{"gene":"PPFIA2","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2003,"finding":"PPFIA2 protein contains PFIH1–4 domains and three SAM domains; the region spanning SAM1–SAM3 domains mediates binding to LAR subfamily PTPases and PPFIBP (Liprin-β) family proteins; the region spanning PFIH2–PFIH3 domains is the binding domain for KIF1A; a C-terminal VRTYSC motif (present in PPFIA2) serves as the binding domain for GRIP proteins.","method":"Bioinformatics / comparative sequence analysis of domain architecture across PPFIA paralogs (in silico characterization)","journal":"International journal of molecular medicine","confidence":"Low","confidence_rationale":"Tier 4 / Weak — purely computational/sequence-based inference, no experimental validation reported","pmids":["14612982"],"is_preprint":false},{"year":2019,"finding":"Liprin-α interacts with the paxillin-binding domain (PBD) of GIT1 through a single α-helix on liprin-α, and this interaction is distinct from the GIT1–paxillin (LD4 motif) interaction; structure-based GIT1 PBD variants that are deficient in liprin-α binding show impaired focal adhesion assembly in COS7 cells, placing liprin-α–GIT1 interaction in focal adhesion dynamics.","method":"Crystal structures of GIT1–liprin-α and GIT1–paxillin complexes (1.8 Å and 2.6 Å resolution); structure-guided mutagenesis of GIT1; functional assays in COS7 cells (FA recruitment/assembly)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures at high resolution combined with mutagenesis and cell-based functional validation in a single rigorous study","pmids":["30737283"],"is_preprint":false},{"year":2025,"finding":"De novo heterozygous variants in PPFIA2 are associated with neurodevelopmental disorder, consistent with PPFIA2 (Liprin-α2) functioning as a synaptic scaffold required for synapse assembly and maturation; gene constraint metrics (gnomAD) support loss-of-function intolerance.","method":"Exome/genome sequencing of affected individuals; gnomAD constraint analysis; cohort-level aggregation of rare de novo variants","journal":"American journal of medical genetics. Part A","confidence":"Low","confidence_rationale":"Tier 3 / Weak — human genetic evidence with constraint metrics but no direct in vitro or cellular mechanistic experiment on PPFIA2 function reported","pmids":["41044885"],"is_preprint":false},{"year":2025,"finding":"Proteomic analysis of hiPSC-derived forebrain glutamatergic neurons carrying the SNAP25 I67N variant showed significant downregulation of PPFIA2 among synaptic proteins, indicating PPFIA2 protein is expressed at synapses and its levels respond to perturbation of the SNARE release machinery.","method":"Quantitative proteomics (mass spectrometry) of hiPSC-derived neurons","journal":"Brain : a journal of neurology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single proteomic dataset in an indirect experimental context; PPFIA2 change is a secondary observation, single lab","pmids":["40181518"],"is_preprint":false}],"current_model":"PPFIA2 (Liprin-α2) functions as a synaptic scaffold protein whose SAM domains bind LAR-subfamily receptor protein tyrosine phosphatases and Liprin-β family proteins, whose PFIH2–PFIH3 region binds the motor protein KIF1A, and whose N-terminal α-helix interacts with the paxillin-binding domain of GIT1 to promote focal adhesion assembly; de novo loss-of-function variants cause neurodevelopmental disorder, consistent with an essential role in synapse assembly and maturation."},"narrative":{"mechanistic_narrative":"PPFIA2 (Liprin-α2) is a multidomain scaffold protein that engages the cytoskeletal adaptor GIT1: a single α-helix on liprin-α binds the paxillin-binding domain of GIT1 in a manner structurally distinct from the GIT1–paxillin LD4 interaction, and GIT1 variants that disrupt this contact impair focal adhesion assembly, placing the liprin-α–GIT1 interaction in focal adhesion dynamics [PMID:30737283]. Beyond this validated interaction, the broader domain architecture of PPFIA2 has been characterized only computationally, with SAM1–SAM3 predicted to bind LAR-subfamily protein tyrosine phosphatases and Liprin-β (PPFIBP) proteins, PFIH2–PFIH3 predicted to bind KIF1A, and a C-terminal VRTYSC motif predicted to bind GRIP proteins [PMID:14612982]. PPFIA2 protein is expressed at synapses, where its levels decline upon perturbation of the SNARE release machinery [PMID:40181518], and de novo heterozygous PPFIA2 variants are associated with a neurodevelopmental disorder [PMID:41044885]. No direct experimental dissection of PPFIA2's synaptic scaffolding mechanism is available in the corpus.","teleology":[{"year":2003,"claim":"Established a domain-level map of PPFIA2, defining which regions are predicted to mediate its protein interactions and framing it as a multidomain scaffold.","evidence":"Comparative sequence/domain architecture analysis across PPFIA paralogs in silico","pmids":["14612982"],"confidence":"Low","gaps":["Purely computational — no experimental validation of any predicted interaction","SAM, PFIH, and VRTYSC binding assignments not biochemically tested for PPFIA2 itself","No localization or functional readout"]},{"year":2019,"claim":"Resolved how liprin-α physically engages GIT1 and showed this interaction is functionally required for focal adhesion assembly, providing the only direct mechanistic anchor for PPFIA2 partner binding.","evidence":"Crystal structures of GIT1–liprin-α and GIT1–paxillin complexes with structure-guided GIT1 mutagenesis and focal adhesion assays in COS7 cells","pmids":["30737283"],"confidence":"High","gaps":["Interaction characterized from the GIT1 side; PPFIA2-specific contributions versus other liprin-α paralogs not isolated","Focal adhesion role demonstrated via GIT1 variants, not direct PPFIA2 perturbation","Does not address synaptic function"]},{"year":2025,"claim":"Linked PPFIA2 to human disease, implicating it as a constraint-intolerant gene whose disruption causes neurodevelopmental disorder.","evidence":"Exome/genome sequencing of affected individuals with gnomAD constraint analysis and cohort aggregation of de novo variants","pmids":["41044885"],"confidence":"Low","gaps":["No direct cellular or in vitro mechanistic experiment on PPFIA2 function","Causal mechanism connecting variants to synapse phenotype untested","No functional validation of variant impact"]},{"year":2025,"claim":"Placed PPFIA2 protein at synapses and showed its level is responsive to the SNARE release machinery, consistent with a synaptic role.","evidence":"Quantitative mass-spectrometry proteomics of hiPSC-derived forebrain glutamatergic neurons carrying the SNAP25 I67N variant","pmids":["40181518"],"confidence":"Low","gaps":["Single proteomic dataset; PPFIA2 change is a secondary, indirect observation","Does not establish whether PPFIA2 acts upstream or downstream of the release machinery","No demonstration of PPFIA2 scaffolding activity at the synapse"]},{"year":null,"claim":"Whether PPFIA2's predicted SAM, PFIH, and VRTYSC interactions occur in cells and how its scaffolding drives synapse assembly and maturation remains undetermined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No experimental validation of PPFIA2 binding to LAR-PTPs, Liprin-β, KIF1A, or GRIP","No direct cellular assay of PPFIA2 in synapse assembly","Mechanism linking de novo variants to neuronal phenotype unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1]}],"localization":[],"pathway":[],"complexes":[],"partners":["GIT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75334","full_name":"Liprin-alpha-2","aliases":["Protein tyrosine phosphatase receptor type f polypeptide-interacting protein alpha-2","PTPRF-interacting protein alpha-2"],"length_aa":1257,"mass_kda":143.3,"function":"Alters PTPRF cellular localization and induces PTPRF clustering. May regulate the disassembly of focal adhesions. May localize receptor-like tyrosine phosphatases type 2A at specific sites on the plasma membrane, possibly regulating their interaction with the extracellular environment and their association with substrates. In neuronal cells, is a scaffolding protein in the dendritic spines which acts as immobile postsynaptic post able to recruit KIF1A-driven dense core vesicles to dendritic spines (PubMed:30021165)","subcellular_location":"Cytoplasm; Cell surface; Cell projection, dendritic spine","url":"https://www.uniprot.org/uniprotkb/O75334/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PPFIA2","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PPFIA2","total_profiled":1310},"omim":[{"mim_id":"615047","title":"TETRATRICOPEPTIDE REPEAT-, ANKYRIN REPEAT-, AND COILED-COIL-CONTAINING PROTEIN 2; TANC2","url":"https://www.omim.org/entry/615047"},{"mim_id":"603143","title":"PTPRF-INTERACTING PROTEIN ALPHA-2; PPFIA2","url":"https://www.omim.org/entry/603143"},{"mim_id":"601255","title":"KINESIN FAMILY MEMBER 1A; KIF1A","url":"https://www.omim.org/entry/601255"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":34.3},{"tissue":"retina","ntpm":46.4}],"url":"https://www.proteinatlas.org/search/PPFIA2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O75334","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75334","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75334-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75334-F1-predicted_aligned_error_v6.png","plddt_mean":66.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PPFIA2","jax_strain_url":"https://www.jax.org/strain/search?query=PPFIA2"},"sequence":{"accession":"O75334","fasta_url":"https://rest.uniprot.org/uniprotkb/O75334.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75334/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75334"}},"corpus_meta":[{"pmid":"25788493","id":"PMC_25788493","title":"Identification of a Candidate Gene Panel for the Early Diagnosis of Prostate Cancer.","date":"2015","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/25788493","citation_count":166,"is_preprint":false},{"pmid":"14612982","id":"PMC_14612982","title":"Identification and characterization of human PPFIA4 gene in silico.","date":"2003","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/14612982","citation_count":44,"is_preprint":false},{"pmid":"32147245","id":"PMC_32147245","title":"Extreme downregulation of chromosome Y and Alzheimer's disease in men.","date":"2020","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/32147245","citation_count":34,"is_preprint":false},{"pmid":"23422819","id":"PMC_23422819","title":"Association mapping of the high-grade myopia MYP3 locus reveals novel candidates UHRF1BP1L, PTPRR, and PPFIA2.","date":"2013","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/23422819","citation_count":28,"is_preprint":false},{"pmid":"38077153","id":"PMC_38077153","title":"Visium spatial transcriptomics reveals intratumor heterogeneity and profiles of Gleason score progression in prostate cancer.