{"gene":"ARMC12","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2021,"finding":"ARMC12 is a mitochondrial peripheral membrane protein that functions as an adherence factor between mitochondria. In testicular germ cells, ARMC12 interacts with mitochondrial proteins MIC60, VDAC2, and VDAC3, as well as TBC1D21 and GK2, to regulate spatiotemporal mitochondrial dynamics during spermiogenesis and mitochondrial sheath formation. TBC1D21 is required for the interaction between ARMC12 and VDAC proteins in vivo.","method":"FLAG-tagged knock-in mice, Armc12-null mice, co-immunoprecipitation, in vivo interaction studies, live cell experiments in cultured cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, multiple genetic KO models with defined cellular phenotype, replicated across multiple protein interactions","pmids":["33536340"],"is_preprint":false},{"year":2021,"finding":"Loss of ARMC12 causes sperm mitochondria to fail elongation at the mitochondrial interlocking step during spermiogenesis, resulting in abnormal mitochondrial coiling along the flagellum, reduced sperm motility, and male sterility in mice.","method":"Armc12-null mouse model, transmission electron microscopy, sperm motility assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular and organismal phenotype, mechanistic step identified","pmids":["33536340"],"is_preprint":false},{"year":2018,"finding":"ARMC12 physically interacts with retinoblastoma binding protein 4 (RBBP4) to facilitate the formation and activity of polycomb repressive complex 2 (PRC2), resulting in transcriptional repression of tumor suppressive genes in neuroblastoma cells.","method":"Co-immunoprecipitation, cell-penetrating inhibitory peptide blocking interaction, gene expression assays, neuroblastoma cell line functional studies","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, mechanistic follow-up with inhibitory peptide and downstream gene expression readout, multiple orthogonal methods","pmids":["30026490"],"is_preprint":false},{"year":2022,"finding":"Biallelic loss-of-function mutations in ARMC12 in humans cause asthenozoospermia with multiple midpiece defects including absent mitochondrial sheath and central pair, scattered or forked axoneme, and incomplete plasma membrane, confirming ARMC12's essential role in mitochondrial sheath integrity in human sperm.","method":"Whole-exome sequencing, Sanger sequencing, transmission electron microscopy, immunofluorescence, CRISPR-Cas9 Armc12-knockout mice","journal":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 2 — human genetic loss-of-function with structural phenotype confirmed in parallel mouse KO model","pmids":["35534203"],"is_preprint":false},{"year":2026,"finding":"ARMC12 acts as a MYC-interacting modulator within liquid condensates in neuroblastoma cells, upregulating nucleoporin-encoding targets (NUP62, NUP93, NUP98) to promote nuclear pore complex biogenesis and facilitate nuclear trafficking of oncogenic effectors, thereby enhancing invasion and metastasis.","method":"Co-immunoprecipitation, mass spectrometry, chromatin immunoprecipitation, dual-luciferase reporter assay, RNA sequencing, gene overexpression and silencing, xenograft models","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in single study, novel mechanism but not yet independently replicated","pmids":["41510169"],"is_preprint":false},{"year":2026,"finding":"A homozygous ARMC12 variant (c.686G>A) causes severe disorganization of mitochondrial sheath structures and loss of axonemal elements in sperm. The localization of mitochondrial proteins COX IV and TOM20 shifts from a dense continuous distribution along the mitochondrial sheath to a discontinuous punctate pattern, without significant downregulation of total protein levels.","method":"Immunofluorescence, Western blotting, scanning electron microscopy, transmission electron microscopy, whole exome sequencing","journal":"Translational andrology and urology","confidence":"Medium","confidence_rationale":"Tier 2-3 — single study with multiple morphological methods, mechanistic detail about protein localization change without functional reconstitution","pmids":["41971121"],"is_preprint":false}],"current_model":"ARMC12 is a mitochondrial peripheral membrane protein that scaffolds mitochondrial adhesion during spermiogenesis by interacting with VDAC2, VDAC3, MIC60, TBC1D21, and GK2 to orchestrate mitochondrial sheath formation in sperm flagella; in neuroblastoma, ARMC12 interacts with RBBP4 to promote PRC2 activity and transcriptional repression of tumor suppressors, and also engages MYC within liquid condensates to drive nuclear pore complex biogenesis via upregulation of NUP62/NUP93/NUP98."},"narrative":{"teleology":[{"year":2018,"claim":"The question of whether ARMC12 participates in epigenetic gene regulation was answered by showing it physically binds RBBP4 to promote PRC2 complex activity and repress tumor suppressor transcription in neuroblastoma, establishing ARMC12 as a chromatin-regulatory cofactor beyond its predicted structural role.","evidence":"Co-immunoprecipitation, cell-penetrating inhibitory peptide, gene expression assays in neuroblastoma cell lines","pmids":["30026490"],"confidence":"High","gaps":["Whether ARMC12–RBBP4 interaction recruits PRC2 to specific genomic loci or acts genome-wide is not resolved","Whether this chromatin role extends to non-cancerous cell types is unknown","Structural basis of the ARMC12–RBBP4 interaction is not determined"]},{"year":2021,"claim":"The long-standing question of how mitochondria adhere and interlock during sperm midpiece formation was addressed by identifying ARMC12 as a mitochondrial peripheral membrane scaffold that bridges mitochondria via interactions with VDAC2, VDAC3, MIC60, TBC1D21, and GK2; Armc12-null mice showed complete failure of mitochondrial elongation and interlocking, causing male sterility.","evidence":"FLAG knock-in and Armc12-null mice, reciprocal co-immunoprecipitation, transmission electron microscopy, sperm motility assays","pmids":["33536340"],"confidence":"High","gaps":["The stoichiometry and architecture of the ARMC12-containing adhesion complex are not defined","Whether ARMC12 directly contacts lipid bilayers or is entirely protein-tethered is unresolved","The signal that triggers ARMC12 recruitment to mitochondria during spermiogenesis is unknown"]},{"year":2022,"claim":"Translation of the mouse findings to human disease was achieved by demonstrating that biallelic ARMC12 loss-of-function mutations cause asthenozoospermia with absent mitochondrial sheath and multiple midpiece defects, confirming ARMC12 as a Mendelian infertility gene.","evidence":"Whole-exome sequencing of infertile men, Sanger validation, TEM of patient sperm, parallel CRISPR Armc12-KO mice","pmids":["35534203"],"confidence":"High","gaps":["Whether partial loss-of-function alleles produce milder phenotypes is not established","Whether ARMC12 mutations affect any tissues besides sperm in humans is unknown"]},{"year":2026,"claim":"The mechanism by which ARMC12 promotes neuroblastoma aggressiveness beyond PRC2 was expanded by showing it interacts with MYC in liquid condensates to transcriptionally upregulate nucleoporins (NUP62, NUP93, NUP98), linking ARMC12 to nuclear pore complex biogenesis and oncogenic nuclear trafficking.","evidence":"Co-IP, mass spectrometry, ChIP, dual-luciferase assays, RNA-seq, xenograft models in neuroblastoma cells","pmids":["41510169"],"confidence":"Medium","gaps":["Independent replication of the ARMC12–MYC condensate interaction is lacking","Whether nucleoporin upregulation is the primary oncogenic output or one of several downstream effects is unresolved","The relationship between the PRC2-promoting and MYC-interacting functions of ARMC12 in the same cell is not clarified"]},{"year":2026,"claim":"Detailed morphological analysis of a patient homozygous ARMC12 missense variant showed that mitochondrial sheath proteins (COX IV, TOM20) redistribute from continuous to punctate patterns without protein-level loss, indicating ARMC12 organizes mitochondrial protein topology rather than stability.","evidence":"Immunofluorescence, Western blot, SEM/TEM, whole-exome sequencing of patient sperm","pmids":["41971121"],"confidence":"Medium","gaps":["Functional reconstitution of the missense variant's effect on inter-mitochondrial adhesion has not been performed","Whether the punctate redistribution reflects a general cristae disorganization or specifically disrupted outer membrane contacts is unclear"]},{"year":null,"claim":"It remains unknown how ARMC12's two distinct cellular roles — mitochondrial scaffolding in germ cells and chromatin/condensate regulation in neuroblastoma — are coordinated, whether tissue-specific splicing or post-translational modifications govern functional switching, and what structural