SMC1A

Chr XXLD

structural maintenance of chromosomes 1A

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

NCBI Gene: 8243ENSG00000072501UniProt: Q14683OMIM: 300040

The protein functions as a structural maintenance of chromosomes component essential for sister chromatid cohesion during cell division and contributes to functional kinetochores and DNA repair through interactions with BRCA1. Mutations cause Cornelia de Lange syndrome 2 and developmental and epileptic encephalopathy 85 with or without midline brain defects through an X-linked dominant inheritance pattern, predominantly through loss-of-function mechanisms. The gene shows extreme intolerance to loss-of-function variants, consistent with haploinsufficiency being pathogenic.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismXLDLOEUF 0.062 OMIM phenotypes
Clinical Summary— SMC1A
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Gene-Disease Validity (ClinGen)
X-linked complex neurodevelopmental disorder · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.
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ClinVar Variants
44 unique Pathogenic / Likely Pathogenic· 74 VUS of 300 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — SMC1A
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint
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
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
LoF OE0.00 (0.00–0.06)
0≤0.351.4
Missense OE0.20 (0.17–0.23)
0≤0.61.4
Synonymous OE0.98
0≤1.21.6
LoF obs/exp: 0 / 48.1Missense obs/exp: 100 / 509.6Syn Z: 0.19
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveSMC1A-related Cornelia de Lange syndromeOTHERmonoallelic_X_heterozygous
definitiveSMC1A-related epileptic encephalopathyLOFmonoallelic_X_heterozygous
DN
0.3097th %ile
GOF
0.3689th %ile
LOF
0.69top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 55% of P/LP variants are LoF · LOEUF 0.06

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

300 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic31
Likely Pathogenic13
VUS74
Likely Benign125
Benign13
Conflicting7
31
Pathogenic
13
Likely Pathogenic
74
VUS
125
Likely Benign
13
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
17
4
10
0
31
Likely Pathogenic
7
6
0
0
13
VUS
2
63
8
1
74
Likely Benign
0
1
51
73
125
Benign
0
3
8
2
13
Conflicting
—7
Total26777776263

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.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
A novel missense variant in the SMC1A gene causing Cornelia de Lange syndrome in a Chinese neonate.
Yang Y et al.·Clin Biochem
2026
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
2025Open 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)
2025Open 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
2025Open Access
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients