RAD54L

Chr 1ADSomatic

RAD54 like

Also known as: HR54, RAD54A, hHR54, hRAD54

NCBI Gene: 8438 ENSG00000085999 UniProt: Q92698 OMIM: 603615

The RAD54L protein is a multifunctional ATPase that repairs DNA double-strand breaks through homologous recombination and acts as a molecular motor to guide RAD51 during the homology search process. Mutations cause autosomal dominant predisposition to adult-onset cancers including invasive ductal breast cancer, colonic adenocarcinoma, and non-Hodgkin lymphoma. The gene shows minimal constraint against loss-of-function variants in the population, consistent with its role as a cancer predisposition gene rather than a cause of severe developmental disorders.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene belongs to the DEAD-like helicase superfamily, and shares similarity with Saccharomyces cerevisiae Rad54, a protein known to be involved in the homologous recombination and repair of DNA. This protein has been shown to play a role in homologous recombination related repair of DNA double-strand breaks. The binding of this protein to double-strand DNA induces a DNA topological change, which is thought to facilitate homologous DNA paring, and stimulate DNA recombination. Alternative splicing results in multiple transcript variants encoding the same protein.[provided by RefSeq, Dec 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismAD/SomaticLOEUF 0.973 OMIM phenotypes

Clinical Summary— RAD54L

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

9 unique Pathogenic / Likely Pathogenic· 670 VUS of 1110 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.97LOEUF

pLI 0.000

Z-score 1.71

OE 0.71 (0.53–0.97)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.25Z-score

OE missense 1.04 (0.95–1.12)

424 obs / 409.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.71 (0.53–0.97)

0≤0.351.4

Missense OE?1.04 (0.95–1.12)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 29 / 40.8Missense obs/exp: 424 / 409.6Syn Z: -0.27

This gene — mechanism propensity

0.6842th %ile

GOF

0.4678th %ile

LOF

0.3648th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

1110 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic6

VUS670

Likely Benign402

Benign3

Conflicting6

Pathogenic

Likely Pathogenic

670

VUS

402

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	3	0	0	3
Likely Pathogenic	2	4	0	0	6
VUS	5	665	0	0	670
Likely Benign	1	50	15	336	402
Benign	0	0	2	1	3
Conflicting	—				6
Total	8	722	17	337	1,090

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap RAD54L — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →