DDX41

Chr 5AD

DEAD-box helicase 41

Also known as: ABS, MPLPF

NCBI Gene: 51428 ENSG00000183258 UniProt: Q9UJV9 OMIM: 608170

The protein encoded by DDX41 is an RNA helicase that functions in pre-mRNA splicing, ribosome biogenesis, and innate immune sensing of nucleic acids. Mutations cause autosomal dominant familial susceptibility to myeloproliferative and lymphoproliferative neoplasms, affecting hematopoietic homeostasis. The gene shows very low tolerance to loss-of-function variants (pLI nearly 1, LOEUF 0.736), indicating it is highly constrained and essential for normal cellular function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure, such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of the DEAD box protein family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. The protein encoded by this gene is a member of the DEAD box protein family and interacts with several spliceosomal proteins. In addition, the encoded protein may recognize the bacterial second messengers cyclic di-GMP and cyclic di-AMP, resulting in the induction of genes involved in the innate immune response. [provided by RefSeq, Jan 2017]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.741 OMIM phenotype

Clinical Summary— DDX41

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Gene-Disease Validity (ClinGen)

DDX41-related hematologic malignancy predisposition syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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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Clinical Trials

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

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.74LOEUF

pLI 0.000

Z-score 2.81

OE 0.50 (0.34–0.74)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.28Z-score

OE missense 0.68 (0.61–0.75)

272 obs / 400.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.50 (0.34–0.74)

0≤0.351.4

Missense OE?0.68 (0.61–0.75)

0≤0.61.4

Synonymous OE?1.28

0≤1.21.6

LoF obs/exp: 18 / 36.3Missense obs/exp: 272 / 400.7Syn Z: -2.77

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveDDX41-related myeloproliferative/lymphoproliferative neoplasms, familial (multiple types), susceptibility toLOFAD

This gene — mechanism propensity

0.78top 25%

GOF

0.6442th %ile

LOF

0.2485th %ile

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

DNprediction above median

GOFprediction above median

LOF1 literature citation · ClinGen HI: Sufficient evidence for dosage pathogenicity

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.

Literature Evidence

LOFQuesada et al (2019; Am J Hematol) used a 81 gene NGS panel to identify DDX41 variants in 34 patients with myeloid neoplasms. Fifty-nine DDX41 variants were detected and 32% were germline identified from cultured skin biopsy. Most germline variants were upstream of the Helicase 2 domain, 28% of thes1

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

References