SMYD4

Summary

SMYD4 (SET and MYND domain containing 4, HGNC:21067) is a protein-coding gene on chromosome 17p13.3, encoding Protein-lysine N-methyltransferase SMYD4 (Q8IYR2). Protein-lysine N-methyltransferase.

Predicted to enable histone deacetylase binding activity. Involved in heart development. Predicted to be active in cytoplasm and nucleus.

Source: NCBI Gene 114826 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 162 total — 1 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_052928

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21067
Approved symbol	SMYD4
Name	SET and MYND domain containing 4
Location	17p13.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1936, ZMYND21
Ensembl gene	ENSG00000186532
Ensembl biotype	protein_coding
OMIM	619134
Entrez	114826

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000305513, ENST00000476292, ENST00000491788, ENST00000570368, ENST00000571854, ENST00000573937, ENST00000576633, ENST00000862287, ENST00000954771, ENST00000954772, ENST00000954773, ENST00000954774

RefSeq mRNA: 1 — MANE Select: NM_052928 NM_052928

CCDS: CCDS11013

Canonical transcript exons

ENST00000305513 — 11 exons

Exon	Start	End
ENSE00001116028	1783035	1783158
ENSE00001238078	1829726	1829902
ENSE00001307767	1804626	1804715
ENSE00001311209	1779485	1781439
ENSE00001313043	1799857	1801024
ENSE00002338304	1786810	1786973
ENSE00002387947	1783360	1783476
ENSE00002406073	1784326	1784461
ENSE00002417767	1787422	1787604
ENSE00003483967	1827861	1828006
ENSE00003608681	1811971	1812115

Expression profiles

Bgee: expression breadth ubiquitous, 193 present calls, max score 89.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.1777 / max 68.7528, expressed in 1662 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
163786	4.2428	1591
163785	0.9350	604

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibialis anterior	UBERON:0001385	89.87	silver quality
ileal mucosa	UBERON:0000331	86.30	silver quality
pancreatic ductal cell	CL:0002079	85.76	silver quality
gastrocnemius	UBERON:0001388	84.80	gold quality
muscle of leg	UBERON:0001383	84.71	gold quality
hindlimb stylopod muscle	UBERON:0004252	84.39	gold quality
deltoid	UBERON:0001476	84.16	silver quality
endothelial cell	CL:0000115	83.33	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.89	gold quality
popliteal artery	UBERON:0002250	82.44	gold quality
tibial artery	UBERON:0007610	82.43	gold quality
calcaneal tendon	UBERON:0003701	81.25	gold quality
mucosa of stomach	UBERON:0001199	81.13	gold quality
left ovary	UBERON:0002119	81.06	gold quality
colonic epithelium	UBERON:0000397	81.05	gold quality
epithelial cell of pancreas	CL:0000083	80.94	gold quality
ganglionic eminence	UBERON:0004023	80.27	gold quality
omental fat pad	UBERON:0010414	80.26	gold quality
peritoneum	UBERON:0002358	80.22	gold quality
secondary oocyte	CL:0000655	80.21	gold quality
right ovary	UBERON:0002118	80.13	gold quality
left uterine tube	UBERON:0001303	80.07	gold quality
adipose tissue of abdominal region	UBERON:0007808	79.91	gold quality
parotid gland	UBERON:0001831	79.86	silver quality
monocyte	CL:0000576	79.64	gold quality
ventricular zone	UBERON:0003053	79.62	gold quality
ectocervix	UBERON:0012249	79.60	gold quality
left adrenal gland cortex	UBERON:0035825	79.58	gold quality
smooth muscle tissue	UBERON:0001135	79.51	gold quality
leukocyte	CL:0000738	79.49	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.04

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

63 targeting SMYD4, 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-4668-3P	100.00	68.74	2635
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6778-3P	99.96	67.29	2693
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-9983-3P	99.94	71.48	3631
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-378A-5P	99.65	66.33	1311
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-12117	99.50	67.57	868
HSA-MIR-302B-5P	99.50	69.49	1857
HSA-MIR-302D-5P	99.50	69.34	1863
HSA-MIR-142-5P	99.48	70.92	2416
HSA-MIR-5590-3P	99.48	70.91	2429
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-488-5P	99.28	68.12	821
HSA-MIR-1264	99.25	66.81	1317
HSA-MIR-7158-5P	99.25	67.95	796
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-6504-3P	99.17	69.31	2891

Literature-anchored findings (GeneRIF, showing 2)

• Smyd4, as a potential tumor suppressor, plays a critical role in breast carcinogenesis at least partly through inhibiting the expression of Pdgfr-alpha. (PMID:19383909)
• SMYD4 monomethylates PRMT5 and forms a positive feedback loop to promote hepatocellular carcinoma progression. (PMID:38438251)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	smyd4	ENSDARG00000060983
mus_musculus	Smyd4	ENSMUSG00000018809
rattus_norvegicus	Smyd4	ENSRNOG00000026783
drosophila_melanogaster	Smyd3	FBGN0011566
drosophila_melanogaster	dao	FBGN0028862
drosophila_melanogaster	SmydA-9	FBGN0030102
drosophila_melanogaster	SmydA-5	FBGN0033061
drosophila_melanogaster	Smyd4-1	FBGN0033427
drosophila_melanogaster	Smyd4-2	FBGN0036282
drosophila_melanogaster	CG18213	FBGN0038470
drosophila_melanogaster	SmydA-8	FBGN0053548
caenorhabditis_elegans	set-18	WBGENE00044070

Paralogs (5): SMYD1 (ENSG00000115593), SMYD5 (ENSG00000135632), ZMYND15 (ENSG00000141497), SMYD2 (ENSG00000143499), SMYD3 (ENSG00000185420)

Protein

Protein identifiers

Protein-lysine N-methyltransferase SMYD4 — Q8IYR2 (reviewed: Q8IYR2)

Alternative names: SET and MYND domain-containing protein 4

All UniProt accessions (5): Q8IYR2, I3L1V4, I3L2P4, I3L428, I3L496

UniProt curated annotations — full annotation on UniProt →

Function. Protein-lysine N-methyltransferase. Monomethylates PRMT5, modulating its transcriptional activity. May also act as a histone methyltransferase. Plays a critical role in cardiac development. Acts as a key epigenetic regulator of gene expression during cardiac development via its dual activities as a methyltransferase and negative regulator of HDAC1.

Subunit / interactions. Interacts (via MYND-type zinc finger) with HDAC1.

Subcellular location. Nucleus. Cytoplasm.

Similarity. Belongs to the class V-like SAM-binding methyltransferase superfamily.

RefSeq proteins (1): NP_443160* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001214	SET_dom	Domain
IPR002893	Znf_MYND	Domain
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR044421	SMYD4_SET	Domain
IPR046341	SET_dom_sf	Homologous_superfamily
IPR052097	SET-MYND_domain_protein	Family

Pfam: PF00856, PF01753

Catalyzed reactions (Rhea), 1 shown:

• L-lysyl-[protein] + S-adenosyl-L-methionine = N(6)-methyl-L-lysyl-[protein] + S-adenosyl-L-homocysteine + H(+) (RHEA:51736)

UniProt features (29 total): binding site 13, sequence variant 10, sequence conflict 3, chain 1, domain 1, zinc finger region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IYR2-F1	85.40	0.67

Functional residue map

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

Ligand- & substrate-binding residues (13): 331; 335; 427; 539–540; 573; 595; 112–114; 296; 299; 309; 312; 318 …

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 74 (showing top): MODULE_205, USF_01, ACATTCC_MIR1_MIR206, GOBP_METHYLATION, GOBP_CIRCULATORY_SYSTEM_DEVELOPMENT, AACATTC_MIR4093P, MYCMAX_03, GOMF_HISTONE_DEACETYLASE_BINDING, GOMF_N_METHYLTRANSFERASE_ACTIVITY, GOMF_PROTEIN_METHYLTRANSFERASE_ACTIVITY, ARNT_01, GOMF_S_ADENOSYLMETHIONINE_DEPENDENT_METHYLTRANSFERASE_ACTIVITY, GOMF_TRANSFERASE_ACTIVITY_TRANSFERRING_ONE_CARBON_GROUPS, GOMF_LYSINE_N_METHYLTRANSFERASE_ACTIVITY, CHYLA_CBFA2T3_TARGETS_UP

GO Biological Process (2): heart development (GO:0007507), methylation (GO:0032259)

GO Molecular Function (7): zinc ion binding (GO:0008270), protein-lysine N-methyltransferase activity (GO:0016279), histone deacetylase binding (GO:0042826), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
animal organ development	1
circulatory system development	1
metabolic process	1
transition metal ion binding	1
protein methyltransferase activity	1
lysine N-methyltransferase activity	1
enzyme binding	1
binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2167 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMYD4	SMYD5	Q6GMV2	845
SMYD4	SMYD3	Q9H7B4	520
SMYD4	EHMT1	Q9H9B1	491
SMYD4	HDAC1	Q13547	481
SMYD4	KMT2E	Q8IZD2	477
SMYD4	SETD4	Q9NVD3	477
SMYD4	RTN4RL1	Q86UN2	474
SMYD4	PRDM4	Q9UKN5	461
SMYD4	ROGDI	Q9GZN7	457
SMYD4	PRDM15	P57071	450
SMYD4	SMYD1	Q8NB12	439
SMYD4	SETD2	Q9BYW2	431
SMYD4	NSD3	Q9BZ95	431
SMYD4	SUV39H2	Q9H5I1	428
SMYD4	LANCL1	O43813	427

IntAct

13 interactions, top by confidence:

A	B	Type	Score
GYPB	TCAF2	psi-mi:“MI:0914”(association)	0.530
SMYD4	ATP5PO	psi-mi:“MI:0915”(physical association)	0.400
SMYD4	H3-4	psi-mi:“MI:0915”(physical association)	0.400
SMYD4	H1-4	psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
PRKY	METTL15	psi-mi:“MI:0914”(association)	0.350
CCT8L2	DVL2	psi-mi:“MI:0914”(association)	0.350
GMCL2	APAF1	psi-mi:“MI:0914”(association)	0.350
SMYD4	ECD	psi-mi:“MI:0914”(association)	0.350
NPAS1	CIBAR1	psi-mi:“MI:0914”(association)	0.350
SLC27A6	NBAS	psi-mi:“MI:0914”(association)	0.350

BioGRID (22): SMYD4 (Affinity Capture-MS), SMYD4 (Reconstituted Complex), SMYD4 (Affinity Capture-MS), SMYD4 (Affinity Capture-RNA), SMYD4 (Proximity Label-MS), SMYD4 (Proximity Label-MS), SMYD4 (Proximity Label-MS), SMYD4 (Affinity Capture-MS), SMYD4 (Affinity Capture-MS), SMYD4 (Affinity Capture-MS), SMYD4 (Affinity Capture-MS), SMYD4 (Affinity Capture-MS), ECD (Affinity Capture-MS), SMYD4 (Affinity Capture-MS), ZNHIT2 (Affinity Capture-MS)

ESM2 similar proteins: A0JPF9, A4D126, A5PKL6, A6QP81, B2GUS6, D2H8V8, E1BCH6, E1BVR9, E9PYK3, F1ND48, G5E8F4, P79106, Q28CZ7, Q32PY6, Q3U269, Q3U3W5, Q3U5Q7, Q3UVV9, Q49MI3, Q4R3W5, Q5F3V0, Q5ND52, Q5R5X9, Q5RCP1, Q5RFM7, Q5RJG7, Q5RL51, Q5S6T3, Q5T8I9, Q5VZV1, Q6AYG3, Q8BIW1, Q8BK58, Q8BQJ6, Q8BTK5, Q8BZ20, Q8C5V5, Q8CAE2, Q8IXQ6, Q8IYR2

Diamond homologs: A9CPT4, C3RZA1, D3ZKV9, E1C5V0, F1QN74, F1RET2, O74467, P97443, Q0P585, Q12529, Q3TYX3, Q4VC12, Q5BJI7, Q5F3V0, Q5R5X9, Q5RGL7, Q5UNT8, Q5ZIZ2, Q6C9E7, Q6GMV2, Q6GN68, Q6GPQ4, Q7M6Z3, Q7TSV3, Q7ZXV5, Q8BTK5, Q8IYR2, Q8NB12, Q8R5A0, Q91YE3, Q96E35, Q9BXT4, Q9CQG3, Q9CWR2, Q9D5Z5, Q9GZT9, Q9H7B4, Q9N3Q8, Q9NRG4, A3M0J3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	125
Likely benign	18
Benign	1

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
153177	GRCh38/hg38 17p13.3-13.2(chr17:150732-5935377)x1	Pathogenic
2685591	GRCh37/hg19 17p13.3(chr17:1225474-2201587)x1	Likely pathogenic

SpliceAI

2668 predictions. Top by Δscore:

Variant	Effect	Δscore
17:1783028:GACTC:G	donor_loss	1.0000
17:1783029:ACTCA:A	donor_loss	1.0000
17:1783030:CTC:C	donor_loss	1.0000
17:1783031:TCA:T	donor_loss	1.0000
17:1783032:CACCC:C	donor_loss	1.0000
17:1783033:A:AC	donor_gain	1.0000
17:1783033:AC:A	donor_gain	1.0000
17:1783033:ACCC:A	donor_loss	1.0000
17:1783034:C:CC	donor_gain	1.0000
17:1783034:C:CG	donor_loss	1.0000
17:1783034:CC:C	donor_gain	1.0000
17:1783156:CTC:C	acceptor_gain	1.0000
17:1783157:TCCTG:T	acceptor_loss	1.0000
17:1783159:C:CC	acceptor_gain	1.0000
17:1783160:T:A	acceptor_loss	1.0000
17:1783473:CGCT:C	acceptor_gain	1.0000
17:1783475:CT:C	acceptor_gain	1.0000
17:1783477:C:CC	acceptor_gain	1.0000
17:1787603:TC:T	acceptor_gain	1.0000
17:1787603:TCCTG:T	acceptor_loss	1.0000
17:1787604:CC:C	acceptor_gain	1.0000
17:1787605:C:G	acceptor_loss	1.0000
17:1787606:T:G	acceptor_loss	1.0000
17:1787614:C:CT	acceptor_gain	1.0000
17:1787615:A:T	acceptor_gain	1.0000
17:1804712:CTCC:C	acceptor_gain	1.0000
17:1812111:CAGGT:C	acceptor_gain	1.0000
17:1812116:C:CC	acceptor_gain	1.0000
17:1827856:CT:C	donor_loss	1.0000
17:1827856:CTTA:C	donor_gain	1.0000

AlphaMissense

5269 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:1800952:G:T	R148S	0.992
17:1787534:G:C	S536R	0.991
17:1787534:G:T	S536R	0.991
17:1787536:T:G	S536R	0.991
17:1812013:A:C	F79L	0.987
17:1812013:A:T	F79L	0.987
17:1812015:A:G	F79L	0.987
17:1787522:G:C	H540Q	0.983
17:1787522:G:T	H540Q	0.983
17:1800951:C:G	R148P	0.982
17:1804660:C:G	R112P	0.982
17:1800648:G:T	A249D	0.981
17:1786909:A:C	F595L	0.980
17:1786909:A:T	F595L	0.980
17:1786911:A:G	F595L	0.980
17:1804651:G:T	A115D	0.979
17:1827973:A:G	W8R	0.979
17:1827973:A:T	W8R	0.979
17:1786939:C:A	R585S	0.978
17:1786939:C:G	R585S	0.978
17:1787521:A:G	S541P	0.977
17:1801019:A:C	C125W	0.977
17:1800111:A:G	L428P	0.976
17:1787524:G:C	H540D	0.974
17:1787546:G:C	F532L	0.974
17:1787546:G:T	F532L	0.974
17:1787548:A:G	F532L	0.974
17:1799898:A:G	L499P	0.972
17:1800938:A:C	C152W	0.971
17:1781347:A:G	L785P	0.970

dbSNP variants (sampled 300 via entrez): RS1000028568 (17:1817907 C>A,T), RS1000044210 (17:1829893 G>GA), RS1000059868 (17:1817745 T>A), RS1000175689 (17:1786957 C>T), RS1000178507 (17:1824921 G>A), RS1000247695 (17:1787250 G>A), RS1000281204 (17:1812634 C>T), RS1000422075 (17:1828737 C>T), RS1000441082 (17:1789284 A>T), RS1000444395 (17:1792109 C>T), RS1000473127 (17:1781203 G>A,C), RS1000485612 (17:1814518 A>C), RS1000486520 (17:1783655 C>G), RS1000526285 (17:1785619 G>A), RS1000549017 (17:1822218 A>T)

Disease associations

OMIM: gene MIM:619134 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST000769_6	Calcium levels	7.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004838	calcium measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Ozone	increases expression, increases abundance, affects expression, affects cotreatment	3
bisphenol A	affects methylation, affects cotreatment, decreases methylation, increases expression	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
methacrylaldehyde	increases expression, increases abundance, affects cotreatment	2
Acrolein	affects cotreatment, increases expression, increases abundance	2
Air Pollutants	affects cotreatment, increases abundance, increases expression, affects expression	2
Benzo(a)pyrene	increases mutagenesis, decreases methylation	2
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
jinfukang	increases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Leflunomide	decreases expression	1
Acetaminophen	increases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Indomethacin	increases expression, affects cotreatment	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Methyl Methanesulfonate	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Cyclosporine	decreases expression	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

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