SMC6

protein-coding

structural maintenance of chromosomes 6, the group of SMC5-6 protein complex|Structural maintenance of chromosomes proteins

Gene summary

Enables DNA secondary structure binding activity and ubiquitin protein ligase binding activity. Involved in several processes, including cellular senescence; host-mediated suppression of viral genome replication; and telomere maintenance via recombination. Located in chromosome and nuclear body. Part of Smc5-Smc6 complex. Is active in nucleus. [provided by Alliance of Genome Resources, Jun 2026]

Previous symbols:

SMC6L1

MANE transcript

NM_001142286.2

Inheritance

—

ClinVar variants

U:95B:4

Top phenotype

Laterality defects, autosomal dominant

gnomAD constraint

pLI —, LoF o/e 0.34

Max pathogenic AF

—

Genomic locus

chr2:17,663,812-17,800,242

External References & Databases

Ensembl (ENSG00000163029)

Transcript & Mutation Effects

hg38 • Region Span ~136.4 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 SMC6 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 86

not providedTotal: 1

Laterality defects, autosomal dominantTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001142286.2. 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			1 clinvar		1 clinvar	2
missense			88 clinvar	3 clinvar		91
nonsense			1 clinvar			1
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	0	0	95	3	1	99

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 57 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001142286.2	RefSeq	NP_001135758.1	26	MANE Select
ENST00000448223.7	Ensembl	ENSP00000404092.2	26	MANE Select
NM_024624.6	RefSeq	NP_078900.1	26	Standard
ENST00000351948.8	Ensembl	ENSP00000323439.4	26	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

SUMOylation of DNA damage response and repair proteins
Post-translational protein modification
SUMO E3 ligases SUMOylate target proteins
Metabolism of proteins
SUMOylation

Biological Process

telomere maintenance via recombination
double-strand break repair via homologous recombination
cellular response to DNA damage stimulus
positive regulation of chromosome segregation
cellular senescence

Molecular Function

protein binding
ATP binding
ubiquitin protein ligase binding

Cellular Component

chromosome, telomeric region
sex chromosome
nucleus
nucleoplasm
PML body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000448223
Coding exons: 26
Length: 136431
Individuals with no LoFs: 125689
Homozygous LoFs: 0
Heterozygous LoFs: 45
Defined: 125734
p: 0.000179

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.21	403	549	0.734	0.0000277	7269
Missense (PolyPhen)		78	152.93	0.51005		2150
Synonymous	-0.738	194	181	1.07	0.00000891	1893
Loss of Function	4.88	22	64.2	0.343	0.00000376	804

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00024	0.00023	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000055	0.000054	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00018	0.00018	rare
South Asian	0.00037	0.00036	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Core component of the SMC5-SMC6 complex, a complex involved in DNA double-strand breaks by homologous recombination. The complex may promote sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to double-strand breaks. The complex is required for telomere maintenance via recombination in ALT (alternative lengthening of telomeres) cell lines and mediates sumoylation of shelterin complex (telosome) components which is proposed to lead to shelterin complex disassembly in ALT-associated PML bodies (APBs). Required for recruitment of telomeres to PML nuclear bodies. SMC5-SMC6 complex may prevent transcription of episomal DNA, such as circular viral DNA genome (PubMed:26983541). {ECO:0000269|PubMed:16810316, ECO:0000269|PubMed:17589526, ECO:0000269|PubMed:26983541}.;

Recessive Scores

pRec: 0.113

Intolerance Scores

LoFtool: 0.830
RVIS EVS: -0.82
RVIS percentile EVS: 11.94

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.779

Gene Damage Prediction

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