PRDM16
protein-codingPR/SET domain 16, the group of Zinc fingers C2H2-type|MicroRNA protein coding host genes|Lysine methyltransferases|PR/SET domain family
Gene summary
The reciprocal translocation t(1;3)(p36;q21) occurs in a subset of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). This gene is located near the 1p36.3 breakpoint and has been shown to be specifically expressed in the t(1:3)(p36,q21)-positive MDS/AML. The protein encoded by this gene is a zinc finger transcription factor and contains an N-terminal PR domain. The translocation results in the overexpression of a truncated version of this protein that lacks the PR domain, which may play an important role in the pathogenesis of MDS and AML. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~369.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0015470
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0018901
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014152
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0005021
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014152
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0014152
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0005021
Submitter: ClinGen
PRDM16 was originally evaluated for AD dilated cardiomyopathy (DCM) by the ClinGen GCEP on 10/25/2019. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 05/30/2025. Since the time of the pervious curation, extensive new evidence has been published and as a result, the classification changed from Limited to Strong Evidence. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. Human genetic evidence supporting this gene-disease relationship includes case-level data. At least 12 loss of function variants (including missense, nonsense, and large deletions) have been reported in humans with DCM. Previous genetic evidence was reviewed using scoring guidance in accordance with SOP v10. The Arndt et. al study, which included analysis of 131 heart biopsies from cases of DCM with or without features of non-compaction, was not scored during this curation due to a limited gene list that did not evaluate other high evidence DCM genes as well as current population frequencies of the identified variants (Arndt et. al, 2013, PMID: 23768516). Additionally, a previously evaluated study from Long et. al reported a 4 month old DCM patient carrying a de novo predicted truncating variant c.1047dupC (p.S350fsX), which was supported by experimental data remained scored from the original curation (PMID: Long et. al, 2017, PMID: 29267541). New genetic evidence included cases from Sun et. al (2023) and Billon et. al (2025). Sun et al report a case of a 3 month boy diagnosed with DCM. Whole exome sequencing revealed a de novo truncating variant c.559C>T (p.Gln187X), which was supported by additional experimental expression evidence (Sun et. al, 2023, PMID: 38113297). Billon et al performed comprehensive cardiovascular multi-gene next generation sequencing on a cohort of 4900 index cases of DCM and/or hypertrabeculation features. 5 scoreable truncating variants were identified in DCM patients, including one de novo variant (Billon et. al, 2025, PMID: 40935858). In addition, this gene-disease assertion is supported by additional experimental evidence including expression, functional, and animal model experiments. Cardiac localization studies have long demonstrated that PRDM16 is expressed in left ventricular (LV) myocardium in human and mouse hearts (Arndt et. al, 2013, PMID: 237685516). iPSCs derived from a proband carrying PRDM16-Q187X showed abnormal organization of the sarcomere proteins, as well as increased apoptosis and elevated markers of cardiac remodeling when compared to control cells (Sun et. al, 2023, PMID: 38113297). Additionally, several animal models were evaluated and determined to provide further support of this gene-disease assertion. PRDM16 knockdown zebrafish and transgenic zebrafish for a c.2104A>T (p.Lys702X) variant demonstrated bradycardia and significantly reduced cardiac output, which was restored in morphant embryos with increased doses of wild-type human PRDM16 (Ardnt et. al, 2013, PMID: 237685516). PRDM16 conditional knockout mice were shown to have significant decrease in ejection fraction (EF) and increase in LV size (Kramer et. al, 2023, PMID: 37395136). Three cardiomyocyte specific mouse models demonstrated signs of DCM including dilated LV and reduced EF (Wu et. al, 2022 PMID: 34915728; Cibi et. al, 2020, PMID: 33086060; Van Wauwe, 2024, PMID: 39304345). Finally, one heterozygous knock in mouse model of a c.888-3C>A splice acceptor variant showed cardiac hypoplasia and reduced systolic dysfunction (Kühnisch et. al, 2023, PMID: 37842925). In summary, with new evidence over time, PRDM16 is now strongly associated with AD DCM. This has been repeatedly demonstrated in both the experimental and clinical settings and has been upheld over time. Although independent reports over a 3 year period contributed to this curation, the panel elected to classify as Strong to allow additional experimental evidence to accumulate before upgrading to a final Definitive classification. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 05/30/2025 (SOP Version 10).
Inheritance Pattern: AD
Disease ID:MONDO:0016333
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular
Intervention: Cardiovascular
Rationale: Individuals have been described as manifesting with findings such as arrhythmias, cardiac valvular abnormalities, and dilated cardiomyopathy, and surveillance (eg, with echocardiogram and electrocardiogram) may allow early medical and/or surgical interventions (eg, intracardiac defibrillator) may be beneficial in terms of reducing disease-associated morbidity and mortality
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PRDM16 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_022114.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 10 | 430 | 9 | 449 | ||
| missense | 1 | 672 | 97 | 5 | 775 | |
| nonsense | 5 | 4 | 9 | 18 | ||
| start loss | 0 | |||||
| frameshift | 4 | 5 | 21 | 30 | ||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 8 | 11 | ||
| Total | 11 | 11 | 720 | 527 | 14 | 1283 |
Highest pathogenic variant AF is 0.0000013687511
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_071397.3 | 17 | MANE Select | |
| Ensembl | ENSP00000270722.5 | 17 | MANE Select | |
| RefSeq | NP_955533.2 | 17 | Standard | |
| Ensembl | ENSP00000367643.2 | 17 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| prdm16 | Danio rerio | Structure: cardiac muscle cell Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Thermogenesis - Homo sapiens (human)
- Differentiation of white and brown adipocyte
- FTO Obesity Variant Mechanism
- PKMTs methylate histone lysines
- Chromatin modifying enzymes
Biological Process
- negative regulation of transcription by RNA polymerase II
- neurogenesis
- negative regulation of transforming growth factor beta receptor signaling pathway
- histone lysine methylation
- somatic stem cell population maintenance
Molecular Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- transcription coactivator activity
- protein binding
- histone-lysine N-methyltransferase activity
- activating transcription factor binding
Cellular Component
- nucleus
- nucleoplasm
- cytosol
- aggresome
- transcriptional repressor complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000270722
- Coding exons
- 17
- Length
- 369454
- Individuals with no LoFs
- 124788
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 4
- Defined
- 124792
- p
- 0.0000160
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.35 | 745 | 856 | 0.870 | 0.0000586 | 8369 |
| Missense (PolyPhen) | 169 | 257.45 | 0.65645 | 2528 | ||
| Synonymous | -1.64 | 447 | 405 | 1.10 | 0.0000335 | 2547 |
| Loss of Function | 5.95 | 4 | 48.9 | 0.0817 | 0.00000242 | 571 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000056 | 0.000056 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Binds DNA and functions as a transcriptional regulator. Functions in the differentiation of brown adipose tissue (BAT) which is specialized in dissipating chemical energy in the form of heat in response to cold or excess feeding while white adipose tissue (WAT) is specialized in the storage of excess energy and the control of systemic metabolism. Together with CEBPB, regulates the differentiation of myoblastic precursors into brown adipose cells. Functions also as a repressor of TGF-beta signaling. Isoform 4 may regulate granulocytes differentiation. {ECO:0000269|PubMed:12816872, ECO:0000269|PubMed:14656887, ECO:0000269|PubMed:19049980}.;
- Disease
- DISEASE: Cardiomyopathy, dilated 1LL (CMD1LL) [MIM:615373]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:23768516}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A chromosomal aberration involving PRDM16 is found in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Reciprocal translocation t(1;3)(p36;q21). Isoform 4 is specifically expressed in adult T-cell leukemia. {ECO:0000269|PubMed:11050005, ECO:0000269|PubMed:12557231}.;
Recessive Scores
- pRec
- 0.191
Intolerance Scores
- LoFtool
- 0.101
- RVIS EVS
- -1.42
- RVIS percentile EVS
- 4.06
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.594
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |