SETD3

Summary

SETD3 (SET domain containing 3, actin N3(tau)-histidine methyltransferase, HGNC:20493) is a protein-coding gene on chromosome 14q32.2, encoding Actin-histidine N-methyltransferase (Q86TU7). Protein-histidine N-methyltransferase that specifically mediates 3-methylhistidine (tele-methylhistidine) methylation of actin at ‘His-73’.

Enables protein-L-histidine N-tele-methyltransferase activity. Involved in actin modification and peptidyl-histidine methylation. Located in cytoplasm.

Source: NCBI Gene 84193 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 97 total
• MANE Select transcript: NM_032233

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20493
Approved symbol	SETD3
Name	SET domain containing 3, actin N3(tau)-histidine methyltransferase
Location	14q32.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ23027
Ensembl gene	ENSG00000183576
Ensembl biotype	protein_coding
OMIM	615671
Entrez	84193

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 26 protein_coding, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000329331, ENST00000331768, ENST00000357563, ENST00000436070, ENST00000446066, ENST00000453764, ENST00000453938, ENST00000489770, ENST00000630307, ENST00000856634, ENST00000856635, ENST00000856636, ENST00000856637, ENST00000856638, ENST00000856639, ENST00000856640, ENST00000856641, ENST00000856642, ENST00000856643, ENST00000856644, ENST00000937358, ENST00000937359, ENST00000937360, ENST00000937361, ENST00000954808, ENST00000954809, ENST00000954810, ENST00000954811, ENST00000954812, ENST00000954813, ENST00000954814

RefSeq mRNA: 2 — MANE Select: NM_032233 NM_032233, NM_199123

CCDS: CCDS9951, CCDS9952

Canonical transcript exons

ENST00000331768 — 13 exons

Exon	Start	End
ENSE00001306699	99480728	99480859
ENSE00001326746	99461192	99461340
ENSE00001327783	99397748	99399125
ENSE00003479105	99465703	99465813
ENSE00003480744	99458279	99458535
ENSE00003503794	99412951	99413065
ENSE00003524073	99463486	99463578
ENSE00003545078	99405205	99405371
ENSE00003551273	99404225	99404310
ENSE00003574060	99459113	99459185
ENSE00003574771	99413876	99413934
ENSE00003646755	99400099	99400259
ENSE00003668504	99406516	99406590

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 97.40.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.6237 / max 152.9178, expressed in 1814 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
144881	16.7831	1809
144878	1.9687	1212
144879	1.1809	843
144877	0.3817	168
144880	0.2675	76
144876	0.0236	4
144873	0.0183	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	97.40	gold quality
gastrocnemius	UBERON:0001388	96.95	gold quality
muscle of leg	UBERON:0001383	96.84	gold quality
nephron tubule	UBERON:0001231	96.66	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.49	gold quality
type B pancreatic cell	CL:0000169	96.37	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.17	gold quality
parotid gland	UBERON:0001831	96.06	gold quality
diaphragm	UBERON:0001103	95.66	gold quality
muscle organ	UBERON:0001630	95.63	gold quality
biceps brachii	UBERON:0001507	95.59	gold quality
cervix squamous epithelium	UBERON:0006922	95.41	gold quality
corpus epididymis	UBERON:0004359	95.40	gold quality
left testis	UBERON:0004533	95.26	gold quality
middle temporal gyrus	UBERON:0002771	95.18	gold quality
olfactory bulb	UBERON:0002264	95.12	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.07	gold quality
right testis	UBERON:0004534	94.97	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.84	gold quality
testis	UBERON:0000473	94.81	gold quality
endometrium epithelium	UBERON:0004811	94.75	gold quality
renal glomerulus	UBERON:0000074	94.69	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.68	gold quality
lower esophagus	UBERON:0013473	94.66	gold quality
colonic epithelium	UBERON:0000397	94.64	gold quality
gluteal muscle	UBERON:0002000	94.64	gold quality
smooth muscle tissue	UBERON:0001135	94.61	gold quality
right atrium auricular region	UBERON:0006631	94.59	gold quality
metanephric glomerulus	UBERON:0004736	94.58	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.58	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.32

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

98 targeting SETD3, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-12121	99.99	66.64	255
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-627-3P	99.90	71.42	3316

Literature-anchored findings (GeneRIF, showing 24)

• MAF1, RNF7 and SETD3 are identified as PCNA-associated proteins in human cells and given this interaction with PCNA, Maf1, RNF7, and SetD3 are potentially involved in DNA replication, DNA repair, or associated processes. (PMID:26030842)
• Results show that high expression levels of SMYD2, SETD3, and NO66 in renal cell tumors. Their low expression levels were significantly associated with shorter disease-specific and disease-free survival. (PMID:26488939)
• data reveal a new SETD3-dependent methylation-based signaling pathway at chromatin that regulates VEGF expression under normoxic and hypoxic conditions. (PMID:27845446)
• these data elucidated that a GSK3beta-FBXW7beta-dependent mechanism controls SETD3 protein levels during the cell cycle and attenuates its oncogenic role in liver tumorigenesis. (PMID:28442573)
• SETD3 protein is the actin-specific histidine N-methyltransferase. (PMID:30526847)
• Low expression of SETD3 is a reliable predictor of poor survival in colorectal cancer patients. SETD3 is a positive regulator of p53-dependent activation of DOX-induced apoptosis. (PMID:30683849)
• Structural analyses, supported by biochemical experiments and enzyme activity assays, indicate that the recognition and methylation of beta-actin by SETD3 are highly sequence specific, and that both SETD3 and beta-actin adopt pronounced conformational changes upon binding to each other (PMID:30785395)
• CircSETD3 inhibits the growth of HCC partly through the circSETD3/miR-421/MAPK14 pathway. (PMID:30795787)
• Findings indicate that SET domain protein 3 (SETD3) down-regulated the expression of kinesin light chain 4 (KLC4), contributing to the radiosensitivity of cervical cancer cells, suggesting targeting SETD3 might be a potential strategy for the clinical management of cervical cancer. (PMID:31235251)
• Study reports structural and molecular determinant(s) of target specificity of actin histidine vs. lysine in the active site of SETD3. To facilitate the methyl transfer reaction, SETD3 provides a local environment that promotes deprotonation of the target nitrogen N3 of histidine (and concomitant protonation of N1). (PMID:31388018)
• SETD3 is regulated by a couple of microRNAs and plays opposing roles in proliferation and metastasis of hepatocellular carcinoma. (PMID:31654063)
• An engineered variant of SETD3 methyltransferase alters target specificity from histidine to lysine methylation. (PMID:31911441)
• SETD3 acts as a prognostic marker in breast cancer patients and modulates the viability and invasion of breast cancer cells. (PMID:32042016)
• Characterization of SETD3 methyltransferase-mediated protein methionine methylation. (PMID:32503840)
• The methyltransferase SETD3-mediated histidine methylation: Biological functions and potential implications in cancers. (PMID:33157163)
• Stabilization of SETD3 by deubiquitinase USP27 enhances cell proliferation and hepatocellular carcinoma progression. (PMID:35018513)
• Importance of Ile71 in beta-actin on histidine methyltransferase SETD3 catalysis. (PMID:35142326)
• Structure-function conservation between the methyltransferases SETD3 and SETD6. (PMID:35550916)
• Proteolytic Activities of Enterovirus 2A Do Not Depend on Its Interaction with SETD3. (PMID:35891342)
• CircSETD3 mediates acquired resistance to gefitinib in non-small lung cancer cells by FXR1/ECT2 pathway. (PMID:36503048)
• The Role of Trp79 in beta-Actin on Histidine Methyltransferase SETD3 Catalysis. (PMID:37581408)
• The EV71 2A protease occupies the central cleft of SETD3 and disrupts SETD3-actin interaction. (PMID:38755176)
• SETD3 functions beyond histidine methylation. (PMID:39299385)
• Examining prestructured beta-actin peptides as substrates of histidine methyltransferase SETD3. (PMID:39488591)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	setd3	ENSDARG00000016513
mus_musculus	Setd3	ENSMUSG00000056770
rattus_norvegicus	Setd3	ENSRNOG00000006587
drosophila_melanogaster	Setd3	FBGN0052732
caenorhabditis_elegans		WBGENE00022173

Paralogs (2): SETD6 (ENSG00000103037), SETD4 (ENSG00000185917)

Protein

Protein identifiers

Actin-histidine N-methyltransferase — Q86TU7 (reviewed: Q86TU7)

Alternative names: Protein-L-histidine N-tele-methyltransferase, SET domain-containing protein 3

All UniProt accessions (3): C9K0W5, Q86TU7, Q6NXR6

UniProt curated annotations — full annotation on UniProt →

Function. Protein-histidine N-methyltransferase that specifically mediates 3-methylhistidine (tele-methylhistidine) methylation of actin at ‘His-73’. Histidine methylation of actin is required for smooth muscle contraction of the laboring uterus during delivery. Does not have protein-lysine N-methyltransferase activity and probably only catalyzes histidine methylation of actin.

Subunit / interactions. Interacts with MYOD1.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Phosphorylated by GSK3B, which is required for recognition by the SCF(FBXW7) complex and subsequent degradation. Ubiquitinated by the SCF(FBXW7) complex following phosphorylation by GSK3B, leading to its degradation by the proteasome.

Domain organisation. The SET domain specifically recognizes and binds actin, suggesting that it does not accommodate substrates diverging from actin.

Miscellaneous. Shows protein-methionine methyltransferase activity in vitro on an actin mutant with a Met instead of a His residue at position 73.

Similarity. Belongs to the class V-like SAM-binding methyltransferase superfamily. SETD3 actin-histidine methyltransferase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q86TU7-1	1	yes
Q86TU7-2	2
Q86TU7-3	3

RefSeq proteins (2): NP_115609, NP_954574 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001214	SET_dom	Domain
IPR015353	Rubisco_LSMT_subst-bd	Domain
IPR025785	SETD3	Family
IPR036464	Rubisco_LSMT_subst-bd_sf	Homologous_superfamily
IPR044428	SETD3_SET	Domain
IPR046341	SET_dom_sf	Homologous_superfamily
IPR050600	SETD3_SETD6_MTase	Family

Pfam: PF00856, PF09273

Enzyme classification (BRENDA):

• EC 2.1.1.85 — protein-histidine N-methyltransferase (BRENDA: 4 organisms, 42 substrates, 8 inhibitors, 37 Km, 37 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
BETA-ACTIN L-HISTIDINE73	—	9
S-ADENOSYL-L-METHIONINE	0.0001–0.0065	9
SYNTHETIC PEPTIDE CORRESPONDING TO RESIDUE 66-80	0.006–0.43	3
ACTIN L-HISTIDINE73	0.021	1
[BETA-ACTIN PEPTIDE(ABU171)]-L-HISTIDINE73	0.0337	1
[BETA-ACTIN PEPTIDE(AHP171)]-L-HISTIDINE73	0.0627	1
[BETA-ACTIN PEPTIDE(CHA171)]-L-HISTIDINE73	0.0583	1
[BETA-ACTIN PEPTIDE(D-ILE71)]-L-HISTIDINE73	0.0788	1
[BETA-ACTIN PEPTIDE(ILE71)]-L-HISTIDINE73	0.044	1
[BETA-ACTIN PEPTIDE(LEU71)]-L-HISTIDINE73	0.0403	1
[BETA-ACTIN PEPTIDE(NLE171)]-L-HISTIDINE73	0.0273	1
[BETA-ACTIN PEPTIDE(NVA171)]-L-HISTIDINE73	0.0454	1
[BETA-ACTIN PEPTIDE(VAL71)]-L-HISTIDINE73	0.0147	1
[BETA-ACTIN PEPTIDE]-3PYRALA73	0.0629	1
[BETA-ACTIN PEPTIDE]-4-TRIAA73	0.0667	1

Catalyzed reactions (Rhea), 1 shown:

• L-histidyl-[protein] + S-adenosyl-L-methionine = N(tele)-methyl-L-histidyl-[protein] + S-adenosyl-L-homocysteine + H(+) (RHEA:19369)

UniProt features (78 total): helix 26, strand 15, mutagenesis site 13, binding site 5, splice variant 4, compositionally biased region 4, turn 4, region of interest 2, chain 1, domain 1, modified residue 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

22 structures.

PDB	Method	Resolution (Å)
6MBK	X-RAY DIFFRACTION	1.69
6OX0	X-RAY DIFFRACTION	1.75
6WK2	X-RAY DIFFRACTION	1.76
6MBJ	X-RAY DIFFRACTION	1.78
6OX3	X-RAY DIFFRACTION	1.78
7W28	X-RAY DIFFRACTION	1.79
6WK1	X-RAY DIFFRACTION	1.89
6OX1	X-RAY DIFFRACTION	1.95
6ICT	X-RAY DIFFRACTION	1.95
6V63	X-RAY DIFFRACTION	2.02
3SMT	X-RAY DIFFRACTION	2.04
6OX2	X-RAY DIFFRACTION	2.09
6OX5	X-RAY DIFFRACTION	2.1
6ICV	X-RAY DIFFRACTION	2.15
6MBL	X-RAY DIFFRACTION	2.2
6OX4	X-RAY DIFFRACTION	2.29
6V62	X-RAY DIFFRACTION	2.36
6JAT	X-RAY DIFFRACTION	2.71
7W29	X-RAY DIFFRACTION	2.9
8X8Q	ELECTRON MICROSCOPY	3.14
7LMS	ELECTRON MICROSCOPY	3.5
8X77	X-RAY DIFFRACTION	3.52

