SATB2

Chr 2AD

SATB homeobox 2

Also known as: C2DELq32q33, DEL2Q32Q33, GLSS

NCBI Gene: 23314 ENSG00000119042 UniProt: Q9UPW6 OMIM: 608148

The protein binds nuclear matrix attachment regions and regulates transcription and chromatin remodeling. Mutations cause Glass syndrome, characterized by isolated cleft palate and cognitive disability, with autosomal dominant inheritance. The mechanism involves loss of function, as the gene is highly intolerant to loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

LOFmechanismADLOEUF 0.091 OMIM phenotype

Clinical Summary— SATB2

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Gene-Disease Validity (ClinGen)

SATB2 associated disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

136 unique Pathogenic / Likely Pathogenic· 179 VUS of 600 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SATB2

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.09LOEUF

pLI 1.000

Z-score 5.32

OE 0.00 (0.00–0.09)

Highly constrained

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

Missense Constraint

4.05Z-score

OE missense 0.44 (0.39–0.50)

183 obs / 415.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.00 (0.00–0.09)

0≤0.351.4

Missense OE0.44 (0.39–0.50)

0≤0.61.4

Synonymous OE1.10

0≤1.21.6

LoF obs/exp: 0 / 32.9Missense obs/exp: 183 / 415.3Syn Z: -1.02

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSATB2-related Glass syndromeLOFAD

0.16100th %ile

GOF

0.2497th %ile

LOF

0.88top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-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.

LOFprediction above median · 1 literature citation · 65% of P/LP variants are LoF · LOEUF 0.09

DN1 literature citation

Literature Evidence

DNThis phenotype was accompanied by osteoporosis, fractures, and tibial bowing in two previously reported adult patients; each possessed SATB2 mutations either predicted or demonstrated to escape nonsense-mediated decay, suggesting that the additional bone defects result from a dominant negative effecPMID:27409069

LOFThe recent identification of SATB2 as a candidate gene responsible for the craniofacial dysmorphologies associated with deletions and translocations at 2q32-q33, one of only three regions of the genome for which haploinsufficiency has been significantly associated with isolated cleft palate, led us PMID:16960803

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.