Human Gene Module / Chromosome 16 / SF3B3

SF3B3splicing factor 3b subunit 3

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 6
Rare Variants / Common Variants
25 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
16q22.1
Associated Disorders
-
Relevance to Autism

Musante et al., 2026 collected clinical and molecular information from 24 unrelated individuals with mostly heterozygous missense variants in the SF3B3 gene exhibiting a congruent phenotype including autism spectrum disorder, developmental delay, intellectual disability, language and motor delay, multiple congenital anomalies, and distinctive craniofacial features confirmed by GestaltMatcher analysis; three of the individuals included in this report were ASD probands from the Simons Simplex Collection and the SPARK cohort previously reported in Satterstrom et al., 2020, Zhou et al., 2022, and Trost et al., 2022. Additional functional assessment of fibroblasts from a subset of individuals with SF3B3 missense variants in Musante et al., 2026 identified reduced SF3B3 protein levels, differential gene expression, increased alternative splicing events, and cell-cycle abnormalities compared to controls.

Molecular Function

This gene encodes subunit 3 of the splicing factor 3b protein complex. Splicing factor 3b, together with splicing factor 3a and a 12S RNA unit, forms the U2 small nuclear ribonucleoproteins complex (U2 snRNP). The splicing factor 3b/3a complex binds pre-mRNA upstream of the intron's branch site in a sequence independent manner and may anchor the U2 snRNP to the pre-mRNA. Splicing factor 3b is also a component of the minor U12-type spliceosome. Subunit 3 has also been identified as a component of the STAGA (SPT3-TAF(II)31-GCN5L acetylase) transcription coactivator-HAT (histone acetyltransferase) complex, and the TFTC (TATA-binding-protein-free TAF(II)-containing complex). These complexes may function in chromatin modification, transcription, splicing, and DNA repair.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
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Reports related to SF3B3 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
2 Support - Wilfert AB et al. (2021) Yes -
3 Support - Zhou X et al. (2022) Yes -
4 Support - Fu JM et al. (2022) Yes -
5 Support - Trost B et al. (2022) Yes -
6 Primary - Luciana Musante et al. () Yes Epilepsy/seizures
Rare Variants   (25)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2669+3_2669+5dup - splice_region_variant De novo - - 35982160 Fu JM et al. (2022)
c.88A>G p.Ile30Val missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.2384A>G p.Asn795Ser missense_variant De novo - Simplex 36368308 Trost B et al. (2022)
c.3579C>T p.Val1193= synonymous_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.376A>G p.Lys126Glu missense_variant De novo - Simplex 41709284 Luciana Musante et al. ()
c.452G>A p.Arg151Gln missense_variant De novo - Simplex 41709284 Luciana Musante et al. ()
c.637C>A p.Leu213Ile missense_variant De novo - Simplex 41709284 Luciana Musante et al. ()
c.647G>A p.Gly216Asp missense_variant De novo - Simplex 41709284 Luciana Musante et al. ()
c.656A>C p.His219Pro missense_variant De novo - Simplex 41709284 Luciana Musante et al. ()
c.914C>T p.Thr305Ile missense_variant De novo - Simplex 41709284 Luciana Musante et al. ()
c.1349C>T p.Ser450Phe missense_variant De novo - Simplex 41709284 Luciana Musante et al. ()
c.1480G>A p.Val494Met missense_variant De novo - Simplex 41709284 Luciana Musante et al. ()
c.1574G>A p.Arg525Gln missense_variant De novo - Simplex 41709284 Luciana Musante et al. ()
c.1922G>A p.Cys641Tyr missense_variant De novo - Simplex 41709284 Luciana Musante et al. ()
c.2012A>G p.Asn671Ser missense_variant De novo - Simplex 41709284 Luciana Musante et al. ()
c.2066C>T p.Thr689Ile missense_variant De novo - Simplex 41709284 Luciana Musante et al. ()
c.2183G>C p.Arg728Pro missense_variant De novo - Simplex 41709284 Luciana Musante et al. ()
c.2506G>A p.Ala836Thr missense_variant De novo - Simplex 41709284 Luciana Musante et al. ()
c.3224C>A p.Ala1075Asp missense_variant De novo - Simplex 41709284 Luciana Musante et al. ()
c.1205A>C p.Asp402Ala missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1762_1764del p.Val588del inframe_deletion De novo - Simplex 41709284 Luciana Musante et al. ()
c.1390C>T p.Arg464Ter stop_gained Unknown Not maternal Simplex 41709284 Luciana Musante et al. ()
c.2364dupT p.Val789CysfsTer5 frameshift_variant De novo - Simplex 41709284 Luciana Musante et al. ()
c.996_1000del p.Val333ArgfsTer9 frameshift_variant Familial - Simplex 34312540 Wilfert AB et al. (2021)
c.1242_1243insCTGGC p.Asn417TrpfsTer21 frameshift_variant De novo - Simplex 41709284 Luciana Musante et al. ()
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2026
2

Initial score established: 2

Krishnan Probability Score

Score 0.41067578672497

Ranking 22604/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99996297833645

Ranking 561/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.9433068990083

Ranking 15637/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.44239551968032

Ranking 998/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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