DDX3X

Chr XXLDXLR

DEAD-box helicase 3 X-linked

Also known as: CAP-Rf, DBX, DDX14, DDX3, HLP2, MRX102, MRXSSB

NCBI Gene: 1654 ENSG00000215301 UniProt: O00571 OMIM: 300160

The protein is an ATP-dependent RNA helicase that regulates transcription, mRNA splicing, mRNA export, and translation in both nuclear and cytoplasmic compartments. Loss-of-function mutations cause X-linked intellectual developmental disorder, Snijders Blok type, which can follow either X-linked dominant or recessive inheritance patterns. The gene is highly intolerant to loss-of-function variants, indicating that haploinsufficiency is the primary disease mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is a member of the large DEAD-box protein family, that is defined by the presence of the conserved Asp-Glu-Ala-Asp (DEAD) motif, and has ATP-dependent RNA helicase activity. This protein has been reported to display a high level of RNA-independent ATPase activity, and unlike most DEAD-box helicases, the ATPase activity is thought to be stimulated by both RNA and DNA. This protein has multiple conserved domains and is thought to play roles in both the nucleus and cytoplasm. Nuclear roles include transcriptional regulation, mRNP assembly, pre-mRNA splicing, and mRNA export. In the cytoplasm, this protein is thought to be involved in translation, cellular signaling, and viral replication. Misregulation of this gene has been implicated in tumorigenesis. This gene has a paralog located in the nonrecombining region of the Y chromosome. Pseudogenes sharing similarity to both this gene and the DDX3Y paralog are found on chromosome 4 and the X chromosome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismXLD/XLRLOEUF 0.121 OMIM phenotype

Clinical Summary— DDX3X

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Gene-Disease Validity (ClinGen)

X-linked syndromic intellectual disability · XLDefinitive

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

352 unique Pathogenic / Likely Pathogenic· 225 VUS of 1111 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 →

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GeneReview available — DDX3X

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.12LOEUF

pLI 1.000

Z-score 4.65

OE 0.00 (0.00–0.12)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

4.33Z-score

OE missense 0.28 (0.23–0.33)

78 obs / 282.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.12)

0≤0.351.4

Missense OE?0.28 (0.23–0.33)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 0 / 25.2Missense obs/exp: 78 / 282.9Syn Z: -0.68

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveDDX3X-related intellectual disabilityLOFmonoallelic_X_heterozygous

definitiveDDX3X-related intellectual developmental disorderOTHERXLR

This gene — mechanism propensity

0.4784th %ile

GOF

0.4283th %ile

LOF

0.71top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 61% of P/LP variants are LoF · LOEUF 0.12 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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

ClinVar Variant Classifications

1111 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic204

Likely Pathogenic148

VUS225

Likely Benign250

Benign65

Conflicting23

204

Pathogenic

148

Likely Pathogenic

225

VUS

250

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	161	41	2	0	204
Likely Pathogenic	55	88	3	2	148
VUS	6	181	33	5	225
Likely Benign	0	4	152	94	250
Benign	0	1	52	12	65
Conflicting	—				23
Total	222	315	242	113	915

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

View in ClinVar →

75 pathogenic / likely-pathogenic (of 86) ClinVar copy-number / structural variants overlap DDX3X — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →