HNRNPK

Chr 9AD

heterogeneous nuclear ribonucleoprotein K

Also known as: AUKS, CSBP, HNRPK, TUNP

NCBI Gene: 3190 ENSG00000165119 UniProt: P61978 OMIM: 600712

The protein functions as an RNA-binding protein that complexes with heterogeneous nuclear RNA in the nucleus, influencing pre-mRNA processing and mRNA metabolism, with a distinct binding preference for poly(C) sequences. Loss-of-function mutations cause Au-Kline syndrome, inherited in an autosomal dominant pattern. 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 belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene is located in the nucleoplasm and has three repeats of KH domains that binds to RNAs. It is distinct among other hnRNP proteins in its binding preference; it binds tenaciously to poly(C). This protein is also thought to have a role during cell cycle progession. Several alternatively spliced transcript variants have been described for this gene, however, not all of them are fully characterized. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.101 OMIM phenotype

Clinical Summary— HNRNPK

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Gene-Disease Validity (ClinGen)

neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome · 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

82 unique Pathogenic / Likely Pathogenic· 103 VUS of 355 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 — HNRNPK

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?

0.10LOEUF

pLI 1.000

Z-score 5.15

OE 0.00 (0.00–0.10)

Highly constrained

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

Missense Constraint?

3.99Z-score

OE missense 0.33 (0.28–0.39)

93 obs / 281.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.10)

0≤0.351.4

Missense OE?0.33 (0.28–0.39)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 0 / 30.9Missense obs/exp: 93 / 281.5Syn Z: -1.22

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveHNRNPK-related Au-Kline syndromeLOFAD

This gene — mechanism propensity

0.2598th %ile

GOF

0.2597th %ile

LOF

0.86top 5%

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

LOFprediction above median · 1 literature citation · 57% of P/LP variants are LoF · LOEUF 0.10 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFClinical spectrum of Kabuki-like syndrome caused by HNRNPK haploinsufficiency.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 28374925 ↗

ClinVar Variant Classifications

355 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic34

Likely Pathogenic48

VUS103

Likely Benign92

Benign48

Conflicting11

Pathogenic

Likely Pathogenic

103

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	27	2	5	0	34
Likely Pathogenic	20	24	4	0	48
VUS	3	87	11	2	103
Likely Benign	0	5	47	40	92
Benign	0	1	44	3	48
Conflicting	—				11
Total	50	119	111	45	336

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

View in ClinVar →

27 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap HNRNPK — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →