VRK1

Chr 14AR

VRK serine/threonine kinase 1

Also known as: HMNR10, PCH1, PCH1A

NCBI Gene: 7443 ENSG00000100749 UniProt: Q99986 OMIM: 602168

The protein is a nuclear serine/threonine kinase that phosphorylates p53, histones, and transcription factors including ATF2 and c-JUN, thereby regulating cell proliferation and transcriptional activity. Autosomal recessive mutations cause pontocerebellar hypoplasia type 1A and distal hereditary motor neuronopathy type 10. The pathogenic mechanism appears to involve dominant-negative effects disrupting normal kinase function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the vaccinia-related kinase (VRK) family of serine/threonine protein kinases. This gene is widely expressed in human tissues and has increased expression in actively dividing cells, such as those in testis, thymus, fetal liver, and carcinomas. Its protein localizes to the nucleus and has been shown to promote the stability and nuclear accumulation of a transcriptionally active p53 molecule and, in vitro, to phosphorylate Thr18 of p53 and reduce p53 ubiquitination. This gene, therefore, may regulate cell proliferation. This protein also phosphorylates histone, casein, and the transcription factors ATF2 (activating transcription factor 2) and c-JUN. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.632 OMIM phenotypes

Clinical Summary— VRK1

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

56 unique Pathogenic / Likely Pathogenic· 66 VUS of 293 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.63LOEUF

pLI 0.002

Z-score 2.94

OE 0.36 (0.22–0.63)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.17Z-score

OE missense 0.78 (0.68–0.88)

167 obs / 215.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.36 (0.22–0.63)

0≤0.351.4

Missense OE?0.78 (0.68–0.88)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 9 / 24.8Missense obs/exp: 167 / 215.2Syn Z: 0.57

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongVRK1-related pontocerebellar hypoplasiaLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6550th %ile

GOF

0.5562th %ile

LOF

0.3452th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

293 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22

Likely Pathogenic34

VUS66

Likely Benign158

Benign5

Pathogenic

Likely Pathogenic

VUS

158

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	19	0	3	0	22
Likely Pathogenic	32	1	1	0	34
VUS	1	55	5	5	66
Likely Benign	0	3	92	63	158
Benign	0	0	5	0	5
Total	52	59	106	68	285

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

View in ClinVar →

4 pathogenic / likely-pathogenic (of 7) ClinVar copy-number / structural variants overlap VRK1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →