RAD21

Chr 8ARAD

RAD21 cohesin complex component

Also known as: CDLS4, HR21, HRAD21, MCD1, MGS, NXP1, SCC1, hHR21

NCBI Gene: 5885 ENSG00000164754 UniProt: O60216 OMIM: 606462

This gene encodes a nuclear phosphoprotein that mediates sister chromatid cohesion during mitosis and is involved in DNA double-strand break repair. Loss-of-function mutations cause Cornelia de Lange syndrome 4 and Mungan syndrome through both autosomal dominant and autosomal recessive inheritance patterns. The protein becomes hyperphosphorylated during M phase and associates with mitotic chromatin at centromere regions.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is highly similar to the gene product of Schizosaccharomyces pombe rad21, a gene involved in the repair of DNA double-strand breaks, as well as in chromatid cohesion during mitosis. This protein is a nuclear phospho-protein, which becomes hyperphosphorylated in cell cycle M phase. The highly regulated association of this protein with mitotic chromatin specifically at the centromere region suggests its role in sister chromatid cohesion in mitotic cells. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAR/ADLOEUF 0.262 OMIM phenotypes

Clinical Summary— RAD21

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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

60 unique Pathogenic / Likely Pathogenic· 208 VUS of 537 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 — RAD21

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.26LOEUF

pLI 0.997

Z-score 4.60

OE 0.10 (0.04–0.26)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.64Z-score

OE missense 0.60 (0.53–0.67)

204 obs / 341.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.10 (0.04–0.26)

0≤0.351.4

Missense OE?0.60 (0.53–0.67)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 3 / 30.3Missense obs/exp: 204 / 341.4Syn Z: -0.27

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveRAD21-related cohesinopathyLOFAD

This gene — mechanism propensity

0.3196th %ile

GOF

0.2198th %ile

LOF

0.78top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 78% of P/LP variants are LoF · LOEUF 0.26 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

Literature Evidence

DNIn this study, we found that an N-terminally truncated human Scc1 shows a dominant-negative effect, and we examined the phenotypes of human cells defective in Scc1 function.1

LOFKrab et al. 2020 gathered a series of 49 individuals from 33 families with what they describe as an "attenuated Cornelia de Lange phenotype" and RAD21 alterations, including 5 de novo LOF variants (p.Gly547Alafs*65, p.Lys406Argfs*4, p.Glu315Glnfs*9, p.Ile206Thrfs*3, and p.Trp23*), 2 LOF variants wit2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

537 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic39

Likely Pathogenic21

VUS208

Likely Benign170

Benign57

Conflicting17

Pathogenic

Likely Pathogenic

208

VUS

170

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	34	4	1	0	39
Likely Pathogenic	13	8	0	0	21
VUS	3	187	15	3	208
Likely Benign	1	12	83	74	170
Benign	0	0	53	4	57
Conflicting	—				17
Total	51	211	152	81	512

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

View in ClinVar →

54 pathogenic / likely-pathogenic (of 68) ClinVar copy-number / structural variants overlap RAD21 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →