Human Gene Module / Chromosome 2 / GIGYF2

GIGYF2GRB10 interacting GYF protein 2

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
12 / 12
Rare Variants / Common Variants
39 / 0
Aliases
GIGYF2, GYF2,  PARK11,  PERQ2,  PERQ3,  TNRC15
Associated Syndromes
-
Chromosome Band
2q37.1
Associated Disorders
-
Relevance to Autism

Three de novo variants in the GIGYF2 gene (1 nonsense, 2 missense) have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=3.40 x 10-4) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015). Clinical characterization of 16 probands from an initial cohort of 10 affected individuals from eight families harboring de novo or dominantly inherited likely gene disruptive variants and 13 affected individuals with de novo missense variants in GIGYF2 in Yu et al., 2026 identified a clinical presentation characterized by speech and language problems (13/13, 100%), autism spectrum disorder (13/15, 86.7%), intellectual disability (13/15, 86.7%), and anxiety (4/7, 57.1%) ; in the same report, a Gigyf2 conditional mouse model was found to exhibit pronounced autistic-like behaviors, cognitive deficits, and anxiety-like behaviors, mirroring phenotypes observed in human patients.

Molecular Function

This gene contains CAG trinucleotide repeats and encodes a protein containing several stretches of polyglutamine residues. The encoded protein may be involved in the regulation of tyrosine kinase receptor signaling. This gene is located in a chromosomal region that was genetically linked to Parkinson disease type 11, and mutations in this gene were thought to be causative for this disease.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to GIGYF2 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
4 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
5 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
6 Support Association of rare missense variants in the second intracellular loop of Na V 1.7 sodium channels with familial autism Rubinstein M , et al. (2016) Yes -
7 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
8 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Vittoria Greco et al. (2025) Yes DD, ID
11 Support - Natividad Avila, Marina et al. (2026) Yes -
12 Recent Recommendation - Yu, Bin et al. (2026) Yes ADHD, epilepsy/seizures
Rare Variants   (39)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.958G>T p.Glu320Ter stop_gained De novo - - 27824329 Wang T , et al. (2016)
c.101C>T p.Pro34Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.493G>T p.Gly165Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.502C>T p.Arg168Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.689G>T p.Arg230Ile missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.821G>A p.Arg274His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.971C>T p.Ser324Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.812T>A p.Met271Lys missense_variant De novo - - 42297935 Yu, Bin et al. (2026)
c.982T>C p.Phe328Leu missense_variant De novo - - 42297935 Yu, Bin et al. (2026)
c.1450C>T p.Arg484Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1592A>G p.Glu531Gly missense_variant De novo - - 33004838 Wang T et al. (2020)
c.1637C>T p.Ser546Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2935C>T p.Arg979Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2071A>G p.Ile691Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2828C>T p.Thr943Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1041C>G p.Phe347Leu missense_variant De novo - - 42297935 Yu, Bin et al. (2026)
c.1972G>A p.Ala658Thr missense_variant De novo - - 42297935 Yu, Bin et al. (2026)
c.2211A>G p.Leu737= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.3896G>T p.Gly1299Val missense_variant De novo - - 42297935 Yu, Bin et al. (2026)
c.779-1G>C - splice_site_variant Familial Maternal - 42297935 Yu, Bin et al. (2026)
c.2416C>T p.Arg806Ter stop_gained De novo - Multiplex 28714951 Lim ET , et al. (2017)
c.612T>A p.Phe204Leu missense_variant De novo - Simplex 42297935 Yu, Bin et al. (2026)
c.1990C>T p.Gln664Ter stop_gained De novo - Simplex 25363768 Iossifov I et al. (2014)
c.149C>T p.Ala50Val missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.2116G>A p.Val706Met missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.2116G>A p.Val706Met missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.3527C>G p.Pro1176Arg missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.817C>T p.Arg273Ter stop_gained Familial Maternal Multiplex 33004838 Wang T et al. (2020)
c.2867G>A p.Arg956Gln missense_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.2930G>A p.Arg977Gln missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.149C>T p.Ala50Val missense_variant Familial Maternal Simplex 33004838 Wang T et al. (2020)
c.850dupA p.Arg284LysfsTer3 frameshift_variant De novo - Simplex 42297935 Yu, Bin et al. (2026)
c.1047T>A p.Asp349Glu missense_variant Familial Paternal - 40731902 Vittoria Greco et al. (2025)
c.3525G>T p.Arg1175Ser missense_variant Familial Paternal - 40731902 Vittoria Greco et al. (2025)
c.3099G>A p.Thr1033= synonymous_variant Familial Paternal - 40731902 Vittoria Greco et al. (2025)
c.1144_1147del p.Asp382GlufsTer2 frameshift_variant De novo - Simplex 42297935 Yu, Bin et al. (2026)
c.3770A>G p.His1257Arg missense_variant De novo - Simplex 41912808 Natividad Avila, Marina et al. (2026)
c.3669G>C p.Gln1223His missense_variant Familial - Extended multiplex 27956748 Rubinstein M , et al. (2016)
c.3163_3173del p.His1055AlafsTer18 frameshift_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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.

10/1/2020
1
icon
1

Score remained at 1

Description

Three de novo variants in the GIGYF2 gene (1 nonsense, 2 missense) have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=3.40 x 10-4) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015). A second de novo loss-of-function (LoF) variant in GIGYF2 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. A de novo postzygotic mosaic nonsense variant in GIGYF2 was identified in an ASD proband in Lim et al., 2017, bringing the total of de novo LoF variants in GIGYF2 to three.

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
10/1/2019
2
icon
1

Decreased from 2 to 1

New Scoring Scheme
Description

Three de novo variants in the GIGYF2 gene (1 nonsense, 2 missense) have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=3.40 x 10-4) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015). A second de novo loss-of-function (LoF) variant in GIGYF2 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. A de novo postzygotic mosaic nonsense variant in GIGYF2 was identified in an ASD proband in Lim et al., 2017, bringing the total of de novo LoF variants in GIGYF2 to three.

Reports Added
[New Scoring Scheme]
7/1/2017
2
icon
2

Decreased from 2 to 2

Description

Three de novo variants in the GIGYF2 gene (1 nonsense, 2 missense) have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=3.40 x 10-4) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015). A second de novo loss-of-function (LoF) variant in GIGYF2 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. A de novo postzygotic mosaic nonsense variant in GIGYF2 was identified in an ASD proband in Lim et al., 2017, bringing the total of de novo LoF variants in GIGYF2 to three.

Reports Added
[Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017]
1/1/2017
2
icon
2

Decreased from 2 to 2

Description

Three de novo variants in the GIGYF2 gene (1 nonsense, 2 missense) have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=3.40 x 10-4) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015). A fourth de novo LoF variant in GIGYF2 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.

Reports Added
[Association of rare missense variants in the second intracellular loop of NaV1.7 sodium channels with familial autism.2016]
10/1/2016
3
icon
2

Decreased from 3 to 2

Description

Three de novo variants in the GIGYF2 gene (1 nonsense, 2 missense) have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=3.40 x 10-4) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015). A fourth de novo LoF variant in GIGYF2 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.

Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016]
1/1/2016
3
icon
3

Decreased from 3 to 3

Description

Three de novo variants in the GIGYF2 gene (1 nonsense, 2 missense) have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=3.40 x 10-4) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Excess of rare, inherited truncating mutations in autism.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
7/1/2015
icon
3

Increased from to 3

Description

Three de novo variants in the GIGYF2 gene (1 nonsense, 2 missense) have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=3.40 x 10-4) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Krishnan Probability Score

Score 0.49228277258555

Ranking 4627/25841 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 0.99999999997935

Ranking 53/18225 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
Iossifov Probability Score

Score 0.948

Ranking 84/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.25896648523786

Ranking 149/18665 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 0.34279934511242

Ranking 2107/20870 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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