Human Gene Module / Chromosome 8 / EPPK1

EPPK1epiplakin 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
11 / 11
Rare Variants / Common Variants
28 / 0
Aliases
EPPK1, EPIPL,  EPIPL1
Associated Syndromes
-
Chromosome Band
8q24.3
Associated Disorders
-
Relevance to Autism

Four non-synonymous postzygotic mosaic mutations (PZMs) in the gene were identified in ASD probands in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (4/571 observed vs. 58/84,448 expected; hypergeometric P-value of 6.6E-04).

Molecular Function

The protein encoded by this gene belongs to the plakin family of proteins, which play a role in the organization of cytoskeletal architecture. This family member is composed of several highly homologous plakin repeats. It may function to maintain the integrity of keratin intermediate filament networks in epithelial cells.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to EPPK1 (11 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 Primary Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
3 Support Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder Krupp DR , et al. (2017) Yes -
4 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
5 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
6 Support - Woodbury-Smith M et al. (2022) Yes -
7 Support - Zhou X et al. (2022) Yes -
8 Support - Cirnigliaro M et al. (2023) Yes -
9 Support - Ayyappan Anitha et al. (2024) Yes -
10 Support - Sawako Furukawa et al. (2025) Yes DD, ID
11 Support - Paola Granata et al. (2024) Yes -
Rare Variants   (28)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.382G>A p.Gly128Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4628C>T p.Thr1543Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.6889C>T p.Gln2297Ter stop_gained De novo - Simplex 28714951 Lim ET , et al. (2017)
c.5106C>T p.Asp1702= synonymous_variant De novo - - 31452935 Feliciano P et al. (2019)
c.3712G>A p.Val1238Met missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2126G>A p.Gly709Asp missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.6794C>T p.Ala2265Val missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.6985C>T p.Leu2329Phe missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.6825C>T p.Pro2275= synonymous_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.6906G>C p.Ser2302= synonymous_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.5101G>A p.Val1701Met missense_variant Familial - - 39654053 Paola Granata et al. (2024)
c.5893C>T p.Arg1965Trp missense_variant Familial - - 39654053 Paola Granata et al. (2024)
c.6193T>A p.Tyr2065Asn missense_variant Familial - - 39654053 Paola Granata et al. (2024)
c.5869G>A p.Val1957Met missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.3G>A p.Met1? initiator_codon_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.6194A>G p.Tyr2065Cys missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.6915C>T p.Arg2305= synonymous_variant De novo - - 35205252 Woodbury-Smith M et al. (2022)
c.7008C>T p.Ile2336= synonymous_variant Familial - Simplex 28867142 Krupp DR , et al. (2017)
c.6807C>T p.Thr2269= synonymous_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.907C>T p.Gln303Ter stop_gained Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.853G>A p.Gly285Ser missense_variant Familial Paternal - 39610113 Sawako Furukawa et al. (2025)
c.2698C>T p.Gln900Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.6608_6609insC p.Arg2204ThrfsTer439 frameshift_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.108dupC p.Arg37GlnfsTer80 frameshift_variant Familial Maternal - 39610113 Sawako Furukawa et al. (2025)
c.6044dup p.Val2016CysfsTer82 frameshift_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.5035C>T p.Arg1679Cys missense_variant Unknown - Multiplex (monozygotic twins) 39038432 Ayyappan Anitha et al. (2024)
c.5590G>A p.Val1864Ile missense_variant Unknown - Multiplex (monozygotic twins) 39038432 Ayyappan Anitha et al. (2024)
c.6507_6508insCGCAGCTCATCTTAGAGTTGATCGAGAAGCAGGAAACCAGCAAC p.Lys2170ArgfsTer5 stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Four non-synonymous postzygotic mosaic mutations (PZMs) in the gene were identified in ASD probands in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (4/571 observed vs. 58/84,448 expected; hypergeometric P-value of 6.6E-04).

Score Delta: Score remained at 2

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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Four non-synonymous postzygotic mosaic mutations (PZMs) in the gene were identified in ASD probands in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (4/571 observed vs. 58/84,448 expected; hypergeometric P-value of 6.6E-04).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Four non-synonymous postzygotic mosaic mutations (PZMs) in the gene were identified in ASD probands in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (4/571 observed vs. 58/84,448 expected; hypergeometric P-value of 6.6E-04).

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

Four non-synonymous postzygotic mosaic mutations (PZMs) in the gene were identified in ASD probands in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (4/571 observed vs. 58/84,448 expected; hypergeometric P-value of 6.6E-04).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
7/1/2017
icon
4

Increased from to 4

Description

Four non-synonymous postzygotic mosaic mutations (PZMs) in the gene were identified in ASD probands in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (4/571 observed vs. 58/84,448 expected; hypergeometric P-value of 6.6E-04).

Krishnan Probability Score

Score 0.40537262621224

Ranking 23182/25841 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 4.9528734152936E-21

Ranking 18011/18225 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 0.9505492444669

Ranking 18536/18665 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 -0.1844561281398

Ranking 15068/20870 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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