Human Gene Module / Chromosome 1 / ZFYVE9

ZFYVE9zinc finger FYVE-type containing 9

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
5 / 6
Rare Variants / Common Variants
6 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
1p32.3
Associated Disorders
-
Relevance to Autism

Functional assessment of de novo 5'UTR variants identified in ASD probands from the Simons Simplex Collection (SSC) by massively parallel reporter assay (MPRA) using polysomes from cell lines in Plassmeyer et al., 2025 reported an ASD-associated 5'UTR variant in the ZFYVE9 gene that resulted in a significant effect on 40S-total RNA enrichment in in cellulo MPRA studies in HEK cells, as well as increased protein expression in a dual-luciferase reporter assay (FDR-adjusted p-value < 0.05). Several de novo variants in this gene, including a de novo loss-of-function variant and a de novo missense variant that was predicted to be deleterious by CADD and REVEL, have been identified in ASD probands from the Simons Simplex Collection and the SPARK cohort (Iossifov et al., 2014; Zhou et al., 2022).

Molecular Function

This gene encodes a double zinc finger motif-containing protein that participates in the transforming growth factor-beta (TGFB) signalling pathway. The encoded protein interacts directly with SMAD2 and SMAD3, and recruits SMAD2 to the TGFB receptor. Suppresion of Zfyve9 in the developing mouse brain resulted in impaired neuronal orientation and migration across the intermediate zone, as well as increased surface expression of the L1 cell adhesion molecule in Zfyve9-suppressed neurons (Mestres et al., 2016).

External Links
Gene CardPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Reports related to ZFYVE9 (6 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 - Iván Mestres et al. (2016) No -
3 Support - Zhou X et al. (2022) Yes -
4 Support - Cirnigliaro M et al. (2023) Yes -
5 Support - Ashlesha Gogate et al. (2024) Yes -
6 Primary - Stephen P Plassmeyer et al. (2025) Yes -
Rare Variants   (6)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2258G>A p.Cys753Tyr missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1461T>G p.Gly487= synonymous_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.-162G>A - 5_prime_UTR_variant De novo - Simplex 41344325 Stephen P Plassmeyer et al. (2025)
c.1276dup p.Ser426LysfsTer4 frameshift_variant De novo - Unknown 35982159 Zhou X et al. (2022)
c.2642T>A p.Phe881Tyr missense_variant Unknown - Simplex 39632905 Ashlesha Gogate et al. (2024)
c.133_134insTG p.His45LeufsTer13 frameshift_variant Familial Paternal Simplex 37506195 Cirnigliaro M et al. (2023)
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 0.56902070340951

Ranking 1070/25841 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 0.94379674355947

Ranking 2787/18225 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 0.83329533234325

Ranking 2939/18665 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 0.42665704499681

Ranking 1157/20870 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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