SMC3

Chr 10AD

structural maintenance of chromosomes 3

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

NCBI Gene: 9126 ENSG00000108055 UniProt: Q9UQE7 OMIM: 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.041 OMIM phenotype

Clinical Summary— SMC3

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Gene-Disease Validity (ClinGen)

Cornelia de Lange syndrome · ADDefinitive

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

80 unique Pathogenic / Likely Pathogenic· 282 VUS of 787 total submissions

Explore recent and relevant literature in Research Assistant →

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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 OE?0.00 (0.00–0.04)

0≤0.351.4

Missense OE?0.28 (0.25–0.32)

0≤0.61.4

Synonymous OE?1.06

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

This gene — mechanism propensity

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 · 20% 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

787 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic26

Likely Pathogenic54

VUS282

Likely Benign273

Benign92

Conflicting39

Pathogenic

Likely Pathogenic

282

VUS

273

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	10	16	0	0	26
Likely Pathogenic	6	47	1	0	54
VUS	13	218	43	8	282
Likely Benign	0	11	149	113	273
Benign	0	0	87	5	92
Conflicting	—				39
Total	29	292	280	126	766

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

View in ClinVar →

24 pathogenic / likely-pathogenic (of 32) ClinVar copy-number / structural variants overlap SMC3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →