58	gold quality
hindlimb stylopod muscle	UBERON:0004252	87.49	gold quality
transverse colon	UBERON:0001157	86.94	gold quality
right lobe of liver	UBERON:0001114	86.90	gold quality
muscle layer of sigmoid colon	UBERON:0035805	86.87	gold quality
body of stomach	UBERON:0001161	86.84	gold quality
gastrocnemius	UBERON:0001388	86.81	gold quality
right frontal lobe	UBERON:0002810	86.77	gold quality
left uterine tube	UBERON:0001303	86.58	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.89

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

10 targets.

Target	Regulation
ACHE
APRT
CCNA2	Repression
CCND1	Activation
CD44
CTNND1
E4F1
PVR
RASSF1
TCF3

Upstream regulators (CollecTRI, top): E4F1, TP53

miRNA regulators (miRDB)

6 targeting E4F1, 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-6835-3P	99.93	70.49	2904
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-597-3P	96.46	68.03	1035

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 41.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 14)

• association of p120E4F with p14ARF enhances cell cycle inhibition (PMID:12446718)
• Specific inactivation of RASSF1A by short interfering RNA disrupts binding of RASSF1A to p120(E4F) in tumor cells. (PMID:14729613)
• E4F1 function involves ER alpha-mediated inhibition of VSMC proliferation and estrogen-related atheroprotection of human (PMID:15579445)
• findings show that full-length E4F1 protein but not its E1A-activated & truncated form interacts in vitro & in vivo with FHL2; this E4F1-FHL2 association occurs in the nuclear compartment & inhibits the capacity of E4F1 to block cell proliferation (PMID:16652157)
• E4F1 is a key posttranslational regulator of p53, which modulates its effector functions involved in alternative cell fates: growth arrest or apoptosis. (PMID:17110336)
• LANP and ATAXN1 interact in E4F-mediated transcriptional repression. (PMID:17557114)
• Short hairpin RNA-mediated depletion of E4F1 induced mitochondrial defects and ROS-mediated death in several myeloid leukemia cell lines. (PMID:21708927)
• results suggest that E4F1 may neutralize the capacity of HBx to activate a p53-dependent, metabolic and growth arrest phenotype in liver cells, thus possibly contributing to the viability and proliferation of HBV-infected cells (PMID:24163401)
• Whole exome sequencing has unraveled the presence of pathogenic mutations in genes encoding non-mitochondrial proteins, such as in the transcription factor E4F1. (PMID:26968897)
• E4F1 silencing inhibits the cell growth through cell-cycle arrest in malignant transformed cells induced by hydroquinone (PMID:30506647)
• Zinc finger protein E4F1 cooperates with PARP-1 and BRG1 to promote DNA double-strand break repair. (PMID:33692124)
• The multifunctional protein E4F1 links P53 to lipid metabolism in adipocytes. (PMID:34857760)
• Multi-Level Control of the ATM/ATR-CHK1 Axis by the Transcription Factor E4F1 in Triple-Negative Breast Cancer. (PMID:36012478)
• Transcription factor E4F1 as a regulator of cell life and disease progression. (PMID:37774036)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	e4f1	ENSDARG00000038243
mus_musculus	E4f1	ENSMUSG00000024137
rattus_norvegicus	E4f1	ENSRNOG00000009224

Paralogs (38): ZFX (ENSG00000005889), ZBTB11 (ENSG00000066422), ZFAT (ENSG00000066827), ZFY (ENSG00000067646), ZNF586 (ENSG00000083828), IKZF5 (ENSG00000095574), ZNF419 (ENSG00000105136), ZNF549 (ENSG00000121406), ZSCAN20 (ENSG00000121903), ZNF304 (ENSG00000131845), PRDM15 (ENSG00000141956), ZNF660 (ENSG00000144792), ZNF711 (ENSG00000147180), ZNF773 (ENSG00000152439), ZNF256 (ENSG00000152454), ZNF837 (ENSG00000152475), ZNF691 (ENSG00000164011), ZNF610 (ENSG00000167554), ZNF562 (ENSG00000171466), ZNF561 (ENSG00000171469), ZNF584 (ENSG00000171574), ZIK1 (ENSG00000171649), ZNF570 (ENSG00000171827), ZSCAN2 (ENSG00000176371), ZNF552 (ENSG00000178935), ZNF154 (ENSG00000179909), ZNF792 (ENSG00000180884), ZNF793 (ENSG00000188227), ZNF548 (ENSG00000188785), ZNF79 (ENSG00000196152), ZNF418 (ENSG00000196724), ZNF772 (ENSG00000197128), ZNF583 (ENSG00000198440), ZNF480 (ENSG00000198464), ZNF551 (ENSG00000204519), ZNF134 (ENSG00000213762), ZNF587B (ENSG00000269343), ZNF8 (ENSG00000278129)

Protein

Protein identifiers

Transcription factor E4F1 — Q66K89 (reviewed: Q66K89)

Alternative names: E4F transcription factor 1, Putative E3 ubiquitin-protein ligase E4F1, RING-type E3 ubiquitin transferase E4F1, Transcription factor E4F, p120E4F, p50E4F

All UniProt accessions (5): Q66K89, H3BN24, H3BQZ4, H3BSL4, H3BUJ7

UniProt curated annotations — full annotation on UniProt →

Function. May function as a transcriptional repressor. May also function as a ubiquitin ligase mediating ubiquitination of chromatin-associated TP53. Functions in cell survival and proliferation through control of the cell cycle. Functions in the p53 and pRB tumor suppressor pathways and regulates the cyclin CCNA2 transcription. Identified as a cellular target of the adenoviral oncoprotein E1A, it is required for both transcriptional activation and repression of viral genes.

Subunit / interactions. Homodimer; binds DNA as a dimer. Forms a complex with CDKN2A and TP53. Interactions with TP53, RB1, ANP32A, BMI1 and FHL2 regulate E4F1 activity. Interacts with HDAC1, HMGA2 and RASSF1. (Microbial infection) Interacts with HBV protein X.

Subcellular location. Nucleus. Nucleoplasm. Cytoplasm.

Tissue specificity. Ubiquitously expressed.

Post-translational modifications. Proteolytic cleavage produces a 50 kDa N-terminal peptide (p50E4F) which has a DNA-binding activity and activates transcription in presence of the adenoviral E1A protein. The major full-length protein (p120E4F) functions as a repressor of transcription. Phosphorylated; p120E4F and p50E4F are both phosphorylated. Phosphorylation is cell cycle-dependent and differentially regulates DNA-binding activity and function of both forms. May be sumoylated by UBE2I upon interaction with CDKN2A.

Induction. Up-regulated by estrogen.

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (3): NP_001275705, NP_001275707, NP_004415* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily

Pfam: PF00096

UniProt features (33 total): zinc finger region 9, mutagenesis site 7, sequence conflict 7, region of interest 6, sequence variant 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q66K89-F1	53.68	0.00

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 50

Mutagenesis-validated functional residues (7):

Position	Phenotype
194	increases dna-binding; when associated with s-197.
197	increases dna-binding; when associated with s-194.
210	alters dna-binding.
237	alters dna-binding; when associated with n-238.
238	alters dna-binding; when associated with l-237.
249	alters dna-binding; when associated with s-250.
250	alters dna-binding; when associated with m-249.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 120 (showing top): GOBP_REGULATION_OF_CELL_CYCLE, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_MITOTIC_CELL_CYCLE, MYB_Q3, CREB_Q3, LEE_CALORIE_RESTRICTION_NEOCORTEX_UP, GOBP_EMBRYO_DEVELOPMENT, GOBP_REGULATION_OF_CELL_CYCLE_PROCESS, MILI_PSEUDOPODIA_CHEMOTAXIS_DN, GOBP_DNA_REPLICATION, GOCC_SPINDLE, DURCHDEWALD_SKIN_CARCINOGENESIS_UP, GOBP_CELL_DIVISION, GOBP_CELL_CYCLE_PROCESS, GOBP_DNA_METABOLIC_PROCESS

GO Biological Process (9): negative regulation of transcription by RNA polymerase II (GO:0000122), DNA replication (GO:0006260), regulation of transcription by RNA polymerase II (GO:0006357), regulation of mitotic cell cycle, embryonic (GO:0009794), regulation of cell cycle process (GO:0010564), protein ubiquitination (GO:0016567), positive regulation of transcription by RNA polymerase II (GO:0045944), cell division (GO:0051301), regulation of cell cycle (GO:0051726)

GO Molecular Function (13): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), zinc ion binding (GO:0008270), cAMP response element binding (GO:0035497), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), ubiquitin protein ligase activity (GO:0061630), DNA binding (GO:0003677), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), spindle (GO:0005819), nuclear body (GO:0016604), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of transcription by RNA polymerase II	2
regulation of DNA-templated transcription	2
transcription cis-regulatory region binding	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
cellular anatomical structure	2
intracellular membraneless organelle	2
negative regulation of DNA-templated transcription	1
DNA metabolic process	1
DNA biosynthetic process	1
regulation of mitotic cell cycle	1
mitotic cell cycle, embryonic	1
cell cycle process	1
regulation of cell cycle	1
protein modification by small protein conjugation	1
positive regulation of DNA-templated transcription	1
cellular process	1
cell cycle	1
regulation of cellular process	1
cis-regulatory region sequence-specific DNA binding	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription repressor activity	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
transcription regulator activity	1
transition metal ion binding	1
RNA polymerase II cis-regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
nucleic acid binding	1
binding	1
catalytic activity	1
cation binding	1
nuclear lumen	1
intracellular anatomical structure	1
microtubule cytoskeleton	1
nucleoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1726 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
E4F1	TP53	P04637	921
E4F1	RASSF1	Q9NS23	842
E4F1	BMI1	P35226	720
E4F1	R4GMX3	R4GMX3	716
E4F1	CDKN2A	P42771	703
E4F1	ANP32A	P39687	594
E4F1	F5H6H0	F5H6H0	559
E4F1	FHL2	Q14192	529
E4F1	CHEK1	O14757	500
E4F1	EZH1	Q92800	496
E4F1	RB1	P06400	474
E4F1	MDM2	Q00987	469
E4F1	MOAP1	Q96BY2	467
E4F1	HIPK2	Q9H2X6	467
E4F1	CCND1	P24385	465

IntAct

68 interactions, top by confidence:

A	B	Type	Score
RASSF1	E4F1	psi-mi:“MI:0915”(physical association)	0.640
RASSF1	E4F1	psi-mi:“MI:0407”(direct interaction)	0.640
E4F1	RASSF1	psi-mi:“MI:0407”(direct interaction)	0.640
E4F1	RASSF1	psi-mi:“MI:0915”(physical association)	0.640
	E4F1	psi-mi:“MI:0915”(physical association)	0.630
E4F1		psi-mi:“MI:0915”(physical association)	0.630
ANP32A	E4F1	psi-mi:“MI:0403”(colocalization)	0.560
E4F1	ANP32A	psi-mi:“MI:0915”(physical association)	0.560
lnx2b	E4F1	psi-mi:“MI:0915”(physical association)	0.540
E4F1	lnx2b	psi-mi:“MI:0407”(direct interaction)	0.540
VWCE	ZNF316	psi-mi:“MI:0914”(association)	0.530
XAGE1A	THAP12	psi-mi:“MI:0914”(association)	0.530
E4F1	ZBTB24	psi-mi:“MI:0914”(association)	0.530
FHL2	CNOT1	psi-mi:“MI:0914”(association)	0.530
E4F1	C1QBP	psi-mi:“MI:0914”(association)	0.530
ABT1	ZNF316	psi-mi:“MI:0914”(association)	0.530
E4F1	X	psi-mi:“MI:0915”(physical association)	0.530
X	E4F1	psi-mi:“MI:0915”(physical association)	0.530
X	E4F1	psi-mi:“MI:0407”(direct interaction)	0.530

BioGRID (171): KRTAP10-4 (Two-hybrid), KRTAP10-7 (Two-hybrid), E4F1 (Two-hybrid), E4F1 (Reconstituted Complex), E4F1 (Affinity Capture-Western), E4F1 (Phenotypic Enhancement), RASSF1 (Reconstituted Complex), E4F1 (Reconstituted Complex), E4F1 (Affinity Capture-Western), E4F1 (Far Western), FHL2 (Two-hybrid), FHL2 (Reconstituted Complex), FHL2 (Affinity Capture-Western), E4F1 (Affinity Capture-Western), TP53 (Affinity Capture-Western)

ESM2 similar proteins: A2A5K6, F1QQA8, G3V893, O08696, O14901, O57415, P36197, P37275, P97691, Q04891, Q07243, Q08050, Q14872, Q16254, Q2QGD7, Q3UH06, Q5EAC5, Q5F293, Q60542, Q62255, Q62947, Q64318, Q66K89, Q6DBW0, Q6YND2, Q7TS63, Q80X44, Q86V15, Q86VK4, Q8BG87, Q8BKX7, Q8BX22, Q8C8V1, Q8CCE9, Q8IVH2, Q91X45, Q92766, Q96CK0, Q99607, Q9BYN7

Diamond homologs: Q4V8R6, Q66K89, Q8CCE9

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
HMGA2	down-regulates	E4F1	binding
E4F1	“up-regulates activity”	TP53	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	130
Likely benign	9
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
3338428	GRCh37/hg19 16p13.3(chr16:2229815-2582030)x4	Likely pathogenic
3362257	NM_004424.5(E4F1):c.430A>C (p.Lys144Gln)	Likely pathogenic

SpliceAI

2455 predictions. Top by Δscore:

Variant	Effect	Δscore
16:2223767:G:GT	donor_gain	1.0000
16:2223768:A:T	donor_gain	1.0000
16:2228520:GGAG:G	donor_gain	1.0000
16:2228521:GAGG:G	donor_gain	1.0000
16:2228522:AGG:A	donor_loss	1.0000
16:2228523:GGTG:G	donor_loss	1.0000
16:2228524:G:C	donor_loss	1.0000
16:2228525:T:G	donor_loss	1.0000
16:2229564:T:A	acceptor_gain	1.0000
16:2229565:G:A	acceptor_gain	1.0000
16:2229566:GCA:G	acceptor_loss	1.0000
16:2229567:CAGG:C	acceptor_loss	1.0000
16:2229568:A:G	acceptor_loss	1.0000
16:2229568:AGGT:A	acceptor_gain	1.0000
16:2229569:GGTG:G	acceptor_gain	1.0000
16:2229672:GTTG:G	donor_gain	1.0000
16:2229674:TGGT:T	donor_loss	1.0000
16:2229676:G:GG	donor_gain	1.0000
16:2229676:GTAAG:G	donor_loss	1.0000
16:2229677:T:G	donor_loss	1.0000
16:2232361:GACG:G	donor_gain	1.0000
16:2232451:CACAG:C	acceptor_loss	1.0000
16:2232454:A:AC	acceptor_loss	1.0000
16:2232454:A:AG	acceptor_gain	1.0000
16:2232454:AG:A	acceptor_gain	1.0000
16:2232455:G:GG	acceptor_gain	1.0000
16:2232455:GG:G	acceptor_gain	1.0000
16:2232455:GGGCA:G	acceptor_gain	1.0000
16:2232574:CGGGT:C	donor_loss	1.0000
16:2232575:GG:G	donor_gain	1.0000

AlphaMissense

5082 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:2232510:T:C	C222R	1.000
16:2232519:T:C	C225R	1.000
16:2232531:T:C	F229L	1.000
16:2232533:C:A	F229L	1.000
16:2232533:C:G	F229L	1.000
16:2232572:C:A	H242Q	1.000
16:2232572:C:G	H242Q	1.000
16:2232773:T:C	C250R	1.000
16:2232794:T:C	F257L	1.000
16:2232796:C:A	F257L	1.000
16:2232796:C:G	F257L	1.000
16:2234655:T:C	F556L	1.000
16:2234657:C:A	F556L	1.000
16:2234657:C:G	F556L	1.000
16:2234718:T:C	C577R	1.000
16:2234727:T:A	C580S	1.000
16:2234727:T:C	C580R	1.000
16:2234728:G:C	C580S	1.000
16:2234739:T:C	F584L	1.000
16:2234740:T:C	F584S	1.000
16:2234741:C:A	F584L	1.000
16:2234741:C:G	F584L	1.000
16:2232335:T:C	C194R	0.999
16:2232356:T:C	F201L	0.999
16:2232357:T:C	F201S	0.999
16:2232358:C:A	F201L	0.999
16:2232358:C:G	F201L	0.999
16:2232466:T:C	L207P	0.999
16:2232510:T:A	C222S	0.999
16:2232511:G:C	C222S	0.999

dbSNP variants (sampled 300 via entrez): RS1000359585 (16:2236089 T>A), RS1000621430 (16:2226800 G>A,T), RS1000656598 (16:2229598 A>G), RS1000704081 (16:2229758 C>A,G,T), RS1001215834 (16:2224634 A>G), RS1001492761 (16:2225371 T>C), RS1001733387 (16:2232671 G>C), RS1001946788 (16:2223042 T>A), RS1001977200 (16:2224882 G>A,C), RS1002007577 (16:2223239 C>A), RS1002029617 (16:2225222 A>G), RS1002277843 (16:2230015 G>A), RS1002879451 (16:2230918 C>T), RS1002980656 (16:2226256 G>A), RS1003158392 (16:2221711 A>G)

Disease associations

OMIM: gene MIM:603022 | disease phenotypes: MIM:608105, MIM:312170

GenCC curated gene-disease

Mondo (2): rolandic epilepsy-paroxysmal exercise-induced dystonia-writer’s cramp syndrome (MONDO:0011970), pyruvate dehydrogenase deficiency (MONDO:0019169)

Orphanet (3): Rolandic epilepsy-paroxysmal exercise-induced dystonia-writer’s cramp syndrome (Orphanet:163727), Pyruvate dehydrogenase deficiency (Orphanet:765), Pyruvate dehydrogenase E1-alpha deficiency (Orphanet:79243)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90000025_79	Appendicular lean mass	1.000000e-17

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004980	appendicular lean mass

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535499	Epilepsy, rolandic with paroxysmal exercise-induced dystonia and writer’s cramp (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects expression, decreases expression	3
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
hydroquinone	affects response to substance, decreases expression, increases expression	2
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
cypermethrin	decreases expression	1
1-hydroxypyrene	decreases expression	1
beta-methylcholine	affects expression	1
ICG 001	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	increases expression	1
Temozolomide	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	1
Atrazine	decreases expression	1
Ellagic Acid	increases expression	1
Ozone	affects expression, increases abundance	1
Selenium	increases expression	1
Smoke	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Asbestos, Crocidolite	decreases expression	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02616484	PHASE3	ACTIVE_NOT_RECRUITING	Trial of Dichloroacetate in Pyruvate Dehydrogenase Complex Deficiency:
NCT03734263	PHASE2	COMPLETED	Use of Phenylbutyrate Therapy for Patients With Pyruvate Dehydrogenase Complex Deficiency.
NCT06340685	PHASE1	RECRUITING	Triheptanoin for Children With Primary-Specific Pyruvate Dehydrogenase Complex (PDC) Deficiency
NCT05257005	Not specified	UNKNOWN	Natural History Study of Pyruvate Dehydrogenase Deficiency
NCT06931262	Not specified	AVAILABLE	Expanded Access Treatment Protocol With DCA for Patients With PDCD