{"gene":"TMEM167A","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2009,"finding":"Kish (TMEM167A ortholog in Drosophila) is a small membrane protein required for the secretory pathway; RNAi knockdown in Drosophila S2 cells blocks secretion of recombinant luciferase, establishing it as a novel component of the metazoan secretory pathway absent from S. cerevisiae.","method":"Genome-wide RNAi screen in Drosophila S2 cells measuring secretion of recombinant luciferase","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide functional screen with defined secretion readout, replicated across multiple hits; foundational identification paper with clear loss-of-function phenotype","pmids":["19942856"],"is_preprint":false},{"year":2015,"finding":"Kish (TMEM167A) functions cell-autonomously in the JNK signaling-dependent active secretion of Tyrosyl-tRNA synthetase (TyrRS) by loser cells during Drosophila cell competition; kish is required for the secretory pathway step that releases TyrRS to attract haemocytes.","method":"Drosophila genetic knockdown (RNAi) of kish in loser cells, combined with haemocyte recruitment assays and JNK pathway epistasis in vivo","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with specific secretion and cell-competition phenotype, single lab, pathway placement via epistasis with JNK","pmids":["26658841"],"is_preprint":false},{"year":2018,"finding":"kish/TMEM167A is required for vesicular trafficking in glioma cells; its downregulation increases recycling endosomes, decreases lysosomes, and reroutes EGFR from recycling endosomes toward proteasomal degradation, thereby impairing glioma growth without affecting normal glia.","method":"RNAi knockdown in Drosophila glioma model and human glioma cells; fluorescence microscopy of endosomal compartments; EGFR localization and degradation assays; cell growth assays","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined endosomal and EGFR trafficking phenotype, orthogonal methods (imaging + biochemistry), single lab","pmids":["30506943"],"is_preprint":false},{"year":2020,"finding":"TMEM167A regulates EGFR vesicular trafficking and signaling in wild-type p53 gliomas; TMEM167A knockdown reduces acidification of intracellular vesicles, impairs autophagy, and alters EGFR trafficking/signaling, an effect phenocopied by vacuolar ATPase inhibition.","method":"TMEM167A siRNA knockdown in wild-type p53 glioma cells; assessment of intracellular vesicle acidification, autophagy markers, EGFR trafficking and signaling; pharmacological comparison with V-ATPase inhibitor; subcutaneous and intracranial tumor growth assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple orthogonal readouts (vesicle pH, autophagy, EGFR signaling), pharmacological epistasis, single lab","pmids":["31947645"],"is_preprint":false},{"year":2023,"finding":"IER3IP1 forms a protein complex with TMEM167A (Golgi transmembrane protein 167A) in B cells, and this complex limits activation of the unfolded protein response mediated by IRE1α and XBP1.","method":"Forward genetic screen in mice (ENU mutagenesis); co-immunoprecipitation / complex formation assay; UPR pathway activation measurement (IRE1α/XBP1) in B cells from hypomorphic Ier3ip1 mice","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal complex identification with defined UPR phenotype in primary cells, single lab, genetic and biochemical orthogonal approaches","pmids":["37934820"],"is_preprint":false},{"year":2025,"finding":"TMEM167A is required for proinsulin trafficking from the ER to the Golgi in pancreatic β cells; biallelic loss-of-function variants (including p.Val59Glu) sensitize β cells to ER stress, impair proinsulin trafficking to the Golgi, and cause β cell dysfunction, establishing TMEM167A as an ER-to-Golgi pathway component essential in β cells and neurons.","method":"TMEM167A siRNA silencing in EndoC-βH1 cells; CRISPR knock-in of p.Val59Glu in iPSCs differentiated to β cells; proinsulin trafficking assays; ER stress assays; functional β cell assays; genome sequencing of MEDS patients","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — patient variant knock-in plus independent cell-line knockdown, multiple orthogonal functional assays (trafficking, ER stress, β cell function), mechanistically dissects ER-to-Golgi role","pmids":["40924476"],"is_preprint":false}],"current_model":"TMEM167A (Kish) is a conserved small membrane protein that functions as an essential component of the ER-to-Golgi secretory and vesicular trafficking pathway: it is required for anterograde cargo trafficking (including proinsulin) from the ER to the Golgi, regulates endosomal recycling versus lysosomal/proteasomal routing of EGFR, participates in JNK-dependent unconventional secretion, forms a complex with IER3IP1 to suppress IRE1α/XBP1-mediated ER stress, and its loss sensitizes β cells and neurons to ER stress, causing a neonatal diabetes–microcephaly–epilepsy syndrome."},"narrative":{"mechanistic_narrative":"TMEM167A (Kish) is a small, conserved membrane protein that functions as an essential component of the early secretory pathway, required for anterograde cargo transport from the ER to the Golgi [PMID:19942856, PMID:40924476]. It was first identified in a genome-wide screen as a metazoan-specific secretory factor whose loss blocks regulated protein secretion [PMID:19942856], and it acts cell-autonomously in JNK-dependent unconventional secretion, including the release of Tyrosyl-tRNA synthetase during Drosophila cell competition [PMID:26658841]. Beyond bulk secretion, TMEM167A governs downstream vesicular trafficking: its loss expands recycling endosomes, depletes lysosomes, impairs intracellular vesicle acidification and autophagy, and reroutes EGFR from recycling toward proteasomal degradation, thereby restraining glioma growth [PMID:30506943, PMID:31947645]. TMEM167A forms a complex with IER3IP1 that limits IRE1α/XBP1-mediated unfolded protein response activation [PMID:37934820]. In pancreatic β cells, TMEM167A is required for proinsulin trafficking from the ER to the Golgi, and biallelic loss-of-function variants (including p.Val59Glu) sensitize β cells to ER stress and cause β cell dysfunction, establishing a causal link to a neonatal-diabetes–microcephaly–epilepsy (MEDS) syndrome [PMID:40924476].","teleology":[{"year":2009,"claim":"Established that TMEM167A/Kish is a bona fide component of the metazoan secretory pathway, defining its core cellular role for the first time.","evidence":"Genome-wide RNAi screen in Drosophila S2 cells with a secreted-luciferase readout","pmids":["19942856"],"confidence":"High","gaps":["Did not define the molecular step (ER exit, ER-to-Golgi, or later) at which Kish acts","No interacting partners or biochemical mechanism identified","No mammalian validation in the founding study"]},{"year":2015,"claim":"Placed TMEM167A in JNK-dependent unconventional secretion, extending its role beyond constitutive secretion to signal-driven cargo release in vivo.","evidence":"Drosophila kish RNAi in loser cells with haemocyte-recruitment assays and JNK epistasis","pmids":["26658841"],"confidence":"Medium","gaps":["Mechanism by which kish couples to JNK signaling not resolved","Whether the same secretory machinery operates in mammalian cells untested","Single laboratory"]},{"year":2018,"claim":"Showed TMEM167A controls endosomal compartment balance and EGFR fate, linking the secretory factor to receptor trafficking and tumor growth.","evidence":"RNAi knockdown in Drosophila and human glioma cells with endosomal/lysosomal imaging and EGFR localization/degradation assays","pmids":["30506943"],"confidence":"Medium","gaps":["Direct molecular mechanism linking TMEM167A loss to recycling-vs-degradation switch unknown","No reconstitution of TMEM167A activity on EGFR","Single laboratory"]},{"year":2020,"claim":"Connected TMEM167A loss to defective vesicle acidification and autophagy, implicating V-ATPase-dependent compartment function in its EGFR-trafficking role.","evidence":"siRNA knockdown in wild-type p53 glioma cells with vesicle-pH, autophagy and EGFR readouts, plus V-ATPase inhibitor phenocopy and tumor growth assays","pmids":["31947645"],"confidence":"Medium","gaps":["Whether TMEM167A acts directly on V-ATPase or upstream of vesicle maturation unclear","p53 context-dependence not mechanistically explained","Single laboratory"]},{"year":2023,"claim":"Identified a physical TMEM167A–IER3IP1 complex that restrains IRE1α/XBP1 UPR signaling, giving TMEM167A a defined partner and a role in ER stress homeostasis.","evidence":"ENU forward genetic screen in mice plus co-immunoprecipitation and IRE1α/XBP1 UPR readouts in primary B cells","pmids":["37934820"],"confidence":"Medium","gaps":["Stoichiometry and structure of the TMEM167A–IER3IP1 complex unknown","How the complex mechanistically dampens IRE1α activation not resolved","Single laboratory"]},{"year":2025,"claim":"Established TMEM167A as essential for proinsulin ER-to-Golgi trafficking and as a causative gene for a neonatal-diabetes–microcephaly–epilepsy syndrome via biallelic loss-of-function variants.","evidence":"siRNA in EndoC-βH1 cells, CRISPR knock-in of p.Val59Glu in iPSC-derived β cells, trafficking and ER-stress assays, and genome sequencing of MEDS patients","pmids":["40924476"],"confidence":"High","gaps":["Molecular function of TMEM167A in the ER-exit/Golgi-entry step not defined at the protein level","Mechanism of neuronal vulnerability underlying microcephaly/epilepsy not dissected","Whether the IER3IP1 complex mediates the proinsulin trafficking role untested"]},{"year":null,"claim":"The biochemical activity of TMEM167A within ER-to-Golgi transport — its direct molecular function, cargo-recognition or vesicle-budding role, and structural basis of the IER3IP1 interaction — remains undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No enzymatic or transport activity assigned","No structural model of TMEM167A or its complexes","Mechanism coupling secretory function to ER-stress suppression unresolved"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[4]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[5]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[4]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3]}],"complexes":[],"partners":["IER3IP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TBQ9","full_name":"Protein kish-A","aliases":["Transmembrane protein 167","Transmembrane protein 167A"],"length_aa":72,"mass_kda":8.1,"function":"Involved in the early part of the secretory pathway","subcellular_location":"Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/Q8TBQ9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM167A","classification":"Not Classified","n_dependent_lines":325,"n_total_lines":1208,"dependency_fraction":0.26903973509933776},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TMEM167A","total_profiled":1310},"omim":[{"mim_id":"620000","title":"TRANSMEMBRANE PROTEIN 167A; TMEM167A","url":"https://www.omim.org/entry/620000"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMEM167A"},"hgnc":{"alias_symbol":["FLJ30508","MGC23909","kish"],"prev_symbol":["TMEM167"]},"alphafold":{"accession":"Q8TBQ9","domains":[{"cath_id":"1.20.5","chopping":"6-70","consensus_level":"high","plddt":69.2917,"start":6,"end":70}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TBQ9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TBQ9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TBQ9-F1-predicted_aligned_error_v6.png","plddt_mean":66.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM167A","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM167A"},"sequence":{"accession":"Q8TBQ9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TBQ9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TBQ9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TBQ9"}},"corpus_meta":[{"pmid":"19942856","id":"PMC_19942856","title":"A 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RNAi knockdown in Drosophila S2 cells blocks secretion of recombinant luciferase, establishing it as a novel component of the metazoan secretory pathway absent from S. cerevisiae.\",\n      \"method\": \"Genome-wide RNAi screen in Drosophila S2 cells measuring secretion of recombinant luciferase\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide functional screen with defined secretion readout, replicated across multiple hits; foundational identification paper with clear loss-of-function phenotype\",\n      \"pmids\": [\"19942856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Kish (TMEM167A) functions cell-autonomously in the JNK signaling-dependent active secretion of Tyrosyl-tRNA synthetase (TyrRS) by loser cells during Drosophila cell competition; kish is required for the secretory pathway step that releases TyrRS to attract haemocytes.\",\n      \"method\": \"Drosophila genetic knockdown (RNAi) of kish in loser cells, combined with haemocyte recruitment assays and JNK pathway epistasis in vivo\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with specific secretion and cell-competition phenotype, single lab, pathway placement via epistasis with JNK\",\n      \"pmids\": [\"26658841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"kish/TMEM167A is required for vesicular trafficking in glioma cells; its downregulation increases recycling endosomes, decreases lysosomes, and reroutes EGFR from recycling endosomes toward proteasomal degradation, thereby impairing glioma growth without affecting normal glia.\",\n      \"method\": \"RNAi knockdown in Drosophila glioma model and human glioma cells; fluorescence microscopy of endosomal compartments; EGFR localization and degradation assays; cell growth assays\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined endosomal and EGFR trafficking phenotype, orthogonal methods (imaging + biochemistry), single lab\",\n      \"pmids\": [\"30506943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TMEM167A regulates EGFR vesicular trafficking and signaling in wild-type p53 gliomas; TMEM167A knockdown reduces acidification of intracellular vesicles, impairs autophagy, and alters EGFR trafficking/signaling, an effect phenocopied by vacuolar ATPase inhibition.\",\n      \"method\": \"TMEM167A siRNA knockdown in wild-type p53 glioma cells; assessment of intracellular vesicle acidification, autophagy markers, EGFR trafficking and signaling; pharmacological comparison with V-ATPase inhibitor; subcutaneous and intracranial tumor growth assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple orthogonal readouts (vesicle pH, autophagy, EGFR signaling), pharmacological epistasis, single lab\",\n      \"pmids\": [\"31947645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IER3IP1 forms a protein complex with TMEM167A (Golgi transmembrane protein 167A) in B cells, and this complex limits activation of the unfolded protein response mediated by IRE1α and XBP1.\",\n      \"method\": \"Forward genetic screen in mice (ENU mutagenesis); co-immunoprecipitation / complex formation assay; UPR pathway activation measurement (IRE1α/XBP1) in B cells from hypomorphic Ier3ip1 mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal complex identification with defined UPR phenotype in primary cells, single lab, genetic and biochemical orthogonal approaches\",\n      \"pmids\": [\"37934820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TMEM167A is required for proinsulin trafficking from the ER to the Golgi in pancreatic β cells; biallelic loss-of-function variants (including p.Val59Glu) sensitize β cells to ER stress, impair proinsulin trafficking to the Golgi, and cause β cell dysfunction, establishing TMEM167A as an ER-to-Golgi pathway component essential in β cells and neurons.\",\n      \"method\": \"TMEM167A siRNA silencing in EndoC-βH1 cells; CRISPR knock-in of p.Val59Glu in iPSCs differentiated to β cells; proinsulin trafficking assays; ER stress assays; functional β cell assays; genome sequencing of MEDS patients\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — patient variant knock-in plus independent cell-line knockdown, multiple orthogonal functional assays (trafficking, ER stress, β cell function), mechanistically dissects ER-to-Golgi role\",\n      \"pmids\": [\"40924476\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM167A (Kish) is a conserved small membrane protein that functions as an essential component of the ER-to-Golgi secretory and vesicular trafficking pathway: it is required for anterograde cargo trafficking (including proinsulin) from the ER to the Golgi, regulates endosomal recycling versus lysosomal/proteasomal routing of EGFR, participates in JNK-dependent unconventional secretion, forms a complex with IER3IP1 to suppress IRE1α/XBP1-mediated ER stress, and its loss sensitizes β cells and neurons to ER stress, causing a neonatal diabetes–microcephaly–epilepsy syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM167A (Kish) is a small, conserved membrane protein that functions as an essential component of the early secretory pathway, required for anterograde cargo transport from the ER to the Golgi [#0, #5]. It was first identified in a genome-wide screen as a metazoan-specific secretory factor whose loss blocks regulated protein secretion [#0], and it acts cell-autonomously in JNK-dependent unconventional secretion, including the release of Tyrosyl-tRNA synthetase during Drosophila cell competition [#1]. Beyond bulk secretion, TMEM167A governs downstream vesicular trafficking: its loss expands recycling endosomes, depletes lysosomes, impairs intracellular vesicle acidification and autophagy, and reroutes EGFR from recycling toward proteasomal degradation, thereby restraining glioma growth [#2, #3]. TMEM167A forms a complex with IER3IP1 that limits IRE1\\u03b1/XBP1-mediated unfolded protein response activation [#4]. In pancreatic \\u03b2 cells, TMEM167A is required for proinsulin trafficking from the ER to the Golgi, and biallelic loss-of-function variants (including p.Val59Glu) sensitize \\u03b2 cells to ER stress and cause \\u03b2 cell dysfunction, establishing a causal link to a neonatal-diabetes\\u2013microcephaly\\u2013epilepsy (MEDS) syndrome [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that TMEM167A/Kish is a bona fide component of the metazoan secretory pathway, defining its core cellular role for the first time.\",\n      \"evidence\": \"Genome-wide RNAi screen in Drosophila S2 cells with a secreted-luciferase readout\",\n      \"pmids\": [\"19942856\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not define the molecular step (ER exit, ER-to-Golgi, or later) at which Kish acts\",\n        \"No interacting partners or biochemical mechanism identified\",\n        \"No mammalian validation in the founding study\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed TMEM167A in JNK-dependent unconventional secretion, extending its role beyond constitutive secretion to signal-driven cargo release in vivo.\",\n      \"evidence\": \"Drosophila kish RNAi in loser cells with haemocyte-recruitment assays and JNK epistasis\",\n      \"pmids\": [\"26658841\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which kish couples to JNK signaling not resolved\",\n        \"Whether the same secretory machinery operates in mammalian cells untested\",\n        \"Single laboratory\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed TMEM167A controls endosomal compartment balance and EGFR fate, linking the secretory factor to receptor trafficking and tumor growth.\",\n      \"evidence\": \"RNAi knockdown in Drosophila and human glioma cells with endosomal/lysosomal imaging and EGFR localization/degradation assays\",\n      \"pmids\": [\"30506943\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct molecular mechanism linking TMEM167A loss to recycling-vs-degradation switch unknown\",\n        \"No reconstitution of TMEM167A activity on EGFR\",\n        \"Single laboratory\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected TMEM167A loss to defective vesicle acidification and autophagy, implicating V-ATPase-dependent compartment function in its EGFR-trafficking role.\",\n      \"evidence\": \"siRNA knockdown in wild-type p53 glioma cells with vesicle-pH, autophagy and EGFR readouts, plus V-ATPase inhibitor phenocopy and tumor growth assays\",\n      \"pmids\": [\"31947645\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether TMEM167A acts directly on V-ATPase or upstream of vesicle maturation unclear\",\n        \"p53 context-dependence not mechanistically explained\",\n        \"Single laboratory\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a physical TMEM167A\\u2013IER3IP1 complex that restrains IRE1\\u03b1/XBP1 UPR signaling, giving TMEM167A a defined partner and a role in ER stress homeostasis.\",\n      \"evidence\": \"ENU forward genetic screen in mice plus co-immunoprecipitation and IRE1\\u03b1/XBP1 UPR readouts in primary B cells\",\n      \"pmids\": [\"37934820\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Stoichiometry and structure of the TMEM167A\\u2013IER3IP1 complex unknown\",\n        \"How the complex mechanistically dampens IRE1\\u03b1 activation not resolved\",\n        \"Single laboratory\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established TMEM167A as essential for proinsulin ER-to-Golgi trafficking and as a causative gene for a neonatal-diabetes\\u2013microcephaly\\u2013epilepsy syndrome via biallelic loss-of-function variants.\",\n      \"evidence\": \"siRNA in EndoC-\\u03b2H1 cells, CRISPR knock-in of p.Val59Glu in iPSC-derived \\u03b2 cells, trafficking and ER-stress assays, and genome sequencing of MEDS patients\",\n      \"pmids\": [\"40924476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular function of TMEM167A in the ER-exit/Golgi-entry step not defined at the protein level\",\n        \"Mechanism of neuronal vulnerability underlying microcephaly/epilepsy not dissected\",\n        \"Whether the IER3IP1 complex mediates the proinsulin trafficking role untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical activity of TMEM167A within ER-to-Golgi transport \\u2014 its direct molecular function, cargo-recognition or vesicle-budding role, and structural basis of the IER3IP1 interaction \\u2014 remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No enzymatic or transport activity assigned\",\n        \"No structural model of TMEM167A or its complexes\",\n        \"Mechanism coupling secretory function to ER-stress suppression unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IER3IP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}