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86TU7-F1	87.37	0.81

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 (5): 254; 275–279; 325–327; 75; 104–106

Post-translational modifications (1): 513

Mutagenesis-validated functional residues (13):

Position	Phenotype
37–42	does not affect ubiquitination and degradation by the scf(fbxw7) complex.
181–185	decreased ubiquitination and degradation by the scf(fbxw7) complex.
215	decreased binding to actin and decreased protein-histidine n-methyltransferase activity.
256	decreased binding to actin and decreased protein-histidine n-methyltransferase activity. increased protein-lysine methyl
256	shows protein-lysine methyltransferase activity toward an actin mutant with a lys instead of a his target residue; when
260–264	does not affect ubiquitination and degradation by the scf(fbxw7) complex.
274	shows protein-lysine methyltransferase activity toward an actin mutant with a lys instead of a his target residue; when
313	abolished protein-histidine n-methyltransferase activity.
313	strongly decreased binding to actin and decreased protein-histidine n-methyltransferase activity.
316	decreased binding to actin and decreased protein-histidine n-methyltransferase activity.
373–378	strongly decreased ubiquitination and degradation by the scf(fbxw7) complex.
512–517	does not affect ubiquitination and degradation by the scf(fbxw7) complex.
565–569	does not affect ubiquitination and degradation by the scf(fbxw7) complex.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-3214841	PKMTs methylate histone lysines
R-HSA-3247509	Chromatin modifying enzymes
R-HSA-4839726	Chromatin organization

MSigDB gene sets: 171 (showing top): MORF_MBD4, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_POSITIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, MORF_HDAC1, GOBP_REGULATION_OF_SMOOTH_MUSCLE_CONTRACTION, YY1_Q6, GOBP_PEPTIDYL_LYSINE_MODIFICATION, GOBP_REGULATION_OF_MUSCLE_CONTRACTION, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOBP_MUSCLE_CONTRACTION, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, MORF_CTBP1, GOBP_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, GOBP_SMOOTH_MUSCLE_CONTRACTION, GOBP_REGULATION_OF_SYSTEM_PROCESS

GO Biological Process (8): peptidyl-histidine methylation (GO:0018021), actin modification (GO:0030047), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of muscle cell differentiation (GO:0051149), regulation of uterine smooth muscle contraction (GO:0070472), chromatin remodeling (GO:0006338), methylation (GO:0032259)

GO Molecular Function (12): transcription coactivator activity (GO:0003713), actin binding (GO:0003779), protein-L-histidine N-tele-methyltransferase activity (GO:0018064), histone H3K4 methyltransferase activity (GO:0042800), histone H3K36 methyltransferase activity (GO:0046975), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), protein binding (GO:0005515), methyltransferase activity (GO:0008168), N-methyltransferase activity (GO:0008170), protein methyltransferase activity (GO:0008276), S-adenosylmethionine-dependent methyltransferase activity (GO:0008757), transferase activity (GO:0016740)

GO Cellular Component (4): chromatin (GO:0000785), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Chromatin modifying enzymes	1
Chromatin organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
methyltransferase activity	3
cellular anatomical structure	3
positive regulation of DNA-templated transcription	2
protein-lysine N-methyltransferase activity	2
histone H3 methyltransferase activity	2
protein methylation	1
peptidyl-histidine modification	1
actin cytoskeleton organization	1
protein modification process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
muscle cell differentiation	1
positive regulation of cell differentiation	1
regulation of muscle cell differentiation	1
regulation of smooth muscle contraction	1
uterine smooth muscle contraction	1
chromatin organization	1
metabolic process	1
transcription coregulator activity	1
cytoskeletal protein binding	1
N-methyltransferase activity	1
protein methyltransferase activity	1
S-adenosylmethionine-dependent methyltransferase activity	1
DNA-binding transcription factor binding	1
binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity, acting on a protein	1
catalytic activity	1
chromosome	1
nuclear lumen	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2022 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SETD3	SETMAR	Q53H47	718
SETD3	SMYD2	Q9NRG4	706
SETD3	ASH1L	Q9NR48	675
SETD3	SETD2	Q9BYW2	639
SETD3	NSD3	Q9BZ95	629
SETD3	SUV39H1	O43463	609
SETD3	NSD1	Q96L73	602
SETD3	CARNMT1	Q8N4J0	586
SETD3	NSD2	O96028	572
SETD3	SMYD3	Q9H7B4	568
SETD3	PLAAT3	P53816	563
SETD3	METTL18	O95568	544
SETD3	SETD4	Q9NVD3	514
SETD3	SMYD5	Q6GMV2	504
SETD3	SETD5	Q9C0A6	498

IntAct

13 interactions, top by confidence:

A	B	Type	Score
PCNA	SETD3	psi-mi:“MI:0915”(physical association)	0.510
SRPK1	SETD3	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
SETD3	LRRC15	psi-mi:“MI:0915”(physical association)	0.400
SETD3	APLNR	psi-mi:“MI:0915”(physical association)	0.370
TEX13A	CNOT1	psi-mi:“MI:0914”(association)	0.350
SETD3	SNX3	psi-mi:“MI:0914”(association)	0.350
BPHL	HSPD1	psi-mi:“MI:0914”(association)	0.350
	VPS37C	psi-mi:“MI:0914”(association)	0.350
	IPO5	psi-mi:“MI:0914”(association)	0.350

BioGRID (45): RFC4 (Affinity Capture-MS), SNX3 (Affinity Capture-MS), RFC2 (Affinity Capture-MS), SETD3 (Affinity Capture-MS), SETD3 (Co-fractionation), SETD3 (Co-fractionation), SETD3 (Co-fractionation), SETD3 (Co-fractionation), SETD3 (Affinity Capture-MS), SETD3 (Affinity Capture-MS), SNX3 (Affinity Capture-MS), PMVK (Affinity Capture-MS), SETD3 (Affinity Capture-RNA), SETD3 (Affinity Capture-MS), SETD3 (Two-hybrid)

ESM2 similar proteins: A2A432, A6H5Z3, A9X1D0, B0VX69, B1MTJ4, B2KI88, B5FW36, C1FXW2, E2R766, E2RBS6, F1LSG8, O43242, O54923, O55047, O70133, P60762, Q13098, Q13619, Q13620, Q29425, Q2KJ46, Q3TCH7, Q4V860, Q5NVP9, Q5R5J4, Q5RAN1, Q5RB36, Q5VIR6, Q5ZKV9, Q5ZLD7, Q5ZML9, Q6AYU1, Q6NRT5, Q6NZH6, Q86TU7, Q8CCB4, Q8CI71, Q8K4Q0, Q8N122, Q8R3S6

Diamond homologs: A9X1D0, B0VX69, B1MTJ4, B2KI88, B5FW36, B7ZUF3, C1FXW2, E2RBS6, G3V6U9, Q5ZML9, Q7SXS7, Q86TU7, Q91WC0, Q9W3U1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	76
Likely benign	3
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

3125 predictions. Top by Δscore:

Variant	Effect	Δscore
14:99399122:CTTC:C	acceptor_gain	1.0000
14:99399123:TTC:T	acceptor_gain	1.0000
14:99399124:TC:T	acceptor_gain	1.0000
14:99399125:CC:C	acceptor_gain	1.0000
14:99399126:C:CC	acceptor_gain	1.0000
14:99400095:TTACC:T	donor_loss	1.0000
14:99400096:TACCT:T	donor_loss	1.0000
14:99400098:C:CG	donor_loss	1.0000
14:99400142:T:C	donor_gain	1.0000
14:99400255:TTCTT:T	acceptor_gain	1.0000
14:99400256:TCTT:T	acceptor_loss	1.0000
14:99400257:CTT:C	acceptor_gain	1.0000
14:99400258:TT:T	acceptor_gain	1.0000
14:99400260:C:CC	acceptor_gain	1.0000
14:99400260:CT:C	acceptor_loss	1.0000
14:99400261:T:G	acceptor_loss	1.0000
14:99404311:C:CC	acceptor_gain	1.0000
14:99405203:A:AC	donor_gain	1.0000
14:99405204:C:CC	donor_gain	1.0000
14:99405377:A:AC	acceptor_gain	1.0000
14:99405377:A:C	acceptor_gain	1.0000
14:99405380:C:CT	acceptor_gain	1.0000
14:99405381:A:T	acceptor_gain	1.0000
14:99405382:G:C	acceptor_gain	1.0000
14:99405382:G:GC	acceptor_gain	1.0000
14:99413964:G:C	acceptor_gain	1.0000
14:99413964:G:GC	acceptor_gain	1.0000
14:99458273:GCTCA:G	donor_loss	1.0000
14:99458274:CTCA:C	donor_loss	1.0000
14:99458275:TCAC:T	donor_loss	1.0000

AlphaMissense

3914 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:99406544:G:T	A299D	1.000
14:99406551:A:G	C297R	1.000
14:99412969:A:C	C277W	1.000
14:99412971:A:G	C277R	1.000
14:99412976:T:A	D275V	1.000
14:99412976:T:G	D275A	1.000
14:99412977:C:G	D275H	1.000
14:99412980:A:G	W274R	1.000
14:99412980:A:T	W274R	1.000
14:99412985:G:C	P272R	1.000
14:99412985:G:T	P272H	1.000
14:99412991:A:G	L270P	1.000
14:99412994:G:T	A269D	1.000
14:99413032:G:C	N256K	1.000
14:99413032:G:T	N256K	1.000
14:99413034:T:C	N256D	1.000
14:99413038:C:A	R254S	1.000
14:99413038:C:G	R254S	1.000
14:99413039:C:A	R254M	1.000
14:99413039:C:G	R254T	1.000
14:99413048:A:T	V251D	1.000
14:99413055:A:G	S249P	1.000
14:99413057:A:T	V248D	1.000
14:99413060:G:T	A247E	1.000
14:99413061:C:G	A247P	1.000
14:99413062:C:A	W246C	1.000
14:99413062:C:G	W246C	1.000
14:99413064:A:G	W246R	1.000
14:99413064:A:T	W246R	1.000
14:99458305:A:C	Y217D	1.000

dbSNP variants (sampled 300 via entrez): RS1000000410 (14:99408748 T>G), RS1000006623 (14:99410147 C>A,T), RS1000031184 (14:99456505 C>A,G), RS1000060854 (14:99450065 C>T), RS1000072731 (14:99474343 T>A,C), RS1000091953 (14:99404558 C>G,T), RS1000100888 (14:99414572 C>G), RS1000153048 (14:99444583 T>C), RS1000205071 (14:99427857 A>G), RS1000247200 (14:99420881 G>A), RS1000257198 (14:99428048 GCA>G), RS1000321032 (14:99421145 G>T), RS1000324917 (14:99463254 C>A), RS1000440009 (14:99410357 A>C), RS1000460058 (14:99462801 A>T)

Disease associations

OMIM: gene MIM:615671 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST003474_8	Scalp hair shape	1.000000e-07
GCST006192_48	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	2.000000e-08
GCST006195_91	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	5.000000e-07
GCST007483_22	Waist-to-hip ratio adjusted for BMI (additive genetic model)	9.000000e-06
GCST007487_32	Waist-to-hip ratio adjusted for BMI (additive genetic model)	9.000000e-06
GCST007500_28	Waist-to-hip ratio adjusted for BMI (additive genetic model)	2.000000e-07
GCST007502_21	Waist-to-hip ratio adjusted for BMI (additive genetic model)	2.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0006527	smoking status measurement
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs77769901	SETD3	3	0.00	1	cyclophosphamide;epirubicin;fluorouracil

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
bisphenol F	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
trichostatin A	affects expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
Sunitinib	increases expression	1
Arsenic	affects methylation	1
Berberine	increases expression	1
Caffeine	affects phosphorylation	1
Cisplatin	increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Diazinon	increases methylation	1
Doxorubicin	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Ribonucleotides	affects binding	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	decreases methylation, increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Cadmium Chloride	decreases expression, increases methylation	1
tert-Butylhydroperoxide	increases expression	1

Cellosaurus cell lines

3 cell lines: 2 transformed cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C8ZI	H1-HeLa+CDHR3 SETD3KO	Cancer cell line	Female
CVCL_F1XE	HEK293T SETD3 KO	Transformed cell line	Female
CVCL_F1XF	HEK293T SETD3-METTL18 DKO	Transformed cell line	Female

Clinical trials (associated diseases)

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