Human Gene Module / Chromosome 9 / SPTAN1

SPTAN1spectrin alpha, non-erythrocytic 1

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
11 / 13
Rare Variants / Common Variants
35 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
9q34.11
Associated Disorders
-
Relevance to Autism

Trio-based whole-exome sequencing of 168 patients with low-functioning ASD at Sun Yat-sen Memorial Hospital in Wu et al., 2025 identified a de novo in-frame insertion variant in the SPTAN1 gene that was classified as likely pathogenic in ClinVar in a patient clinically diagnosed with ASD based on DSM-5 criteria and presenting with global developmental delay/intellectual disability. A de novo loss-of-function variant and multiple de novo missense variants, many of which are predicted to be deleterious by one or more in silico tools, have been identified in SPTAN1 in ASD probands from the Simons Simplex Collection, the SPARK cohort, the Autism Sequencing Consortium, the MSSNG cohort, the iHART cohort, and a cohort of 22 Bulgarian ASD probands (Iossifov et al., 2014; Ruzzo et al., 2019; Feliciano et al., 2019; Satterstrom et al., 2020; Zhou et al., 2022; Fu et al., 2022; Tan et al., 2025; Belenska-Todorova et al., 2025). Autism spectrum disorder has also been reported in a subset of individuals presenting with SPTAN1-associated disorders, including DEE5 and DEVEP (Syrbe et al., 2017; Marco Hernandez et al., 2022; Luongo-Zink et al., 2022).

Molecular Function

Spectrins are a family of filamentous cytoskeletal proteins that function as essential scaffold proteins that stabilize the plasma membrane and organize intracellular organelles. Spectrins are composed of alpha and beta dimers that associate to form tetramers linked in a head-to-head arrangement. This gene encodes an alpha spectrin that is specifically expressed in nonerythrocytic cells. The encoded protein has been implicated in other cellular functions including DNA repair and cell cycle regulation. Mutations in this gene are the cause of early infantile epileptic encephalopathy-5 (DEE5; OMIM 613477) and developmental delay with or without epilepsy (DEVEP; OMIM 620540).

External Links
Gene CardPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Reports related to SPTAN1 (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support - Steffen Syrbe et al. (2017) No ASD, ADHD, ID
3 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
4 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
5 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
6 Support - Ana Victoria Marco Hernández et al. (2022) No ASD, ID, epilepsy/seizures
7 Support - C Luongo-Zink et al. (2022) Yes -
8 Support - Hu C et al. (2022) Yes -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Fu JM et al. (2022) Yes -
11 Support - Senwei Tan et al. () Yes -
12 Support - Lyudmila Belenska-Todorova et al. (2025) Yes -
13 Primary - Ruohao Wu et al. (2025) Yes -
Rare Variants   (35)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
G>A p.? splice_site_variant De novo - Multiplex 39472663 Senwei Tan et al. ()
c.6625G>A p.Asp2209Asn missense_variant Unknown - - 35741772 Hu C et al. (2022)
c.5826T>G p.Ile1942Met missense_variant De novo - - 35982160 Fu JM et al. (2022)
c.101C>T p.Thr34Ile missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
- p.Ala927_Lys1002del copy_number_loss De novo - - 29050398 Steffen Syrbe et al. (2017)
c.533G>A p.Gly178Asp missense_variant De novo - - 29050398 Steffen Syrbe et al. (2017)
c.917C>T p.Ala306Val missense_variant De novo - - 29050398 Steffen Syrbe et al. (2017)
c.2666C>G p.Ser889Cys missense_variant De novo - - 35620303 C Luongo-Zink et al. (2022)
c.222C>T p.Asp74= synonymous_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.3716A>G p.His1239Arg missense_variant De novo - - 29050398 Steffen Syrbe et al. (2017)
c.4828C>T p.Arg1610Trp missense_variant De novo - - 29050398 Steffen Syrbe et al. (2017)
c.5326C>T p.Arg1776Trp missense_variant De novo - - 29050398 Steffen Syrbe et al. (2017)
c.6184C>T p.Arg2062Trp missense_variant De novo - - 29050398 Steffen Syrbe et al. (2017)
c.6811G>A p.Glu2271Lys missense_variant De novo - - 29050398 Steffen Syrbe et al. (2017)
c.7079T>C p.Leu2360Pro missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.4075C>T p.Arg1359Trp missense_variant De novo - Unknown 35982159 Zhou X et al. (2022)
c.7079T>C p.Leu2360Pro missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.7395C>T p.Phe2465= synonymous_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.7079T>C p.Leu2360Pro missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.1093C>A p.Arg365Ser missense_variant De novo - Multiplex 31398340 Ruzzo EK , et al. (2019)
c.5936A>G p.Glu1979Gly missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.6619_6621del p.Glu2207del inframe_deletion Unknown - - 29050398 Steffen Syrbe et al. (2017)
c.6622_6624del p.Asn2208del inframe_deletion De novo - - 29050398 Steffen Syrbe et al. (2017)
c.6370C>T p.Arg2124Cys missense_variant De novo - Simplex 31452935 Feliciano P et al. (2019)
c.7250C>T p.Ala2417Val missense_variant De novo - Simplex 31452935 Feliciano P et al. (2019)
c.1390_1398dup p.Glu464_Cys466dup inframe_insertion De novo - - 41127290 Ruohao Wu et al. (2025)
c.6908_6916dup p.Asp2303_2305dup inframe_insertion De novo - - 29050398 Steffen Syrbe et al. (2017)
c.6850_6852del p.Asp2284del inframe_deletion De novo - Simplex 29050398 Steffen Syrbe et al. (2017)
c.6908_6916del p.Asp2303_Leu2305del inframe_deletion De novo - - 29050398 Steffen Syrbe et al. (2017)
c.6910_6918del p.Gln2304_Gly2306del inframe_deletion De novo - - 29050398 Steffen Syrbe et al. (2017)
c.6922C>T p.Arg2308Cys missense_variant De novo - - 40558542 Lyudmila Belenska-Todorova et al. (2025)
c.6923_6928dup p.Arg2308_Met2309dup inframe_insertion De novo - - 29050398 Steffen Syrbe et al. (2017)
c.3292C>A p.Arg1098Ser missense_variant De novo - Simplex 34590414 Ana Victoria Marco Hernández et al. (2022)
c.6908_6916del p.Asp2303_Leu2305del inframe_deletion De novo - Simplex 34590414 Ana Victoria Marco Hernández et al. (2022)
c.6546_6556dup p.Asn2186ArgfsTer82 frameshift_variant De novo - Simplex 34590414 Ana Victoria Marco Hernández et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

10/1/2025
3

Initial score established: 3

Krishnan Probability Score

Score 0.50047578398474

Ranking 2078/25841 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 0.99999999999979

Ranking 32/18225 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 0.9468210620489

Ranking 17025/18665 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 0.37067717324481

Ranking 1781/20870 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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