SETD3

protein-coding

SET domain containing 3, actin histidine methyltransferase, the group of SET domain containing

Gene summary

Enables protein-L-histidine N-tele-methyltransferase activity. Involved in actin modification and peptidyl-histidine methylation. Located in cytoplasm. [provided by Alliance of Genome Resources, Jul 2025]

Previous symbols:

C14orf154

MANE transcript

NM_032233.3

Inheritance

—

ClinVar variants

U:83B:7

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr14:99,397,748-99,480,889

External References & Databases

Ensembl (ENSG00000183576)

Transcript & Mutation Effects

hg38 • Region Span ~83.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SETD3 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 79

not providedTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032233.3. 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			2 clinvar		4 clinvar	6
missense			77 clinvar	3 clinvar		80
nonsense			2 clinvar			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	83	3	4	90

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 72 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032233.3	RefSeq	NP_115609.2	12	MANE Select
ENST00000331768.10	Ensembl	ENSP00000327436.5	12	MANE Select
NM_199123.2	RefSeq	NP_954574.1	8	Standard
ENST00000329331.7	Ensembl	ENSP00000327910.3	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysine degradation - Homo sapiens (human)
Histone Modifications
PKMTs methylate histone lysines
Chromatin modifying enzymes
Chromatin organization

Biological Process

histone H3-K36 methylation
peptidyl-lysine trimethylation
peptidyl-lysine monomethylation
peptidyl-lysine dimethylation
positive regulation of transcription, DNA-templated

Molecular Function

RNA polymerase II activating transcription factor binding
transcription coactivator activity
protein-lysine N-methyltransferase activity
histone-lysine N-methyltransferase activity
histone methyltransferase activity (H3-K4 specific)

Cellular Component

nuclear chromatin
nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000331768
Coding exons: 12
Length: 83134
Individuals with no LoFs: 125722
Homozygous LoFs: 0
Heterozygous LoFs: 26
Defined: 125748
p: 0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.45	260	335	0.776	0.0000192	3908
Missense (PolyPhen)		36	79.185	0.45463		890
Synonymous	-0.823	140	128	1.09	0.00000821	1119
Loss of Function	3.66	9	30.9	0.291	0.00000187	335

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00016	0.00016	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.00016	0.00016	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Histone methyltransferase that methylates 'Lys-4' and 'Lys-36' of histone H3 (H3K4me and H3K36me). Acts as a transcriptional activator. Plays an important role in the transcriptional regulation of muscle cell differentiation via interaction with MYOD1. {ECO:0000250|UniProtKB:Q91WC0}.;

Recessive Scores

pRec: 0.107

Intolerance Scores

LoFtool: 0.416
RVIS EVS: -0.93
RVIS percentile EVS: 9.55

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.290

Gene Damage Prediction

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