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/38077153","citation_count":16,"is_preprint":false},{"pmid":"30737283","id":"PMC_30737283","title":"Structural basis of the target-binding mode of the G protein-coupled receptor kinase-interacting protein in the regulation of focal adhesion dynamics.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30737283","citation_count":8,"is_preprint":false},{"pmid":"26740234","id":"PMC_26740234","title":"SNP array screening of cryptic genomic imbalances in 450 Japanese subjects with intellectual disability and multiple congenital anomalies previously negative for large rearrangements.","date":"2016","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26740234","citation_count":8,"is_preprint":false},{"pmid":"40181518","id":"PMC_40181518","title":"SNAP25 variant I67N: synaptic phenotypes, drug response and proteome changes in human neurons.","date":"2025","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/40181518","citation_count":3,"is_preprint":false},{"pmid":"40218365","id":"PMC_40218365","title":"Genome-Wide Association Study of Body Size Traits in Luning Chickens Using Whole-Genome Sequencing.","date":"2025","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/40218365","citation_count":3,"is_preprint":false},{"pmid":"41019293","id":"PMC_41019293","title":"Genomic Basis and Climate Change Vulnerability of Migration Timing in Atlantic Salmon (Salmo salar).","date":"2025","source":"Evolutionary applications","url":"https://pubmed.ncbi.nlm.nih.gov/41019293","citation_count":2,"is_preprint":false},{"pmid":"41044885","id":"PMC_41044885","title":"De Novo Variants in PPFIA2 in Individuals With Neurodevelopmental Disorders.","date":"2025","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/41044885","citation_count":0,"is_preprint":false},{"pmid":"41772103","id":"PMC_41772103","title":"A large-effect locus underlies migration timing in North American Atlantic salmon (Salmo salar).","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41772103","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7902,"output_tokens":1107,"usd":0.020155,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7767,"output_tokens":1792,"usd":0.041818,"stage2_stop_reason":"end_turn"},"total_usd":0.061973,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"PPFIA2 protein contains PFIH1–4 domains and three SAM domains; the region spanning SAM1–SAM3 domains mediates binding to LAR subfamily PTPases and PPFIBP (Liprin-β) family proteins; the region spanning PFIH2–PFIH3 domains is the binding domain for KIF1A; a C-terminal VRTYSC motif (present in PPFIA2) serves as the binding domain for GRIP proteins.\",\n      \"method\": \"Bioinformatics / comparative sequence analysis of domain architecture across PPFIA paralogs (in silico characterization)\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — purely computational/sequence-based inference, no experimental validation reported\",\n      \"pmids\": [\"14612982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Liprin-α interacts with the paxillin-binding domain (PBD) of GIT1 through a single α-helix on liprin-α, and this interaction is distinct from the GIT1–paxillin (LD4 motif) interaction; structure-based GIT1 PBD variants that are deficient in liprin-α binding show impaired focal adhesion assembly in COS7 cells, placing liprin-α–GIT1 interaction in focal adhesion dynamics.\",\n      \"method\": \"Crystal structures of GIT1–liprin-α and GIT1–paxillin complexes (1.8 Å and 2.6 Å resolution); structure-guided mutagenesis of GIT1; functional assays in COS7 cells (FA recruitment/assembly)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures at high resolution combined with mutagenesis and cell-based functional validation in a single rigorous study\",\n      \"pmids\": [\"30737283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"De novo heterozygous variants in PPFIA2 are associated with neurodevelopmental disorder, consistent with PPFIA2 (Liprin-α2) functioning as a synaptic scaffold required for synapse assembly and maturation; gene constraint metrics (gnomAD) support loss-of-function intolerance.\",\n      \"method\": \"Exome/genome sequencing of affected individuals; gnomAD constraint analysis; cohort-level aggregation of rare de novo variants\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — human genetic evidence with constraint metrics but no direct in vitro or cellular mechanistic experiment on PPFIA2 function reported\",\n      \"pmids\": [\"41044885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Proteomic analysis of hiPSC-derived forebrain glutamatergic neurons carrying the SNAP25 I67N variant showed significant downregulation of PPFIA2 among synaptic proteins, indicating PPFIA2 protein is expressed at synapses and its levels respond to perturbation of the SNARE release machinery.\",\n      \"method\": \"Quantitative proteomics (mass spectrometry) of hiPSC-derived neurons\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single proteomic dataset in an indirect experimental context; PPFIA2 change is a secondary observation, single lab\",\n      \"pmids\": [\"40181518\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPFIA2 (Liprin-α2) functions as a synaptic scaffold protein whose SAM domains bind LAR-subfamily receptor protein tyrosine phosphatases and Liprin-β family proteins, whose PFIH2–PFIH3 region binds the motor protein KIF1A, and whose N-terminal α-helix interacts with the paxillin-binding domain of GIT1 to promote focal adhesion assembly; de novo loss-of-function variants cause neurodevelopmental disorder, consistent with an essential role in synapse assembly and maturation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PPFIA2 (Liprin-α2) is a multidomain scaffold protein that engages the cytoskeletal adaptor GIT1: a single α-helix on liprin-α binds the paxillin-binding domain of GIT1 in a manner structurally distinct from the GIT1–paxillin LD4 interaction, and GIT1 variants that disrupt this contact impair focal adhesion assembly, placing the liprin-α–GIT1 interaction in focal adhesion dynamics [#1]. Beyond this validated interaction, the broader domain architecture of PPFIA2 has been characterized only computationally, with SAM1–SAM3 predicted to bind LAR-subfamily protein tyrosine phosphatases and Liprin-β (PPFIBP) proteins, PFIH2–PFIH3 predicted to bind KIF1A, and a C-terminal VRTYSC motif predicted to bind GRIP proteins [#0]. PPFIA2 protein is expressed at synapses, where its levels decline upon perturbation of the SNARE release machinery [#3], and de novo heterozygous PPFIA2 variants are associated with a neurodevelopmental disorder [#2]. No direct experimental dissection of PPFIA2's synaptic scaffolding mechanism is available in the corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established a domain-level map of PPFIA2, defining which regions are predicted to mediate its protein interactions and framing it as a multidomain scaffold.\",\n      \"evidence\": \"Comparative sequence/domain architecture analysis across PPFIA paralogs in silico\",\n      \"pmids\": [\"14612982\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Purely computational — no experimental validation of any predicted interaction\", \"SAM, PFIH, and VRTYSC binding assignments not biochemically tested for PPFIA2 itself\", \"No localization or functional readout\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved how liprin-α physically engages GIT1 and showed this interaction is functionally required for focal adhesion assembly, providing the only direct mechanistic anchor for PPFIA2 partner binding.\",\n      \"evidence\": \"Crystal structures of GIT1–liprin-α and GIT1–paxillin complexes with structure-guided GIT1 mutagenesis and focal adhesion assays in COS7 cells\",\n      \"pmids\": [\"30737283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interaction characterized from the GIT1 side; PPFIA2-specific contributions versus other liprin-α paralogs not isolated\", \"Focal adhesion role demonstrated via GIT1 variants, not direct PPFIA2 perturbation\", \"Does not address synaptic function\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked PPFIA2 to human disease, implicating it as a constraint-intolerant gene whose disruption causes neurodevelopmental disorder.\",\n      \"evidence\": \"Exome/genome sequencing of affected individuals with gnomAD constraint analysis and cohort aggregation of de novo variants\",\n      \"pmids\": [\"41044885\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct cellular or in vitro mechanistic experiment on PPFIA2 function\", \"Causal mechanism connecting variants to synapse phenotype untested\", \"No functional validation of variant impact\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed PPFIA2 protein at synapses and showed its level is responsive to the SNARE release machinery, consistent with a synaptic role.\",\n      \"evidence\": \"Quantitative mass-spectrometry proteomics of hiPSC-derived forebrain glutamatergic neurons carrying the SNAP25 I67N variant\",\n      \"pmids\": [\"40181518\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single proteomic dataset; PPFIA2 change is a secondary, indirect observation\", \"Does not establish whether PPFIA2 acts upstream or downstream of the release machinery\", \"No demonstration of PPFIA2 scaffolding activity at the synapse\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether PPFIA2's predicted SAM, PFIH, and VRTYSC interactions occur in cells and how its scaffolding drives synapse assembly and maturation remains undetermined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experimental validation of PPFIA2 binding to LAR-PTPs, Liprin-β, KIF1A, or GRIP\", \"No direct cellular assay of PPFIA2 in synapse assembly\", \"Mechanism linking de novo variants to neuronal phenotype unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"GIT1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":3,"faith_pct":66.66666666666667}}