SETBP1

Chr 18AD

SET binding protein 1

NCBI Gene: 26040ENSG00000152217UniProt: Q9Y6X0

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal dominant 29MIM #616078
AD
Schinzel-Giedion midface retraction syndromeMIM #269150
AD
UniProtMyelodysplastic syndrome
UniProtLeukemia, acute myelogenous
UniProtLeukemia, chronic myeloid, atypical
UniProtLeukemia, juvenile myelomonocytic
592
ClinVar variants
43
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— SETBP1
🧬
Gene-Disease Validity (ClinGen)
Schinzel-Giedion syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
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.
📋
ClinVar Variants
43 Pathogenic / Likely Pathogenic· 312 VUS of 592 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.11LOEUF
pLI 1.000
Z-score 5.95
OE 0.02 (0.01–0.11)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

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.
1.10Z-score
OE missense 0.90 (0.84–0.95)
776 obs / 866.8 exp
Tolerant

Mild missense constraint

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.0.02 (0.01–0.11)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.90 (0.84–0.95)
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.1.07
0≤1.21.6
LoF obs/exp: 1 / 43.3Missense obs/exp: 776 / 866.8Syn Z: -1.06

ClinVar Variant Classifications

592 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic34
Likely Pathogenic9
VUS312
Likely Benign186
Benign45
Conflicting6
34
Pathogenic
9
Likely Pathogenic
312
VUS
186
Likely Benign
45
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
14
2
18
0
34
Likely Pathogenic
3
1
5
0
9
VUS
2
297
13
0
312
Likely Benign
0
42
15
129
186
Benign
0
27
1
17
45
Conflicting
—6
Total1936952146592

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

View in ClinVar →

Protein Context — Lollipop Plot

SETBP1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SETBP1-related developmental and expressive language delay

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

SETBP1-related Schinzel-Giedion midface retraction syndrome

definitive
ADGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder, autosomal dominant 29

MIM #616078

Molecular basis of disorder known

Autosomal dominant

Schinzel-Giedion midface retraction syndrome

MIM #269150

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — SETBP1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Refining analyses of copy number variation identifies specific genes associated with developmental delay.
Coe BP et al.·Nat Genet
2014
Chronic neutrophilic leukemia and atypical chronic myeloid leukemia: 2024 update on diagnosis, genetics, risk stratification, and management.
Szuber N et al.·Am J Hematol
2024Review
Genomics of myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes.
Patnaik MM et al.·Hematology Am Soc Hematol Educ Program
2020Review
Clinical and Molecular Determinants of Clonal Evolution in Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria.
Gurnari C et al.·J Clin Oncol
2023
Molecular landscape and clonal architecture of adult myelodysplastic/myeloproliferative neoplasms.
Palomo L et al.·Blood
2020
De novo mutations in moderate or severe intellectual disability.
Hamdan FF et al.·PLoS Genet
2014
Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia.
Elena C et al.·Blood
2016Cohort
SETBP1 is dispensable for normal and malignant hematopoiesis.
Tanaka A et al.·Leukemia
2023
Germline and somatic genetic landscape of pediatric myelodysplastic syndromes.
Kotmayer L et al.·Haematologica
2025Review
Ibrutinib With Rituximab in First-Line Treatment of Older Patients With Mantle Cell Lymphoma.
Jain P et al.·J Clin Oncol
2022Clinical trial
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Behavioral and Prefrontal Circuit Deficits in a Newly Developed Setbp1 Haploinsufficiency Mouse Model.
Howard MA et al.·Biol Psychiatry Glob Open Sci
2026🔓 Open AccessFunctional
Human iPSCs-based modeling unveils SETBP1 as a driver of chromatin rewiring in GATA2 deficiency.
Pera J et al.·Nat Commun
2025🔓 Open AccessFunctional
Case Report: Whole-exome sequencing revealed a de novo variant in SETBP1 gene in a Chinese family with developmental delay.
Pan J et al.·Front Genet
2025🔓 Open AccessCase report
SETBP1 variants outside the degron disrupt DNA-binding, transcription and neuronal differentiation capacity to cause a heterogeneous neurodevelopmental disorder.
Wong MMK et al.·Nat Commun
2025🔓 Open Access
Association of Genetic Risk Variants in SETBP1, FANCM, and LSP1 with Familial Breast Cancer in the Pakistani Pashtun Population.
Shah H et al.·Pak J Med Sci
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools