{"gene":"KRT2","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2003,"finding":"Mutations in the highly conserved alpha-helical rod domain (1A and 2B subdomain) of the type II keratin mK6irs1/Krt2-6g gene cause wavy coat phenotype in mice; a deletion hotspot (N140del) and amino acid substitutions (A431D, L424W) in this domain disrupt hair formation, identifying this keratin's rod domain as essential for normal hair shaft structure.","method":"Positional cloning, sequencing of multiple independent mutant alleles, genotype-phenotype correlation","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — positional cloning with multiple independent alleles converging on same hotspot; single lab but strong genetic convergence","pmids":["14573483"],"is_preprint":false},{"year":2006,"finding":"Missense mutations in the helix initiation motif (1A subdomain) of Krt71 (formerly Krt2-6g) at residues 143 and 146 cause formation of filamentous aggregates in the inner root sheath (Henle's and Huxley's layers) of the hair follicle, leading to bending of the hair shaft; this demonstrates that the helix initiation motif of this keratin is required for linear intermediate filament formation in the inner root sheath.","method":"ENU mutagenesis screen, mutation mapping, morphological analysis of hair follicle intermediate filaments","journal":"Mammalian genome : official journal of the International Mammalian Genome Society","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent ENU alleles with identical morphological phenotype and localized aggregate formation; single lab","pmids":["17143583"],"is_preprint":false},{"year":2016,"finding":"Mutations in KRT2 cause superficial epidermolytic ichthyosis, establishing that KRT2 encodes a keratin required for the structural integrity of the superficial epidermis; specific dominant mutations lead to epidermolytic hyperkeratosis pathology.","method":"Clinical genetic sequencing, genotype-phenotype correlation across 26 families","journal":"Acta dermato-venereologica","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — multiple independent families with dominant KRT2 mutations and consistent superficial epidermal phenotype; well-replicated across labs","pmids":["26581228"],"is_preprint":false},{"year":2020,"finding":"A somatic missense mutation (p.Asn186Asp) in KRT2, detected in lesional skin DNA at 25% allelic frequency and at very low frequency in blood, is sufficient to cause epidermolytic nevus, demonstrating that a dominant KRT2 mutation acting at the mosaic level disrupts epidermal keratin intermediate filament function in a tissue-restricted manner.","method":"Molecular genetic testing of lesional skin DNA vs. blood DNA; allele frequency quantification","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — somatic mutation detected by direct sequencing with allele frequency quantification; single lab, single case but orthogonal tissue comparison","pmids":["33081034"],"is_preprint":false},{"year":2022,"finding":"A recurrent hotspot mutation p.Glu487Lys in KRT2 causes superficial epidermolytic ichthyosis, identifying residue E487 in the keratin 2 protein as functionally critical; deep phenotyping of 34 reported cases with this mutation shows variable expressivity including variable erythroderma.","method":"Clinical molecular genetics, aggregation of reported cases with identical KRT2 mutation","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — clinical case series with mutation identification; no in vitro or structural validation of mechanism","pmids":["35887135"],"is_preprint":false}],"current_model":"KRT2 encodes a type II keratin whose conserved alpha-helical rod domain (including the helix initiation motif) is required for proper intermediate filament assembly in suprabasal epidermis and the inner root sheath of hair follicles; dominant mutations in this domain—whether germline or somatic—disrupt filament organization, causing epidermolytic pathology (superficial epidermolytic ichthyosis or epidermolytic nevus), while recurrent hotspot mutations at specific residues (e.g., E487K, N140) identify positions critical for keratin function."},"narrative":{"mechanistic_narrative":"KRT2 encodes a type II keratin required for the structural integrity of the suprabasal, superficial epidermis, where it assembles into intermediate filaments [PMID:26581228]. Dominant mutations in KRT2 cause superficial epidermolytic ichthyosis with epidermolytic hyperkeratosis pathology, and a recurrent hotspot substitution at residue E487 marks a position critical for keratin function [PMID:26581228, PMID:35887135]. The same disruption can arise somatically: a mosaic p.Asn186Asp mutation confined to lesional skin produces epidermolytic nevus, showing that a single dominant KRT2 allele compromises epidermal filament function in a tissue-restricted manner [PMID:33081034]. Work on the related murine type II keratin Krt71 establishes the rod domain and its helix initiation motif as essential for linear intermediate filament assembly, where missense mutations generate filamentous aggregates and structural failure of the tissue [PMID:14573483, PMID:17143583]. Beyond these genotype-phenotype correlations, no biochemical or structural characterization of KRT2 filament assembly is present in the available corpus.","teleology":[{"year":2003,"claim":"Established that the conserved alpha-helical rod domain of a type II keratin is functionally essential, by linking rod-domain mutations to a structural tissue phenotype.","evidence":"Positional cloning and sequencing of multiple independent mutant alleles in mouse (Krt2-6g/mK6irs1), genotype-phenotype correlation of wavy coat","pmids":["14573483"],"confidence":"Medium","gaps":["Findings are in mouse Krt71, not human KRT2","No biochemical reconstitution of filament assembly defect","Hotspot residues defined genetically, not structurally"]},{"year":2006,"claim":"Localized the requirement to the helix initiation motif of the 1A subdomain, showing this motif is needed for linear intermediate filament formation rather than filaments forming aberrant aggregates.","evidence":"ENU mutagenesis screen with two independent alleles at residues 143/146 and morphological analysis of inner root sheath intermediate filaments","pmids":["17143583"],"confidence":"Medium","gaps":["Mouse keratin, not human KRT2","Aggregation mechanism inferred from morphology, not biochemistry","Single lab"]},{"year":2016,"claim":"Defined human KRT2 as the gene whose dominant mutations cause superficial epidermolytic ichthyosis, establishing its role in superficial epidermal integrity.","evidence":"Clinical genetic sequencing and genotype-phenotype correlation across 26 families","pmids":["26581228"],"confidence":"Medium","gaps":["No structural model of mutant filament disruption","Mechanism inferred from inheritance pattern, not direct assay"]},{"year":2020,"claim":"Showed that a mosaic somatic KRT2 mutation is sufficient to cause localized epidermolytic disease, extending the dominant-disruption model to tissue-restricted, post-zygotic events.","evidence":"Molecular genetic testing of lesional skin versus blood DNA with allele frequency quantification (p.Asn186Asp at 25% in lesion)","pmids":["33081034"],"confidence":"Medium","gaps":["Single case","No functional assay of the p.Asn186Asp variant","Filament-level consequence inferred from phenotype"]},{"year":2022,"claim":"Identified residue E487 as a recurrent hotspot for superficial epidermolytic ichthyosis, pinpointing a position critical to keratin 2 function and documenting variable expressivity.","evidence":"Clinical molecular genetics and aggregation of 34 reported cases sharing the p.Glu487Lys mutation","pmids":["35887135"],"confidence":"Low","gaps":["No in vitro or structural validation of the E487K mechanism","Source of variable expressivity unexplained","Case-series only"]},{"year":null,"claim":"How specific KRT2 rod-domain mutations biochemically disrupt intermediate filament assembly, and the basis for variable expressivity, remain uncharacterized.","evidence":"","pmids":[],"confidence":"Low","gaps":["No in vitro filament assembly reconstitution for human KRT2","No structural model of mutant rod-domain interactions","Keratin partner pairing not characterized in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2]}],"localization":[],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P35908","full_name":"Keratin, type II cytoskeletal 2 epidermal","aliases":["Cytokeratin-2e","CK-2e","Epithelial keratin-2e","Keratin-2 epidermis","Keratin-2e","K2e","Type-II keratin Kb2"],"length_aa":639,"mass_kda":65.4,"function":"Probably contributes to terminal cornification (PubMed:1380918). Associated with keratinocyte activation, proliferation and keratinization (PubMed:12598329). Required for maintenance of corneocytes and keratin filaments in suprabasal keratinocytes in the epidermis of the ear, potentially via moderation of expression and localization of keratins and their partner proteins (By similarity). Plays a role in the establishment of the epidermal barrier on plantar skin (By similarity)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P35908/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KRT2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KRT2","total_profiled":1310},"omim":[{"mim_id":"618084","title":"PEELING SKIN SYNDROME 6; PSS6","url":"https://www.omim.org/entry/618084"},{"mim_id":"609165","title":"ICHTHYOSIS WITH CONFETTI; IWC","url":"https://www.omim.org/entry/609165"},{"mim_id":"607936","title":"PEELING SKIN SYNDROME 4; PSS4","url":"https://www.omim.org/entry/607936"},{"mim_id":"607602","title":"ICHTHYOSIS, ANNULAR EPIDERMOLYTIC, 1; AEI1","url":"https://www.omim.org/entry/607602"},{"mim_id":"600194","title":"KERATIN 2, TYPE II; KRT2","url":"https://www.omim.org/entry/600194"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Intermediate filaments","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skin 1","ntpm":4421.9}],"url":"https://www.proteinatlas.org/search/KRT2"},"hgnc":{"alias_symbol":["KRTE"],"prev_symbol":["KRT2A"]},"alphafold":{"accession":"P35908","domains":[{"cath_id":"1.20.5","chopping":"345-440","consensus_level":"medium","plddt":91.3427,"start":345,"end":440}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35908","model_url":"https://alphafold.ebi.ac.uk/files/AF-P35908-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P35908-F1-predicted_aligned_error_v6.png","plddt_mean":63.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KRT2","jax_strain_url":"https://www.jax.org/strain/search?query=KRT2"},"sequence":{"accession":"P35908","fasta_url":"https://rest.uniprot.org/uniprotkb/P35908.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35908/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35908"}},"corpus_meta":[{"pmid":"26581228","id":"PMC_26581228","title":"Expanding the Clinical and Genetic Spectrum of KRT1, KRT2 and KRT10 Mutations in Keratinopathic Ichthyosis.","date":"2016","source":"Acta dermato-venereologica","url":"https://pubmed.ncbi.nlm.nih.gov/26581228","citation_count":48,"is_preprint":false},{"pmid":"14573483","id":"PMC_14573483","title":"A small deletion hotspot in the type II keratin gene mK6irs1/Krt2-6g on mouse chromosome 15, a candidate for causing the wavy hair of the caracul (Ca) mutation.","date":"2003","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14573483","citation_count":44,"is_preprint":false},{"pmid":"17143583","id":"PMC_17143583","title":"Morphologic and molecular characterization of two novel Krt71 (Krt2-6g) mutations: Krt71rco12 and Krt71rco13.","date":"2006","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/17143583","citation_count":29,"is_preprint":false},{"pmid":"33081034","id":"PMC_33081034","title":"First Case of KRT2 Epidermolytic Nevus and Novel Clinical and Genetic Findings in 26 Italian Patients with Keratinopathic Ichthyoses.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33081034","citation_count":12,"is_preprint":false},{"pmid":"27265811","id":"PMC_27265811","title":"The expression of KRT2 and its effect on melanogenesis in alpaca skins.","date":"2016","source":"Acta histochemica","url":"https://pubmed.ncbi.nlm.nih.gov/27265811","citation_count":10,"is_preprint":false},{"pmid":"1379621","id":"PMC_1379621","title":"Genetic linkage analysis of the murine developmental mutant velvet coat (Ve) and the distal chromosome 15 developmental genes Hox-3.1, Rar-g, Wnt-1, and Krt-2.","date":"1992","source":"The Journal of experimental zoology","url":"https://pubmed.ncbi.nlm.nih.gov/1379621","citation_count":7,"is_preprint":false},{"pmid":"35887135","id":"PMC_35887135","title":"Deep Phenotyping of Superficial Epidermolytic Ichthyosis due to a Recurrent Mutation in KRT2.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35887135","citation_count":6,"is_preprint":false},{"pmid":"33555633","id":"PMC_33555633","title":"Epidermolytic epidermal nevus caused by a somatic mutation in KRT2.","date":"2021","source":"Pediatric dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/33555633","citation_count":2,"is_preprint":false},{"pmid":"22435621","id":"PMC_22435621","title":"Genetic variation in the 5'UTR of the KRT2.13 gene of sheep.","date":"2011","source":"Animal science journal = Nihon chikusan Gakkaiho","url":"https://pubmed.ncbi.nlm.nih.gov/22435621","citation_count":1,"is_preprint":false},{"pmid":"39761764","id":"PMC_39761764","title":"Tissue-specific expression, functional analysis, and polymorphism of the KRT2 gene in sheep horn.","date":"2025","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/39761764","citation_count":0,"is_preprint":false},{"pmid":"39619568","id":"PMC_39619568","title":"ABHD1 Facilitates Intermediate Filament-Mediated Endothelial Cell Chemotaxis by Regulating KRT1 and KRT2 in Diabetic Retinopathy.","date":"2024","source":"Journal of diabetes research","url":"https://pubmed.ncbi.nlm.nih.gov/39619568","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6496,"output_tokens":1253,"usd":0.019141,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7921,"output_tokens":1961,"usd":0.044315,"stage2_stop_reason":"end_turn"},"total_usd":0.063456,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Mutations in the highly conserved alpha-helical rod domain (1A and 2B subdomain) of the type II keratin mK6irs1/Krt2-6g gene cause wavy coat phenotype in mice; a deletion hotspot (N140del) and amino acid substitutions (A431D, L424W) in this domain disrupt hair formation, identifying this keratin's rod domain as essential for normal hair shaft structure.\",\n      \"method\": \"Positional cloning, sequencing of multiple independent mutant alleles, genotype-phenotype correlation\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — positional cloning with multiple independent alleles converging on same hotspot; single lab but strong genetic convergence\",\n      \"pmids\": [\"14573483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Missense mutations in the helix initiation motif (1A subdomain) of Krt71 (formerly Krt2-6g) at residues 143 and 146 cause formation of filamentous aggregates in the inner root sheath (Henle's and Huxley's layers) of the hair follicle, leading to bending of the hair shaft; this demonstrates that the helix initiation motif of this keratin is required for linear intermediate filament formation in the inner root sheath.\",\n      \"method\": \"ENU mutagenesis screen, mutation mapping, morphological analysis of hair follicle intermediate filaments\",\n      \"journal\": \"Mammalian genome : official journal of the International Mammalian Genome Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent ENU alleles with identical morphological phenotype and localized aggregate formation; single lab\",\n      \"pmids\": [\"17143583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mutations in KRT2 cause superficial epidermolytic ichthyosis, establishing that KRT2 encodes a keratin required for the structural integrity of the superficial epidermis; specific dominant mutations lead to epidermolytic hyperkeratosis pathology.\",\n      \"method\": \"Clinical genetic sequencing, genotype-phenotype correlation across 26 families\",\n      \"journal\": \"Acta dermato-venereologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple independent families with dominant KRT2 mutations and consistent superficial epidermal phenotype; well-replicated across labs\",\n      \"pmids\": [\"26581228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A somatic missense mutation (p.Asn186Asp) in KRT2, detected in lesional skin DNA at 25% allelic frequency and at very low frequency in blood, is sufficient to cause epidermolytic nevus, demonstrating that a dominant KRT2 mutation acting at the mosaic level disrupts epidermal keratin intermediate filament function in a tissue-restricted manner.\",\n      \"method\": \"Molecular genetic testing of lesional skin DNA vs. blood DNA; allele frequency quantification\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — somatic mutation detected by direct sequencing with allele frequency quantification; single lab, single case but orthogonal tissue comparison\",\n      \"pmids\": [\"33081034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A recurrent hotspot mutation p.Glu487Lys in KRT2 causes superficial epidermolytic ichthyosis, identifying residue E487 in the keratin 2 protein as functionally critical; deep phenotyping of 34 reported cases with this mutation shows variable expressivity including variable erythroderma.\",\n      \"method\": \"Clinical molecular genetics, aggregation of reported cases with identical KRT2 mutation\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — clinical case series with mutation identification; no in vitro or structural validation of mechanism\",\n      \"pmids\": [\"35887135\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KRT2 encodes a type II keratin whose conserved alpha-helical rod domain (including the helix initiation motif) is required for proper intermediate filament assembly in suprabasal epidermis and the inner root sheath of hair follicles; dominant mutations in this domain—whether germline or somatic—disrupt filament organization, causing epidermolytic pathology (superficial epidermolytic ichthyosis or epidermolytic nevus), while recurrent hotspot mutations at specific residues (e.g., E487K, N140) identify positions critical for keratin function.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KRT2 encodes a type II keratin required for the structural integrity of the suprabasal, superficial epidermis, where it assembles into intermediate filaments [#2]. Dominant mutations in KRT2 cause superficial epidermolytic ichthyosis with epidermolytic hyperkeratosis pathology, and a recurrent hotspot substitution at residue E487 marks a position critical for keratin function [#2, #4]. The same disruption can arise somatically: a mosaic p.Asn186Asp mutation confined to lesional skin produces epidermolytic nevus, showing that a single dominant KRT2 allele compromises epidermal filament function in a tissue-restricted manner [#3]. Work on the related murine type II keratin Krt71 establishes the rod domain and its helix initiation motif as essential for linear intermediate filament assembly, where missense mutations generate filamentous aggregates and structural failure of the tissue [#0, #1]. Beyond these genotype-phenotype correlations, no biochemical or structural characterization of KRT2 filament assembly is present in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that the conserved alpha-helical rod domain of a type II keratin is functionally essential, by linking rod-domain mutations to a structural tissue phenotype.\",\n      \"evidence\": \"Positional cloning and sequencing of multiple independent mutant alleles in mouse (Krt2-6g/mK6irs1), genotype-phenotype correlation of wavy coat\",\n      \"pmids\": [\n        \"14573483\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Findings are in mouse Krt71, not human KRT2\",\n        \"No biochemical reconstitution of filament assembly defect\",\n        \"Hotspot residues defined genetically, not structurally\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Localized the requirement to the helix initiation motif of the 1A subdomain, showing this motif is needed for linear intermediate filament formation rather than filaments forming aberrant aggregates.\",\n      \"evidence\": \"ENU mutagenesis screen with two independent alleles at residues 143/146 and morphological analysis of inner root sheath intermediate filaments\",\n      \"pmids\": [\n        \"17143583\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mouse keratin, not human KRT2\",\n        \"Aggregation mechanism inferred from morphology, not biochemistry\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined human KRT2 as the gene whose dominant mutations cause superficial epidermolytic ichthyosis, establishing its role in superficial epidermal integrity.\",\n      \"evidence\": \"Clinical genetic sequencing and genotype-phenotype correlation across 26 families\",\n      \"pmids\": [\n        \"26581228\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of mutant filament disruption\",\n        \"Mechanism inferred from inheritance pattern, not direct assay\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed that a mosaic somatic KRT2 mutation is sufficient to cause localized epidermolytic disease, extending the dominant-disruption model to tissue-restricted, post-zygotic events.\",\n      \"evidence\": \"Molecular genetic testing of lesional skin versus blood DNA with allele frequency quantification (p.Asn186Asp at 25% in lesion)\",\n      \"pmids\": [\n        \"33081034\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single case\",\n        \"No functional assay of the p.Asn186Asp variant\",\n        \"Filament-level consequence inferred from phenotype\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified residue E487 as a recurrent hotspot for superficial epidermolytic ichthyosis, pinpointing a position critical to keratin 2 function and documenting variable expressivity.\",\n      \"evidence\": \"Clinical molecular genetics and aggregation of 34 reported cases sharing the p.Glu487Lys mutation\",\n      \"pmids\": [\n        \"35887135\"\n      ],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No in vitro or structural validation of the E487K mechanism\",\n        \"Source of variable expressivity unexplained\",\n        \"Case-series only\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How specific KRT2 rod-domain mutations biochemically disrupt intermediate filament assembly, and the basis for variable expressivity, remain uncharacterized.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No in vitro filament assembly reconstitution for human KRT2\",\n        \"No structural model of mutant rod-domain interactions\",\n        \"Keratin partner pairing not characterized in the corpus\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0005198\",\n        \"supporting_discovery_ids\": [\n          0,\n          1,\n          2\n        ]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005882\",\n        \"supporting_discovery_ids\": [\n          1\n        ]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-1266738\",\n        \"supporting_discovery_ids\": [\n          2\n        ]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}