SMC3

Chr 10AD

structural maintenance of chromosomes 3

Also known as: BAM, BMH, CDLS3, CSPG6, HCAP, SMC3L1

NCBI Gene: 9126ENSG00000108055UniProt: Q9UQE7

This gene belongs to the SMC3 subfamily of SMC proteins. The encoded protein occurs in certain cell types as either an intracellular, nuclear protein or a secreted protein. The nuclear form, known as structural maintenance of chromosomes 3, is a component of the multimeric cohesin complex that holds together sister chromatids during mitosis, enabling proper chromosome segregation. Post-translational modification of the encoded protein by the addition of chondroitin sulfate chains gives rise to the secreted proteoglycan bamacan, an abundant basement membrane protein. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Cornelia de Lange syndrome 3MIM #610759
AD
579
ClinVar variants
52
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— SMC3
🧬
Gene-Disease Validity (ClinGen)
Cornelia de Lange syndrome · ADDefinitive

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
52 Pathogenic / Likely Pathogenic· 233 VUS of 579 total submissions

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.
0.04LOEUF
pLI 1.000
Z-score 8.26
OE 0.00 (0.00–0.04)
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.
6.40Z-score
OE missense 0.28 (0.25–0.32)
178 obs / 630.1 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 (0.00–0.04)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.28 (0.25–0.32)
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.1.06
0≤1.21.6
LoF obs/exp: 0 / 79.5Missense obs/exp: 178 / 630.1Syn Z: -0.65

ClinVar Variant Classifications

579 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20
Likely Pathogenic32
VUS233
Likely Benign224
Benign61
Conflicting9
20
Pathogenic
32
Likely Pathogenic
233
VUS
224
Likely Benign
61
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
6
14
0
20
Likely Pathogenic
4
23
5
0
32
VUS
6
184
41
2
233
Likely Benign
0
5
131
88
224
Benign
0
0
60
1
61
Conflicting
—9
Total1021825191579

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

View in ClinVar →

Protein Context — Lollipop Plot

SMC3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SMC3-related Cornelia de Lange syndrome

definitive
ADUndeterminedUncertain
Dev. DisordersSkeletal
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Cornelia de Lange syndrome 3

MIM #610759

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — SMC3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genetic determinants of micronucleus formation in vivo.
Adams DJ et al.·Nature
2024
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
Cornelia de Lange Spectrum.
Ascaso Á et al.·An Pediatr (Engl Ed)
2024
Cohesin complex-associated holoprosencephaly.
Kruszka P et al.·Brain
2019
Cohesin mutations in myeloid malignancies.
Jann JC et al.·Blood
2021Review
Subunit-specific analysis of cohesin-mutant myeloid malignancies reveals distinct ontogeny and outcomes.
Jann JC et al.·Leukemia
2024
Genome Instability and Senescence Are Markers of Cornelia de Lange Syndrome Cells.
Di Nardo M et al.·Cells
2024
A Chinese Case of Cornelia de Lange Syndrome Caused by a Pathogenic Variant in SMC3 and a Literature Review.
Li R et al.·Front Endocrinol (Lausanne)
2021Review
Characteristics and clinical outcomes of patients with myeloid malignancies and cohesin mutations.
Khouri MR et al.·Cancer
2025Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools