HNRNPU

Chr 1AD

heterogeneous nuclear ribonucleoprotein U

Also known as: DEE54, EIEE54, GRIP120, HNRNPU-AS1, HNRPU, SAF-A, SAFA, U21.1

NCBI Gene: 3192 ENSG00000153187 UniProt: Q00839 OMIM: 602869

The protein binds heterogeneous nuclear RNA and scaffold-attached region DNA to form ribonucleoprotein complexes in the nucleus. Loss-of-function mutations cause developmental and epileptic encephalopathy 54 through autosomal dominant inheritance. The gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as the disease mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of a family of proteins that bind nucleic acids and function in the formation of ribonucleoprotein complexes in the nucleus with heterogeneous nuclear RNA (hnRNA). The encoded protein has affinity for both RNA and DNA, and binds scaffold-attached region (SAR) DNA. Mutations in this gene have been associated with epileptic encephalopathy, early infantile, 54. A pseudogene of this gene has been identified on chromosome 14. [provided by RefSeq, Jun 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.111 OMIM phenotype

Clinical Summary— HNRNPU

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

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

157 unique Pathogenic / Likely Pathogenic· 358 VUS of 1204 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 — HNRNPU

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?

0.11LOEUF

pLI 1.000

Z-score 5.84

OE 0.02 (0.01–0.11)

Highly constrained

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

Missense Constraint?

3.37Z-score

OE missense 0.56 (0.50–0.62)

253 obs / 455.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.02 (0.01–0.11)

0≤0.351.4

Missense OE?0.56 (0.50–0.62)

0≤0.61.4

Synonymous OE?1.28

0≤1.21.6

LoF obs/exp: 1 / 41.7Missense obs/exp: 253 / 455.5Syn Z: -2.83

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveHNRNPU-related epileptic encephalopathyLOFAD

This gene — mechanism propensity

0.16100th %ile

GOF

0.2597th %ile

LOF

0.84top 5%

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

LOFprediction above median · 1 literature citation · 85% of P/LP variants are LoF · LOEUF 0.11 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFUnique and variable clinical features are related to loss-of-function or haploinsufficiency of HNRNPU.1

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

References

1.PMID 29858110 ↗

ClinVar Variant Classifications

1204 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic107

Likely Pathogenic50

VUS358

Likely Benign526

Benign77

Conflicting55

107

Pathogenic

Likely Pathogenic

358

VUS

526

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	97	4	6	0	107
Likely Pathogenic	37	8	5	0	50
VUS	10	323	21	4	358
Likely Benign	1	85	178	262	526
Benign	0	24	49	4	77
Conflicting	—				55
Total	145	444	259	270	1,173

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

View in ClinVar →

97 pathogenic / likely-pathogenic (of 110) ClinVar copy-number / structural variants overlap HNRNPU — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →