STRADB

Chr 2

STE20 related adaptor beta

Also known as: ALS2CR2, CALS-21, ILPIP, ILPIPA, PAPK, PRO1038, STLK6

NCBI Gene: 55437 ENSG00000082146 UniProt: Q9C0K7 OMIM: 607333

This gene encodes a pseudokinase that forms a complex with CAB39/MO25 to activate the master kinase STK11/LKB1, which regulates cell polarity and energy metabolism. Mutations cause Polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE) syndrome, an autosomal recessive disorder characterized by fetal polyhydramnios, macrocephaly, and early-onset epilepsy. The gene is tolerant to loss-of-function variation (LOEUF 0.689), consistent with recessive inheritance requiring biallelic mutations for disease manifestation.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein that belongs to the serine/threonine protein kinase STE20 subfamily. One of the active site residues in the protein kinase domain of this protein is altered, and it is thus a pseudokinase. This protein is a component of a complex involved in the activation of serine/threonine kinase 11, a master kinase that regulates cell polarity and energy-generating metabolism. This complex regulates the relocation of this kinase from the nucleus to the cytoplasm, and it is essential for G1 cell cycle arrest mediated by this kinase. The protein encoded by this gene can also interact with the X chromosome-linked inhibitor of apoptosis protein, and this interaction enhances the anti-apoptotic activity of this protein via the JNK1 signal transduction pathway. Two pseudogenes, located on chromosomes 1 and 7, have been found for this gene. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2011]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.69

Clinical Summary— STRADB

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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

37 VUS of 53 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.69LOEUF

pLI 0.001

Z-score 2.68

OE 0.39 (0.24–0.69)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.54Z-score

OE missense 0.71 (0.62–0.81)

153 obs / 216.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.39 (0.24–0.69)

0≤0.351.4

Missense OE?0.71 (0.62–0.81)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 9 / 22.8Missense obs/exp: 153 / 216.6Syn Z: 0.25

This gene — mechanism propensity

0.6551th %ile

GOF

0.6833th %ile

LOF

0.3647th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction 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

53 submitted variants in ClinVar

ClinVar

Classification Summary

VUS37

Likely Benign1

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	36	1	0	37
Likely Benign	1	0	0	1
Benign	0	0	1	1
Total	37	1	1	39

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

View in ClinVar →

29 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap STRADB — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →