SMC3

Chr 10AD

structural maintenance of chromosomes 3

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

NCBI Gene: 9126ENSG00000108055UniProt: Q9UQE7OMIM: 606062

The SMC3 protein is a component of the cohesin complex that holds sister chromatids together during mitosis, enabling proper chromosome segregation. Loss-of-function mutations cause Cornelia de Lange syndrome 3, inherited in an autosomal dominant pattern. The gene is extremely intolerant to loss-of-function variants, indicating haploinsufficiency as the likely pathogenic mechanism.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismADLOEUF 0.041 OMIM phenotype
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
23 unique Pathogenic / Likely Pathogenic· 133 VUS of 300 total submissions
Explore recent and relevant literature in Research Assistant →
📖
GeneReview available — SMC3
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
0.04LOEUF
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
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
LoF OE0.00 (0.00–0.04)
0≤0.351.4
Missense OE0.28 (0.25–0.32)
0≤0.61.4
Synonymous OE1.06
0≤1.21.6
LoF obs/exp: 0 / 79.5Missense obs/exp: 178 / 630.1Syn Z: -0.65
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveSMC3-related Cornelia de Lange syndromeOTHERAD
DN
0.3196th %ile
GOF
0.3293th %ile
LOF
0.69top 10%

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

LOFprediction above median · 30% of P/LP variants are LoF · LOEUF 0.04

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

Pathogenic8
Likely Pathogenic15
VUS133
Likely Benign116
Benign5
Conflicting3
8
Pathogenic
15
Likely Pathogenic
133
VUS
116
Likely Benign
5
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
4
1
0
8
Likely Pathogenic
4
9
2
0
15
VUS
4
112
15
2
133
Likely Benign
0
4
60
52
116
Benign
0
0
4
1
5
Conflicting
—3
Total111298255280

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.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
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
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