SMC5

protein-coding

structural maintenance of chromosomes 5, the group of Structural maintenance of chromosomes proteins|SMC5-6 protein complex

Gene summary

Enables DNA secondary structure binding activity. Involved in several processes, including DNA recombination; host-mediated suppression of viral genome replication; and positive regulation of cell cycle process. Located in chromosome and nuclear body. Part of Smc5-Smc6 complex. Is active in nucleus. Implicated in mosaic variegated aneuploidy syndrome. [provided by Alliance of Genome Resources, Jun 2026]

Previous symbols:

SMC5L1

MANE transcript

NM_015110.4

Inheritance

ClinVar variants

P:4U:125B:10

Top phenotype

Atelis syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.34

Max pathogenic AF

—

Genomic locus

chr9:70,258,978-70,354,873

External References & Databases

Ensembl (ENSG00000198887)

Transcript & Mutation Effects

hg38 • Region Span ~95.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Atelis syndrome 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0859576

Submitter: G2P

Atelis syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859576

Submitter: PanelApp Australia

Atelis syndrome 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0859576

Submitter: Ambry Genetics

Atelis syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859576

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Atelis syndrome 2AR

Manifestation: Cardiovascular; Craniofacial; Dental; Hematologic; Neurologic; Oncologic; Ophthalmologic

Intervention: Allergy/Immunology/Infectious; Cardiovascular; Oncologic

Rationale: Individuals have been described with congenital heart anomalies, and awareness may enable prompt recognition and management; The condition may involve increased risk of hematologic malignancy, and awareness may allow prompt diagnosis and management

Refs: 36333305

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SMC5 variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 122

not providedTotal: 7

Atelis syndrome 2Total: 6

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

not specifiedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015110.4. 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			3 clinvar	1 clinvar	3 clinvar	7
missense	1 clinvar		121 clinvar	5 clinvar	1 clinvar	128
nonsense	1 clinvar	1 clinvar				2
start loss						0
frameshift		1 clinvar				1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	2	2	125	6	4	139

Highest pathogenic variant AF is 0.0000020528373

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 55 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015110.4	RefSeq	NP_055925.2	25	MANE Select
ENST00000361138.7	Ensembl	ENSP00000354957.5	25	MANE Select
ENST00000884400.1	Ensembl	ENSP00000554459.1	24	Standard
ENST00000884401.1	Ensembl	ENSP00000554460.1	23	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
double-strand break repair via nonhomologous end joining
cellular response to DNA damage stimulus
sister chromatid cohesion

Molecular Function

protein binding
ATP 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: ENST00000361138
Coding exons: 25
Length: 95868
Individuals with no LoFs: 125694
Homozygous LoFs: 0
Heterozygous LoFs: 54
Defined: 125748
p: 0.000215

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.08	487	559	0.871	0.0000290	7267
Missense (PolyPhen)		129	209.31	0.61632		2720
Synonymous	0.247	186	190	0.977	0.00000953	1921
Loss of Function	4.92	22	64.7	0.340	0.00000361	823

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0.00011	0.000099	rare
East Asian	0.00040	0.00038	rare
Finnish	0.00033	0.00032	rare
European (Non-Finnish)	0.00022	0.00021	rare
South Asian	0.00014	0.00013	rare
Other	0.00036	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Core component of the SMC5-SMC6 complex, a complex involved in repair of 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. Required for sister chromatid cohesion during prometaphase and mitotic progression; the function seems to be independent of SMC6. 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:19502785, ECO:0000269|PubMed:26983541}.;

Recessive Scores

pRec: 0.116

Intolerance Scores

LoFtool: 0.689
RVIS EVS: -0.28
RVIS percentile EVS: 33.53

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.656

Gene Damage Prediction

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