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

LOFmechanismAR/ADLOEUF 0.262 OMIM phenotypes

Clinical Summary— RAD21

🧬

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.

💊

Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

📖

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 OE0.10 (0.04–0.26)

0≤0.351.4

Missense OE0.60 (0.53–0.67)

0≤0.61.4

Synonymous OE1.03

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

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 · LOEUF 0.26

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.PMID:12200439

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 witPMID:32193685

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