SMC1A

Chr XXLD

structural maintenance of chromosomes 1A

Also known as: CDLS2, DEE85, DXS423E, EIEE85, SB1.8, SMC1, SMC1L1, SMC1alpha

NCBI Gene: 8243ENSG00000072501UniProt: Q14683

Proper cohesion of sister chromatids is a prerequisite for the correct segregation of chromosomes during cell division. The cohesin multiprotein complex is required for sister chromatid cohesion. This complex is composed partly of two structural maintenance of chromosomes (SMC) proteins, SMC3 and either SMC1B or the protein encoded by this gene. Most of the cohesin complexes dissociate from the chromosomes before mitosis, although those complexes at the kinetochore remain. Therefore, the encoded protein is thought to be an important part of functional kinetochores. In addition, this protein interacts with BRCA1 and is phosphorylated by ATM, indicating a potential role for this protein in DNA repair. This gene, which belongs to the SMC gene family, is located in an area of the X-chromosome that escapes X inactivation. Mutations in this gene result in Cornelia de Lange syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

Primary Disease Associations & Inheritance

Cornelia de Lange syndrome 2MIM #300590
XLD
Developmental and epileptic encephalopathy 85, with or without midline brain defectsMIM #301044
XLD
484
ClinVar variants
97
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— SMC1A
🧬
Gene-Disease Validity (ClinGen)
X-linked complex neurodevelopmental disorder · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
97 Pathogenic / Likely Pathogenic· 205 VUS of 484 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.06LOEUF
pLI 1.000
Z-score 6.43
OE 0.00 (0.00–0.06)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
6.45Z-score
OE missense 0.20 (0.17–0.23)
100 obs / 509.6 exp
Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.06)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.20 (0.17–0.23)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.98
0≤1.21.6
LoF obs/exp: 0 / 48.1Missense obs/exp: 100 / 509.6Syn Z: 0.19

ClinVar Variant Classifications

484 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic63
Likely Pathogenic34
VUS205
Likely Benign156
Benign20
Conflicting6
63
Pathogenic
34
Likely Pathogenic
205
VUS
156
Likely Benign
20
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
28
11
24
0
63
Likely Pathogenic
13
12
9
0
34
VUS
1
171
28
5
205
Likely Benign
0
2
70
84
156
Benign
0
2
17
1
20
Conflicting
—6
Total4219814890484

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

View in ClinVar →

Protein Context — Lollipop Plot

SMC1A · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SMC1A-related Cornelia de Lange syndrome

definitive
Monoallelic X HeterozygousUndeterminedAltered Gene Product Structure
Dev. DisordersSkeletal
G2P ↗
missense variantinframe deletioninframe insertion

SMC1A-related epileptic encephalopathy

definitive
Monoallelic X HeterozygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Cornelia de Lange syndrome 2

MIM #300590

Molecular basis of disorder known

X-linked dominant

Developmental and epileptic encephalopathy 85, with or without midline brain defects

MIM #301044

Molecular basis of disorder known

X-linked dominant
📖
GeneReview available — SMC1A
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
X-Linked Epilepsies: A Narrative Review.
Bernardo P et al.·Int J Mol Sci
2024Review
Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms.
Kaur M et al.·Am J Med Genet A
2023Functional
The expanding phenotypes of cohesinopathies: one ring to rule them all!
Piché J et al.·Cell Cycle
2019Review
Cohesin complex-associated holoprosencephaly.
Kruszka P et al.·Brain
2019
The multiple facets of the SMC1A gene.
Musio A·Gene
2020Review
Cornelia de Lange Spectrum.
Ascaso Á et al.·An Pediatr (Engl Ed)
2024
SMC1A epilepsy syndrome: clinical data from a large international cohort.
Gibellato E et al.·Am J Med Genet A
2024Cohort
Phenotypes and Genotypes in Patients with SMC1A-Related Developmental and Epileptic Encephalopathy.
Bozarth XL et al.·Genes (Basel)
2023Cohort
[Developmental and epileptic encephalopathy 85 caused by SMC1A gene truncating variation: 4 cases report and literature review].
Ye YZ et al.·Zhonghua Er Ke Za Zhi
2022Review
Subunit-specific analysis of cohesin-mutant myeloid malignancies reveals distinct ontogeny and outcomes.
Jann JC et al.·Leukemia
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Mutation type-specific transcriptomic signatures and readthrough therapy rescue in SMC1A-related developmental and epileptic encephalopathy.
Di Nardo M et al.·Epilepsia
2026
The sex-biased chromatin modifier SMC1A promotes autoimmunity by shaping inflammatory pathways in patients with SLE.
Kosmara D et al.·Nat Commun
2025🔓 Open AccessCohort
Linking Genotype to Clinical Features in SMC1A-Related Phenotypes: From Cornelia de Lange Syndrome to Developmental and Epileptic Encephalopathy, a Comprehensive Review.
Astorino MF et al.·Genes (Basel)
2025🔓 Open AccessReview
Postzygotic mosaicism in SMC1A and the first reported case of a female with Cornelia de Lange syndrome.
Gil-Salvador M et al.·Sci Rep
2025🔓 Open Access
Generation and characterization of human iPSC lines from two patients with therapy-resistant epilepsy carrying nonsense heterozygous variants in the SMC1A gene.
Paulis M et al.·Stem Cell Res
2025Cohort
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Rare DisordersUndiagnosed DisordersDisorders of Unknown Prevalence

Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

RECRUITING
NCT01793168Sanford HealthStarted 2010-07

External Resources

Links to major genomics databases and tools