features of the armadillo-repeat domain mediate its diverse protein–protein interactions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of ARMC12 or any of its complexes exists","Tissue-specific regulation of ARMC12 expression and isoform usage is not characterized","Whether ARMC12 has functions outside testis and neuroblastoma contexts is unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,3,5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,4]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1,3,5]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,1,3]}],"complexes":["PRC2 (via RBBP4 bridging)"],"partners":["VDAC2","VDAC3","MIC60","TBC1D21","GK2","RBBP4","MYC"],"other_free_text":[]},"mechanistic_narrative":"ARMC12 is an armadillo-repeat protein that functions as a mitochondrial peripheral membrane scaffold essential for mitochondrial sheath assembly during spermiogenesis and as a chromatin-regulatory cofactor in neuroblastoma. In testicular germ cells, ARMC12 interacts with VDAC2, VDAC3, MIC60, TBC1D21, and GK2 to mediate inter-mitochondrial adhesion and orchestrate mitochondrial elongation, interlocking, and helical coiling along the sperm flagellum; loss of ARMC12 in mice causes failed mitochondrial sheath formation, immotile sperm, and male sterility, and biallelic loss-of-function mutations in humans cause asthenozoospermia with absent mitochondrial sheath and midpiece structural defects [PMID:33536340, PMID:35534203, PMID:41971121]. In neuroblastoma cells, ARMC12 binds RBBP4 to promote PRC2 assembly and H3K27me3-mediated transcriptional repression of tumor suppressor genes, and separately engages MYC within liquid condensates to upregulate nucleoporins NUP62, NUP93, and NUP98, enhancing nuclear pore complex biogenesis and oncogenic nuclear trafficking [PMID:30026490, PMID:41510169]."},"prefetch_data":{"uniprot":{"accession":"Q5T9G4","full_name":"Armadillo repeat-containing protein 12","aliases":[],"length_aa":340,"mass_kda":38.6,"function":"Essential for male fertility and sperm mitochondrial sheath formation (By similarity). Required for proper mitochondrial elongation and coiling along the flagellum during the formation of the mitochondrial sheath (By similarity). Facilitates the growth and aggressiveness of neuroblastoma cells (PubMed:30026490). Increases the EZH2 activity and H3K27me3 levels in a RBBP4-dependent manner, and facilitates the enrichment of polycomb repressive complex 2 and H3K27me3 on gene promoters, resulting in transcriptional repression of tumor suppressors affecting the proliferation, invasion, and metastasis of tumor cells (PubMed:30026490)","subcellular_location":"Nucleus; Mitochondrion outer membrane","url":"https://www.uniprot.org/uniprotkb/Q5T9G4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ARMC12","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ARMC12","total_profiled":1310},"omim":[{"mim_id":"620744","title":"SPERMATOGENIC FAILURE 90; SPGF90","url":"https://www.omim.org/entry/620744"},{"mim_id":"620377","title":"ARMADILLO REPEAT-CONTAINING PROTEIN 12; ARMC12","url":"https://www.omim.org/entry/620377"},{"mim_id":"258150","title":"SPERMATOGENIC FAILURE 1; SPGF1","url":"https://www.omim.org/entry/258150"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"testis","ntpm":58.4}],"url":"https://www.proteinatlas.org/search/ARMC12"},"hgnc":{"alias_symbol":["FLJ25390"],"prev_symbol":["C6orf81"]},"alphafold":{"accession":"Q5T9G4","domains":[{"cath_id":"1.20.58","chopping":"49-145","consensus_level":"medium","plddt":89.349,"start":49,"end":145},{"cath_id":"1.25.40","chopping":"201-319","consensus_level":"medium","plddt":95.8903,"start":201,"end":319}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T9G4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T9G4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T9G4-F1-predicted_aligned_error_v6.png","plddt_mean":85.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ARMC12","jax_strain_url":"https://www.jax.org/strain/search?query=ARMC12"},"sequence":{"accession":"Q5T9G4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5T9G4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5T9G4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T9G4"}},"corpus_meta":[{"pmid":"33536340","id":"PMC_33536340","title":"ARMC12 regulates spatiotemporal mitochondrial dynamics during spermiogenesis and is required for male fertility.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33536340","citation_count":61,"is_preprint":false},{"pmid":"30026490","id":"PMC_30026490","title":"Armadillo repeat containing 12 promotes neuroblastoma progression through interaction with retinoblastoma binding protein 4.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30026490","citation_count":47,"is_preprint":false},{"pmid":"34912852","id":"PMC_34912852","title":"ARMC Subfamily: Structures, Functions, Evolutions, Interactions, and Diseases.","date":"2021","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/34912852","citation_count":25,"is_preprint":false},{"pmid":"35534203","id":"PMC_35534203","title":"Biallelic mutations in ARMC12 cause asthenozoospermia and multiple midpiece defects in humans and mice.","date":"2022","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35534203","citation_count":10,"is_preprint":false},{"pmid":"37274192","id":"PMC_37274192","title":"FKBP5 genetic variants are associated with respiratory- and sleep-related parameters in Chinese patients with obstructive sleep apnea.","date":"2023","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/37274192","citation_count":6,"is_preprint":false},{"pmid":"41971121","id":"PMC_41971121","title":"Homozygous ARMC12 variant causes multiple morphological abnormalities of the sperm flagella.","date":"2026","source":"Translational andrology and urology","url":"https://pubmed.ncbi.nlm.nih.gov/41971121","citation_count":0,"is_preprint":false},{"pmid":"41510169","id":"PMC_41510169","title":"Dual targeting of AMRC12 and Malassezia globosa disrupts MYC liquid condensates-driven nuclear pore complex biogenesis in neuroblastoma.","date":"2026","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/41510169","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5396,"output_tokens":1530,"usd":0.019569},"stage2":{"model":"claude-opus-4-6","input_tokens":4765,"output_tokens":2064,"usd":0.113138},"total_usd":0.132707,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"ARMC12 is a mitochondrial peripheral membrane protein that functions as an adherence factor between mitochondria. In testicular germ cells, ARMC12 interacts with mitochondrial proteins MIC60, VDAC2, and VDAC3, as well as TBC1D21 and GK2, to regulate spatiotemporal mitochondrial dynamics during spermiogenesis and mitochondrial sheath formation. TBC1D21 is required for the interaction between ARMC12 and VDAC proteins in vivo.\",\n      \"method\": \"FLAG-tagged knock-in mice, Armc12-null mice, co-immunoprecipitation, in vivo interaction studies, live cell experiments in cultured cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, multiple genetic KO models with defined cellular phenotype, replicated across multiple protein interactions\",\n      \"pmids\": [\"33536340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of ARMC12 causes sperm mitochondria to fail elongation at the mitochondrial interlocking step during spermiogenesis, resulting in abnormal mitochondrial coiling along the flagellum, reduced sperm motility, and male sterility in mice.\",\n      \"method\": \"Armc12-null mouse model, transmission electron microscopy, sperm motility assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular and organismal phenotype, mechanistic step identified\",\n      \"pmids\": [\"33536340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ARMC12 physically interacts with retinoblastoma binding protein 4 (RBBP4) to facilitate the formation and activity of polycomb repressive complex 2 (PRC2), resulting in transcriptional repression of tumor suppressive genes in neuroblastoma cells.\",\n      \"method\": \"Co-immunoprecipitation, cell-penetrating inhibitory peptide blocking interaction, gene expression assays, neuroblastoma cell line functional studies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, mechanistic follow-up with inhibitory peptide and downstream gene expression readout, multiple orthogonal methods\",\n      \"pmids\": [\"30026490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Biallelic loss-of-function mutations in ARMC12 in humans cause asthenozoospermia with multiple midpiece defects including absent mitochondrial sheath and central pair, scattered or forked axoneme, and incomplete plasma membrane, confirming ARMC12's essential role in mitochondrial sheath integrity in human sperm.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing, transmission electron microscopy, immunofluorescence, CRISPR-Cas9 Armc12-knockout mice\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human genetic loss-of-function with structural phenotype confirmed in parallel mouse KO model\",\n      \"pmids\": [\"35534203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ARMC12 acts as a MYC-interacting modulator within liquid condensates in neuroblastoma cells, upregulating nucleoporin-encoding targets (NUP62, NUP93, NUP98) to promote nuclear pore complex biogenesis and facilitate nuclear trafficking of oncogenic effectors, thereby enhancing invasion and metastasis.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, chromatin immunoprecipitation, dual-luciferase reporter assay, RNA sequencing, gene overexpression and silencing, xenograft models\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in single study, novel mechanism but not yet independently replicated\",\n      \"pmids\": [\"41510169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"A homozygous ARMC12 variant (c.686G>A) causes severe disorganization of mitochondrial sheath structures and loss of axonemal elements in sperm. The localization of mitochondrial proteins COX IV and TOM20 shifts from a dense continuous distribution along the mitochondrial sheath to a discontinuous punctate pattern, without significant downregulation of total protein levels.\",\n      \"method\": \"Immunofluorescence, Western blotting, scanning electron microscopy, transmission electron microscopy, whole exome sequencing\",\n      \"journal\": \"Translational andrology and urology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — single study with multiple morphological methods, mechanistic detail about protein localization change without functional reconstitution\",\n      \"pmids\": [\"41971121\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARMC12 is a mitochondrial peripheral membrane protein that scaffolds mitochondrial adhesion during spermiogenesis by interacting with VDAC2, VDAC3, MIC60, TBC1D21, and GK2 to orchestrate mitochondrial sheath formation in sperm flagella; in neuroblastoma, ARMC12 interacts with RBBP4 to promote PRC2 activity and transcriptional repression of tumor suppressors, and also engages MYC within liquid condensates to drive nuclear pore complex biogenesis via upregulation of NUP62/NUP93/NUP98.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ARMC12 is an armadillo-repeat protein that functions as a mitochondrial peripheral membrane scaffold essential for mitochondrial sheath assembly during spermiogenesis and as a chromatin-regulatory cofactor in neuroblastoma. In testicular germ cells, ARMC12 interacts with VDAC2, VDAC3, MIC60, TBC1D21, and GK2 to mediate inter-mitochondrial adhesion and orchestrate mitochondrial elongation, interlocking, and helical coiling along the sperm flagellum; loss of ARMC12 in mice causes failed mitochondrial sheath formation, immotile sperm, and male sterility, and biallelic loss-of-function mutations in humans cause asthenozoospermia with absent mitochondrial sheath and midpiece structural defects [PMID:33536340, PMID:35534203, PMID:41971121]. In neuroblastoma cells, ARMC12 binds RBBP4 to promote PRC2 assembly and H3K27me3-mediated transcriptional repression of tumor suppressor genes, and separately engages MYC within liquid condensates to upregulate nucleoporins NUP62, NUP93, and NUP98, enhancing nuclear pore complex biogenesis and oncogenic nuclear trafficking [PMID:30026490, PMID:41510169].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"The question of whether ARMC12 participates in epigenetic gene regulation was answered by showing it physically binds RBBP4 to promote PRC2 complex activity and repress tumor suppressor transcription in neuroblastoma, establishing ARMC12 as a chromatin-regulatory cofactor beyond its predicted structural role.\",\n      \"evidence\": \"Co-immunoprecipitation, cell-penetrating inhibitory peptide, gene expression assays in neuroblastoma cell lines\",\n      \"pmids\": [\"30026490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ARMC12–RBBP4 interaction recruits PRC2 to specific genomic loci or acts genome-wide is not resolved\",\n        \"Whether this chromatin role extends to non-cancerous cell types is unknown\",\n        \"Structural basis of the ARMC12–RBBP4 interaction is not determined\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The long-standing question of how mitochondria adhere and interlock during sperm midpiece formation was addressed by identifying ARMC12 as a mitochondrial peripheral membrane scaffold that bridges mitochondria via interactions with VDAC2, VDAC3, MIC60, TBC1D21, and GK2; Armc12-null mice showed complete failure of mitochondrial elongation and interlocking, causing male sterility.\",\n      \"evidence\": \"FLAG knock-in and Armc12-null mice, reciprocal co-immunoprecipitation, transmission electron microscopy, sperm motility assays\",\n      \"pmids\": [\"33536340\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The stoichiometry and architecture of the ARMC12-containing adhesion complex are not defined\",\n        \"Whether ARMC12 directly contacts lipid bilayers or is entirely protein-tethered is unresolved\",\n        \"The signal that triggers ARMC12 recruitment to mitochondria during spermiogenesis is unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Translation of the mouse findings to human disease was achieved by demonstrating that biallelic ARMC12 loss-of-function mutations cause asthenozoospermia with absent mitochondrial sheath and multiple midpiece defects, confirming ARMC12 as a Mendelian infertility gene.\",\n      \"evidence\": \"Whole-exome sequencing of infertile men, Sanger validation, TEM of patient sperm, parallel CRISPR Armc12-KO mice\",\n      \"pmids\": [\"35534203\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether partial loss-of-function alleles produce milder phenotypes is not established\",\n        \"Whether ARMC12 mutations affect any tissues besides sperm in humans is unknown\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"The mechanism by which ARMC12 promotes neuroblastoma aggressiveness beyond PRC2 was expanded by showing it interacts with MYC in liquid condensates to transcriptionally upregulate nucleoporins (NUP62, NUP93, NUP98), linking ARMC12 to nuclear pore complex biogenesis and oncogenic nuclear trafficking.\",\n      \"evidence\": \"Co-IP, mass spectrometry, ChIP, dual-luciferase assays, RNA-seq, xenograft models in neuroblastoma cells\",\n      \"pmids\": [\"41510169\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Independent replication of the ARMC12–MYC condensate interaction is lacking\",\n        \"Whether nucleoporin upregulation is the primary oncogenic output or one of several downstream effects is unresolved\",\n        \"The relationship between the PRC2-promoting and MYC-interacting functions of ARMC12 in the same cell is not clarified\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Detailed morphological analysis of a patient homozygous ARMC12 missense variant showed that mitochondrial sheath proteins (COX IV, TOM20) redistribute from continuous to punctate patterns without protein-level loss, indicating ARMC12 organizes mitochondrial protein topology rather than stability.\",\n      \"evidence\": \"Immunofluorescence, Western blot, SEM/TEM, whole-exome sequencing of patient sperm\",\n      \"pmids\": [\"41971121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional reconstitution of the missense variant's effect on inter-mitochondrial adhesion has not been performed\",\n        \"Whether the punctate redistribution reflects a general cristae disorganization or specifically disrupted outer membrane contacts is unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how ARMC12's two distinct cellular roles — mitochondrial scaffolding in germ cells and chromatin/condensate regulation in neuroblastoma — are coordinated, whether tissue-specific splicing or post-translational modifications govern functional switching, and what structural features of the armadillo-repeat domain mediate its diverse protein–protein interactions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of ARMC12 or any of its complexes exists\",\n        \"Tissue-specific regulation of ARMC12 expression and isoform usage is not characterized\",\n        \"Whether ARMC12 has functions outside testis and neuroblastoma contexts is unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 3, 5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1, 3, 5]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"complexes\": [\n      \"PRC2 (via RBBP4 bridging)\"\n    ],\n    \"partners\": [\n      \"VDAC2\",\n      \"VDAC3\",\n      \"MIC60\",\n      \"TBC1D21\",\n      \"GK2\",\n      \"RBBP4\",\n      \"MYC\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}