PRDM16

Chr 1AD

PR/SET domain 16

ENSG00000142611 UniProt: Q9HAZ2 OMIM: 605557

This gene encodes a transcription regulator that acts as both a histone methyltransferase and chromatin adapter, controlling brown adipocyte differentiation, regulatory T-cell development, and cardiac mitochondrial function. Mutations cause dilated cardiomyopathy and left ventricular noncompaction with autosomal dominant inheritance. The gene is highly constrained against loss-of-function mutations (pLI 0.9999, LOEUF 0.187), indicating that pathogenic variants are likely to have severe functional consequences.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Transcription regulator that acts both as a histone methyltransferase or chromatin adapter, depending on the context (PubMed:12816872). In the cytoplasm, acts as a histone methyltransferase, which catalyzes monomethylation of 'Lys-9' of free histone H3 (H3K9me1) during translation (By similarity). Monomethylated histone H3 is then transported to the nucleus and incorporated into nucleosomes where SUV39H methyltransferases (SUV39H1 and SUV39H2) use it as a substrate to catalyze histone H3 'Lys-9' trimethylation (H3K9me3) (By similarity). Probably one of the primary histone methyltransferases along with MECOM/PRDM3 that direct cytoplasmic H3K9me1 methylation (By similarity). In the nucleus, acts as a key chromatin adapter that mediates differentiation of brown and beige adipocytes, which are specialized in dissipating chemical energy in the form of heat in response to cold or excess feeding (By similarity). Following recruitment to chromatin by PPARG nuclear receptor, promotes differentiation of myoblastic precursors into brown adipose cells (By similarity). Mechanistically, acts by mediating recruitment of (1) EHMT1 histone methyltransferase, thereby inhibiting the expression of white adipose-selective genes or (2) mediator complex, activating genes that are highly expressed in brown adipocytes, such as UCP1, PPARA, and PPARGC1A (By similarity). Also mediates differentiation of beige adipocytes from white adipose cells following recruitment by PPARG (By similarity). In addition to adipocyte differentiation, also involved in tolerance to gut microbiota: following recruitment to chromatin by RORgammaT (RORC) in a subset of antigen-presenting cells, promotes differentiation of peripherally-induced regulatory T-cells (pTreg), which suppress inflammatory responses to commensal microorganisms (By similarity). Also required in adult heart to preserve mitochondrial function and inhibit hypertrophy with advanced age (By similarity). Functions as a repressor of TGF-beta signaling (PubMed:19049980)

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Cardiomyopathy, dilated, 1LLMIM #615373

Left ventricular noncompaction 8MIM #615373

Clinical highlights

Gene–disease validity (ClinGen)

Strong · dilated cardiomyopathy · AD · ClinGen 2026

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

173

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.19

LOEUF· LoF intol.

LOF

Mechanism· predicted

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.19LOEUF

pLI 1.000

Z-score 5.95

OE 0.08 (0.04–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.35Z-score

OE missense 0.87 (0.82–0.93)

745 obs / 855.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.08 (0.04–0.19)

0≤0.351.4

Missense OE?0.87 (0.82–0.93)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 4 / 48.9Missense obs/exp: 745 / 855.9Syn Z: -1.64

Background carrier burden — how many people carry a rare variant somewhere in PRDM16?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 28

1,725 rare PASS variants

Rare truncating (LoF)

1 in 5,700

54 rare PASS variants

Rare synonymous (reference)

1 in 34

836 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PRDM16. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 39	1 in 9,600
South Asian	~43k	1 in 25	1 in 1,200
Remaining (unassigned)	~30k	1 in 22	1 in 3,800
European (Finnish)	~27k	1 in 73	≈ 1 in 7,900
Admixed American	~22k	1 in 24	≈ 1 in 7,900
African / African American	~21k	1 in 26	1 in 1,900
East Asian	~20k	1 in 30	≈ 1 in 8,500
Ashkenazi Jewish	~13k	1 in 79	≈ 1 in 5,500
Middle Eastern	~2,884	1 in 25	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.