SMC5

Chr 9AR

structural maintenance of chromosomes 5

Also known as: ATELS2, SMC5L1

NCBI Gene: 23137 ENSG00000198887 UniProt: Q8IY18 OMIM: 609386

SMC5 encodes a core component of the SMC5-SMC6 complex that repairs DNA double-strand breaks through homologous recombination, maintains telomeres, and ensures proper sister chromatid cohesion during cell division. Mutations cause Atelis syndrome 2, inherited in an autosomal recessive pattern. The gene is highly constrained against loss-of-function variants, indicating its critical cellular function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Enables DNA secondary structure binding activity. Involved in several processes, including DNA recombination; negative regulation by host of viral genome replication; and positive regulation of cell cycle process. Located in cell junction; 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, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.491 OMIM phenotype

Clinical Summary— SMC5

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 119 VUS of 159 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.49LOEUF

pLI 0.000

Z-score 4.92

OE 0.34 (0.24–0.49)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.08Z-score

OE missense 0.87 (0.81–0.94)

487 obs / 558.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.34 (0.24–0.49)

0≤0.351.4

Missense OE?0.87 (0.81–0.94)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 22 / 64.7Missense obs/exp: 487 / 558.9Syn Z: 0.25

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateSMC5-related developmental disorderOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6549th %ile

GOF

0.5366th %ile

LOF

0.2777th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

159 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic2

VUS119

Likely Benign7

Benign5

Pathogenic

Likely Pathogenic

119

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	2	0	0	3
Likely Pathogenic	2	0	0	0	2
VUS	0	119	0	0	119
Likely Benign	0	5	1	1	7
Benign	0	1	1	3	5
Total	3	127	2	4	136

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

40 pathogenic / likely-pathogenic (of 45) ClinVar copy-number / structural variants overlap SMC5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →