PRKRA

Chr 2AR

protein activator of interferon induced protein kinase EIF2AK2

Also known as: DYT16, HSD14, PACT, RAX

NCBI Gene: 8575 ENSG00000180228 UniProt: O75569 OMIM: 603424

This gene encodes a protein kinase that activates PKR leading to translation inhibition and apoptosis, and is required for siRNA production by DICER1. Mutations cause dystonia 16, an autosomal recessive movement disorder. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.558), suggesting some intolerance to complete loss of function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein kinase activated by double-stranded RNA which mediates the effects of interferon in response to viral infection. Mutations in this gene have been associated with dystonia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.561 OMIM phenotype

Clinical Summary— PRKRA

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 84 VUS of 221 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PRKRA

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.56LOEUF

pLI 0.417

Z-score 2.71

OE 0.22 (0.10–0.56)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.58Z-score

OE missense 0.65 (0.55–0.76)

103 obs / 159.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.22 (0.10–0.56)

0≤0.351.4

Missense OE?0.65 (0.55–0.76)

0≤0.61.4

Synonymous OE?0.83

0≤1.21.6

LoF obs/exp: 3 / 13.9Missense obs/exp: 103 / 159.0Syn Z: 0.97

This gene — mechanism propensity

0.6357th %ile

GOF

0.5269th %ile

LOF

0.50top 25%

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative 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

LOF40% 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.

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

221 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic4

VUS84

Likely Benign76

Benign21

Conflicting6

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	1	3	0	0	4
VUS	6	57	19	2	84
Likely Benign	1	7	47	21	76
Benign	1	3	15	2	21
Conflicting	—				6
Total	10	70	81	25	192

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

View in ClinVar →

28 pathogenic / likely-pathogenic (of 39) ClinVar copy-number / structural variants overlap PRKRA — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →