STK3

Chr 8

serine/threonine kinase 3

Also known as: KRS1, MST2

NCBI Gene: 6788 ENSG00000104375 UniProt: Q9Y6E0

The protein is a serine/threonine kinase that promotes apoptosis in response to stress stimuli and regulates cellular migration, axon regeneration, and multiple signaling pathways including Hippo and MAPK. Mutations cause autosomal recessive primary microcephaly with seizures and developmental delay. The gene shows very low constraint against loss-of-function variants, consistent with the recessive inheritance pattern observed in affected patients.

ResearchSummary from RefSeq, UniProt

This gene encodes a serine/threonine protein kinase activated by proapoptotic molecules indicating the encoded protein functions as a growth suppressor. Cleavage of the protein product by caspase removes the inhibitory C-terminal portion. The N-terminal portion is transported to the nucleus where it homodimerizes to form the active kinase which promotes the condensation of chromatin during apoptosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.87

Clinical Summary— STK3

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Population Constraint (gnomAD)

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

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 98 VUS of 123 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.87LOEUF

pLI 0.000

Z-score 2.06

OE 0.56 (0.37–0.87)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.58Z-score

OE missense 0.73 (0.65–0.82)

194 obs / 266.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.56 (0.37–0.87)

0≤0.351.4

Missense OE?0.73 (0.65–0.82)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 14 / 25.1Missense obs/exp: 194 / 266.4Syn Z: 0.58

This gene — mechanism propensity

0.80top 25%

GOF

0.74top 25%

LOF

0.2873th %ile

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

GOFprediction above median

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.

ClinVar Variant Classifications

123 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS98

Likely Benign2

Benign2

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	0	2
Likely Pathogenic	0	0	0	0
VUS	98	0	0	98
Likely Benign	1	0	1	2
Benign	1	0	1	2
Total	100	2	2	104

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

View in ClinVar →

33 pathogenic / likely-pathogenic (of 46) ClinVar copy-number / structural variants overlap STK3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →