STAT5B

Chr 17ARAD

signal transducer and activator of transcription 5B

Also known as: GHISID2, STAT5

NCBI Gene: 6777 ENSG00000173757 UniProt: P51692

The protein encoded by this gene is a member of the STAT family of transcription factors. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein mediates the signal transduction triggered by various cell ligands, such as IL2, IL4, CSF1, and different growth hormones. It has been shown to be involved in diverse biological processes, such as TCR signaling, apoptosis, adult mammary gland development, and sexual dimorphism of liver gene expression. This gene was found to fuse to retinoic acid receptor-alpha (RARA) gene in a small subset of acute promyelocytic leukemias (APLL). The dysregulation of the signaling pathways mediated by this protein may be the cause of the APLL. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Growth hormone insensitivity with immune dysregulation 1, autosomal recessiveMIM #245590

Growth hormone insensitivity with immune dysregulation 2, autosomal dominantMIM #618985

Active trials

Pathogenic / LP

390

ClinVar variants

Pubs (1 yr)

4.0

Missense Z· constrained

0.22

LOEUF· LoF intolerant

Clinical Summary— STAT5B

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Gene-Disease Validity (ClinGen)

growth hormone insensitivity with immune dysregulation 1, autosomal recessive · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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

23 Pathogenic / Likely Pathogenic· 200 VUS of 390 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.22LOEUF

pLI 1.000

Z-score 5.73

OE 0.10 (0.05–0.22)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

4.00Z-score

OE missense 0.47 (0.42–0.53)

212 obs / 450.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.10 (0.05–0.22)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.47 (0.42–0.53)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.91

0≤1.21.6

LoF obs/exp: 5 / 47.8Missense obs/exp: 212 / 450.7Syn Z: 0.98

0.4389th %ile

GOF

0.5269th %ile

LOF

0.58top 25%

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

LOF35% of P/LP variants are LoF · LOEUF 0.22

GOF1 literature citation

DN1 literature citation

Literature Evidence

DNWe conclude that these STAT5B variants exert dominant-negative effects through distinct pathomechanisms, manifesting in milder clinical GHIS with general sparing of the immune system.PMID:29844444

GOFJAK inhibition in early-onset somatic, nonclonal STAT5B gain-of-function disease.PMID:33290916

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

390 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18

Likely Pathogenic5

VUS200

Likely Benign163

Benign2

Conflicting2

Pathogenic

Likely Pathogenic

200

VUS

163

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	0	12	0	18
Likely Pathogenic	2	2	1	0	5
VUS	1	175	16	8	200
Likely Benign	0	0	60	103	163
Benign	0	0	2	0	2
Conflicting	—				2
Total	9	177	91	111	390

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

View in ClinVar →

Protein Context — Lollipop Plot

STAT5B · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

STAT5B-related growth hormone insensitivity with immunodeficiency

strong

ARLoss Of FunctionAbsent Gene Product

Dev. Disorders

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

IGF1 Deficiency

Global Patient Registry to Monitor Long-term Safety and Effectiveness of Increlex® in Children and Adolescents With Severe Primary Insulin-like Growth Factor-1 Deficiency (SPIGFD).

RECRUITING

NCT00903110Esteve Pharmaceuticals, S.A.Started 2008-12-09

Increlex®

Prolymphocytic LeukemiaT-cell Leukemia

Observatory of Prolymphocytic Leukemia T

RECRUITING

NCT04411043French Innovative Leukemia OrganisationStarted 2020-07-01

Molecular caracterization

Clinical Literature

Landmark / reviewRecent case evidence

Full-Text Mentions

NLP-detected gene mentions in article bodies · via PubTator3