DDX41

Chr 5AD

DEAD-box helicase 41

Also known as: ABS, MPLPF

NCBI Gene: 51428 ENSG00000183258 UniProt: Q9UJV9

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.

Summary from RefSeq, OMIM, UniProt

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Primary Disease Associations & Inheritance

{Myeloproliferative/lymphoproliferative neoplasms, familial (multiple types), susceptibility to}MIM #616871

Active trials

Pubs (1 yr)

P/LP submissions

17%

P/LP missense

0.74

LOEUF

LOF*

Mechanism· G2P

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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ClinVar Variants

41 unique Pathogenic / Likely Pathogenic· 243 VUS of 500 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — DDX41

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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 OE0.50 (0.34–0.74)

0≤0.351.4

Missense OE0.68 (0.61–0.75)

0≤0.61.4

Synonymous OE1.28

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

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 · 61% of P/LP variants are LoF

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 thesPMID:30963592

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