POLR3K

protein-coding

RNA polymerase III subunit K, the group of RNA polymerase subunits

Gene summary

This gene encodes a small essential subunit of RNA polymerase III, the polymerase responsible for synthesizing transfer and small ribosomal RNAs in eukaryotes. The carboxy-terminal domain of this subunit shares a high degree of sequence similarity to the carboxy-terminal domain of an RNA polymerase II elongation factor. This similarity in sequence is supported by functional studies showing that this subunit is required for proper pausing and termination during transcription. Pseudogenes of this gene are found on chromosomes 13 and 17.[provided by RefSeq, Jul 2010]

MANE transcript

NM_016310.5

Inheritance

ClinVar variants

P:2U:16B:4

Top phenotype

Leukodystrophy, hypomyelinating 21

gnomAD constraint

pLI —, LoF o/e 0.39

Max pathogenic AF

—

Genomic locus

chr16:46,407-53,608

External References & Databases

Ensembl (ENSG00000161980)

Transcript & Mutation Effects

hg38 • Region Span ~7.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

leukodystrophy, hypomyelinating, 21LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0030263

Submitter: ClinGen

The association of POLR3K variants with autosomal recessive hypomyelinating leukodystrophy-21 (HLD21; OMIM:619310) was first described in 2018 (PMID: 30584594). Reported phenotypes include developmental delay, loss of motor skills, nystagmus, ataxia, dystonia and spasticity, growth delay, microcephaly, gastrointestinal issues, cryptorchidism, hypogonadotropic hypogonadism, hypodontia, and hypomyelination. Three variants in three unrelated patients have been described in the literature. Dorboz et al described two unrelated patients, both from consanguineous parents and both from Algeria, who each harbor the same homozygous mutation (c.212T>C; p.Arg41Trp). A third individual was described in Perrier, et al, 2024, with compound heterozygous variants (c.322G>T; p.Asp108Tyr and c.200_327del; p.Glu67Glyfs*18). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) or inheritance pattern in these cases, and found that the spectrum of phenotypic variability could exist. Therefore, these cases have been lumped into one entity, HDL21 (OMIM:619310). The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is supported by experimental evidence, namely evidence related to biochemical function. There are several studies that demonstrate the the function of the POL3 complex (PMID: 33558764, PMID:34395538, PMID:16362040), of which POLR3A, POLR3B and POLR1C, and POLR3K (among others) are a part, but few studies describe the specific function of the POLR3K gene. One study by Girbig et al, 2021 (PMID: 33558764) showed that POLR3K is located at the active site of the POL3 complex that transcribes mRNA to produce proteins for myelination. POLR3K forms the portion of the active site that holds the mRNA in a clamp like manner, and variants in POLR3K prevent it from undergoing a conformational switch that enables the release of transcribed mRNA, preventing re-use and thus decreasing efficiency of transcription. In summary, there is limited evidence supporting the relationship between POLR3K and HDL21, also referred to as POLR3K-related disorder. More experimental and case level evidence is needed to establish a definitive disease association. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date September 10, 2025 (SOP Version 11).

leukodystrophy, hypomyelinating, 21STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030263

Submitter: PanelApp Australia

leukodystrophy, hypomyelinating, 21LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0030263

Submitter: Ambry Genetics

leukodystrophy, hypomyelinating, 21LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0030263

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Leukodystrophy, hypomyelinating 21AR

Manifestation: Gastrointestinal; Genitourinary; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 30584594

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to POLR3K variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 14

Leukodystrophy, hypomyelinating, 21Total: 5

not providedTotal: 3

Acromesomelic dysplasia 4Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016310.5. 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				4 clinvar		4
missense	2 clinvar		16 clinvar			18
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	2	0	16	4	0	22

Highest pathogenic variant AF is 0.00000684803

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016310.5	RefSeq	NP_057394.3	3	MANE Select
ENST00000293860.6	Ensembl	ENSP00000293860.5	3	MANE Select
ENST00000913642.1	Ensembl	ENSP00000583701.1	2	Standard
ENST00000913642.2	Ensembl	ENSP00000583701.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
polr3k	Danio rerio	Structure: hematopoietic multipotent progenitor cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

polr3k

Danio rerio

Structure: hematopoietic multipotent progenitor cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Pyrimidine metabolism - Homo sapiens (human)
Cytosolic DNA-sensing pathway - Homo sapiens (human)
RNA polymerase - Homo sapiens (human)
Purine metabolism - Homo sapiens (human)
Epstein-Barr virus infection - Homo sapiens (human)

Biological Process

transcription by RNA polymerase III
termination of RNA polymerase III transcription
tRNA 3'-trailer cleavage
innate immune response
defense response to virus

Molecular Function

RNA polymerase III activity
nucleic acid binding
DNA-directed 5'-3' RNA polymerase activity
zinc ion binding

Cellular Component

nucleoplasm
RNA polymerase III complex
nucleolus
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000293860
Coding exons: 3
Length: 7222
Individuals with no LoFs: 125743
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125747
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0886	70	67.9	1.03	0.00000383	706
Missense (PolyPhen)		13	15.418	0.84318		189
Synonymous	-1.01	30	23.8	1.26	0.00000122	199
Loss of Function	1.26	2	5.07	0.394	2.17e-7	56

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
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: dbNSFP

Function: FUNCTION: DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Component of RNA polymerase III which synthesizes small RNAs, such as 5S rRNA and tRNAs. Plays a key role in sensing and limiting infection by intracellular bacteria and DNA viruses. Acts as nuclear and cytosolic DNA sensor involved in innate immune response. Can sense non-self dsDNA that serves as template for transcription into dsRNA. The non-self RNA polymerase III transcripts, such as Epstein-Barr virus-encoded RNAs (EBERs) induce type I interferon and NF- Kappa-B through the RIG-I pathway (By similarity). {ECO:0000250, ECO:0000269|PubMed:19609254, ECO:0000269|PubMed:19631370}.;

Recessive Scores

pRec: 0.111

Intolerance Scores

LoFtool: 0.180
RVIS EVS: -0.19
RVIS percentile EVS: 39.68

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.694

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium