id: Q92535
gene_symbol: PIGC
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PIGC (phosphatidylinositol N-acetylglucosaminyltransferase subunit C; also known
  as GPI2) is a multi-pass endoplasmic reticulum membrane protein that is a required,
  non-catalytic subunit of the glycosylphosphatidylinositol N-acetylglucosaminyltransferase
  (GPI-GnT) complex. This complex catalyzes the first committed step of GPI-anchor
  biosynthesis: transfer of N-acetylglucosamine from UDP-N-acetylglucosamine onto
  phosphatidylinositol to form GlcNAc-PI. Within the complex the catalytic subunit
  is PIGA; PIGC is one of the accessory/structural subunits, alongside PIGH, PIGP,
  PIGQ (GPI1), PIGY and the regulatory factor DPM2. PIGC is the human homologue of
  Saccharomyces cerevisiae Gpi2. Loss-of-function variants in PIGC cause an autosomal
  recessive inherited GPI-deficiency disorder (glycosylphosphatidylinositol biosynthesis
  defect 16, GPIBD16) presenting as a developmental and epileptic encephalopathy with
  global developmental delay, intellectual disability and seizures, reflecting reduced
  cell-surface expression of GPI-anchored proteins.
existing_annotations:
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      GPI anchor biosynthetic process is the core biological process of PIGC as a
      subunit of the GPI-GnT complex that performs the first step of GPI-anchor
      biosynthesis. The IBA (phylogenetic) call is consistent with the experimental
      literature and with the well-conserved role of the yeast orthologue GPI2.
    action: ACCEPT
    reason: >-
      Directly supported by the demonstrated role of PIG-C in the first, committed
      step of GPI biosynthesis and conserved across the PIGC/GPI2 family. This is
      the core function of the gene.
    supported_by:
    - reference_id: PMID:8806613
      supporting_text: mediated by at least three genes in mammalian cells (PIG-A, PIG-H and PIG-C)
- term:
    id: GO:0000506
    label: glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT)
      complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: >-
      PIGC is a component of the GPI-GnT complex. The IBA assignment of complex
      membership is well supported by direct experimental evidence in human cells
      and by conservation of the complex across eukaryotes.
    action: ACCEPT
    reason: >-
      Complex membership is directly demonstrated experimentally (see PMID:9463366,
      PMID:10944123, PMID:16162815) and the phylogenetic inference is consistent
      with this. This is a core aspect of PIGC's biology.
    supported_by:
    - reference_id: PMID:9463366
      supporting_text: four mammalian gene products form a protein complex in the endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      PIGC localizes to the endoplasmic reticulum membrane, where the GPI-GnT complex
      operates. This IEA call (from the UniProt subcellular-location mapping) agrees
      with direct experimental evidence.
    action: ACCEPT
    reason: >-
      The ER-membrane localization is experimentally established (PMID:8806613,
      PMID:16162815) and matches the UniProt subcellular location; the mapping is
      correct and specific.
    supported_by:
    - reference_id: file:human/PIGC/PIGC-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic assignment (InterPro IPR009450 / UniPathway UPA00196) of the core
      GPI-anchor biosynthetic process. Consistent with the experimental and IBA
      evidence; correct and appropriately specific.
    action: ACCEPT
    reason: >-
      The InterPro/UniPathway-driven mapping correctly reflects PIGC's role in the
      first step of GPI biosynthesis. This is a duplicate of the core BP call from
      other evidence sources.
    supported_by:
    - reference_id: PMID:8806613
      supporting_text: mediated by at least three genes in mammalian cells (PIG-A, PIG-H and PIG-C)
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: >-
      Generic "membrane" localization from the InterPro-to-GO mapping. Not wrong
      (PIGC is a multi-pass membrane protein) but far less informative than the
      specific and experimentally supported endoplasmic reticulum membrane term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Subsumed by the more specific and better-supported GO:0005789 (endoplasmic
      reticulum membrane). The bare "membrane" term adds no specificity beyond what
      the ER-membrane annotation already conveys.
    supported_by:
    - reference_id: file:human/PIGC/PIGC-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10944123
  qualifier: enables
  review:
    summary: >-
      IntAct IPI annotation recording a physical interaction between PIGC and DPM2
      (UniProtKB:O94777). This reflects PIGC's participation in the GPI-GnT complex,
      where DPM2 associates through interactions with PIG-A, PIG-C and GPI1, but the
      bare "protein binding" term is uninformative about molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidelines, GO:0005515 "protein binding" is too generic to convey
      function. The biologically meaningful content of this interaction (membership
      of the GPI-GnT complex) is already captured by GO:0000506. Retained but marked
      as over-annotated rather than removed, as the IntAct interaction itself is valid.
    supported_by:
    - reference_id: PMID:10944123
      supporting_text: associates with GPI-GnT through interactions with PIG-A, PIG-C and
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9463366
  qualifier: enables
  review:
    summary: >-
      IntAct IPI annotation recording a physical interaction between PIGC and PIGQ
      (GPI1; UniProtKB:Q9BRB3). Consistent with PIGC and GPI1 co-assembling in the
      GPI-GnT complex, but the bare "protein binding" term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic "protein binding" is discouraged as uninformative. The functional
      significance (PIGC's assembly into the GPI-GnT complex with PIGA, PIGH, PIGC
      and GPI1) is already represented by the GPI-GnT complex annotation (GO:0000506).
    supported_by:
    - reference_id: PMID:9463366
      supporting_text: four mammalian gene products form a protein complex in the endoplasmic reticulum membrane
- term:
    id: GO:0000506
    label: glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT)
      complex
  evidence_type: IPI
  original_reference_id: PMID:16162815
  qualifier: part_of
  review:
    summary: >-
      ComplexPortal assignment of PIGC to the GPI-GnT complex based on the seven-component
      complex characterized in this study. Core, well-supported cellular-component
      annotation.
    action: ACCEPT
    reason: >-
      PMID:16162815 defines the GPI-GnT complex composition (PIGA, PIGC, PIGH, PIGP,
      PIGQ, PIGY, DPM2) with PIG-A as the catalytic subunit; PIGC is a bona fide
      component. Core function.
    supported_by:
    - reference_id: PMID:16162815
      supporting_text: the catalytic subunit PIG-A
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:16162815
  qualifier: located_in
  review:
    summary: >-
      Direct experimental evidence places PIGC (with the GPI-GnT complex) in the
      endoplasmic reticulum membrane. Core, well-supported localization.
    action: ACCEPT
    reason: >-
      The GPI-GnT complex containing PIGC is an ER-membrane complex; ER-membrane
      localization is directly demonstrated and is the site of PIGC function.
    supported_by:
    - reference_id: PMID:9463366
      supporting_text: four mammalian gene products form a protein complex in the endoplasmic reticulum membrane
- term:
    id: GO:0000506
    label: glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT)
      complex
  evidence_type: IDA
  original_reference_id: PMID:16162815
  qualifier: part_of
  review:
    summary: >-
      Direct experimental evidence (co-precipitation / reconstitution) that PIGC is
      part of the GPI-GnT complex. Duplicate of the ComplexPortal and IBA complex
      calls; core cellular-component annotation.
    action: ACCEPT
    reason: >-
      Experimentally demonstrated membership of the seven-component GPI-GnT complex.
      This is a core aspect of PIGC's biology.
    supported_by:
    - reference_id: PMID:16162815
      supporting_text: the catalytic subunit PIG-A
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:16162815
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental evidence for PIGC's involvement in GPI-anchor biosynthesis
      via the GPI-GnT complex that performs the first step of the pathway. Core BP.
    action: ACCEPT
    reason: >-
      PIGC is required for the initial GPI-GnT reaction; loss of complex components
      abolishes surface GPI-anchored protein expression. Core function of the gene.
    supported_by:
    - reference_id: PMID:9463366
      supporting_text: The protein complex had GPI-GlcNAc transferase (GPI-GnT) activity in vitro
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:27694521
  qualifier: involved_in
  review:
    summary: >-
      Patient-derived and engineered PIGC variants (L189W; L212P/R21X) reduce surface
      expression of GPI-anchored proteins, providing mutational (IMP) evidence that
      PIGC is required for GPI-anchor biosynthesis. Core BP.
    action: ACCEPT
    reason: >-
      Loss-of-function PIGC variants cause a GPI-deficiency disorder (GPIBD16) with
      reduced surface GPI-anchored protein expression, directly supporting PIGC's
      requirement for the GPI-anchor biosynthetic process.
    supported_by:
    - reference_id: PMID:27694521
      supporting_text: PIGC joins the list of genes in which mutations result in defective
    - reference_id: PMID:27694521
      supporting_text: reduction of surface expression of GPI-anchored proteins
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162730
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author statement placing the first-step GPI reaction (and
      its multimeric enzyme, including PIGC) in the endoplasmic reticulum membrane.
      Consistent with the direct experimental localization.
    action: ACCEPT
    reason: >-
      Duplicate of the experimentally supported ER-membrane localization; correct
      and specific. Core localization.
    supported_by:
    - reference_id: PMID:9463366
      supporting_text: four mammalian gene products form a protein complex in the endoplasmic reticulum membrane
- term:
    id: GO:0000506
    label: glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT)
      complex
  evidence_type: IDA
  original_reference_id: PMID:10944123
  qualifier: part_of
  review:
    summary: >-
      Direct experimental evidence that PIGC is part of the GPI-GnT complex, here
      characterized as consisting of at least PIG-A, PIG-H, PIG-C and GPI1 (plus
      PIG-P and the regulator DPM2). Core cellular-component annotation.
    action: ACCEPT
    reason: >-
      PMID:10944123 experimentally defines the GPI-GnT complex including PIG-C.
      Consistent with all other complex-membership annotations; core function.
    supported_by:
    - reference_id: PMID:10944123
      supporting_text: PIG-A, PIG-H, PIG-C and GPI1
- term:
    id: GO:0003824
    label: catalytic activity
  evidence_type: TAS
  original_reference_id: PMID:8806613
  qualifier: enables
  review:
    summary: >-
      Legacy TAS (ProtInc, 2003) annotation of the very general term "catalytic
      activity". The catalytic activity of the GPI-GnT complex resides in the PIG-A
      subunit; PIGC is a required accessory/structural subunit and is not itself the
      catalytic component. The broad "catalytic activity" term is therefore an
      over-annotation for this subunit and is uninformative even as a complex-level
      statement.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      PIGC is a non-catalytic subunit: PMID:16162815 explicitly identifies PIG-A as
      "the catalytic subunit". Assigning the root-level "catalytic activity" molecular
      function to PIGC overstates and mis-locates the enzymatic activity, which belongs
      to PIGA / the complex as a whole. The GOA carries no PIGC-specific glycosyltransferase
      MF, so no replacement molecular-function term is proposed for this subunit.
    supported_by:
    - reference_id: PMID:16162815
      supporting_text: the catalytic subunit PIG-A
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: PMID:8806613
  qualifier: located_in
  review:
    summary: >-
      Traceable-author statement (original cloning paper) that PIG-C is an ER membrane
      protein. Consistent with the direct experimental and IEA localization. Core.
    action: ACCEPT
    reason: >-
      The original characterization describes PIG-C as a 297-residue membrane protein
      in the endoplasmic reticulum, matching all other localization evidence. Core
      localization.
    supported_by:
    - reference_id: PMID:8806613
      supporting_text: mediated by at least three genes in mammalian cells (PIG-A, PIG-H and PIG-C)
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:8806613
  qualifier: involved_in
  review:
    summary: >-
      Traceable-author statement that PIG-C is one of the genes involved in the first
      step of GPI-anchor biosynthesis. Core BP; duplicate of the other GPI-anchor
      biosynthesis annotations.
    action: ACCEPT
    reason: >-
      The cloning study assigns PIG-C to the first step of GPI biosynthesis, matching
      the IBA, IEA, IDA and IMP evidence. This is the core function of the gene.
    supported_by:
    - reference_id: PMID:8806613
      supporting_text: mediated by at least three genes in mammalian cells (PIG-A, PIG-H and PIG-C)
core_functions:
- description: >-
    Non-catalytic subunit of the GPI-GnT complex that is required for the first
    committed step of GPI-anchor biosynthesis (GlcNAc transfer from UDP-GlcNAc onto
    phosphatidylinositol), acting in the endoplasmic reticulum membrane. The catalytic
    activity resides in the PIGA subunit, so no independent catalytic molecular function
    is assigned to PIGC.
  directly_involved_in:
  - id: GO:0006506
    label: GPI anchor biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  in_complex:
    id: GO:0000506
    label: glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT)
      complex
  supported_by:
  - reference_id: file:human/PIGC/PIGC-uniprot.txt
    supporting_text: acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the
  - reference_id: PMID:9463366
    supporting_text: The protein complex had GPI-GlcNAc transferase (GPI-GnT) activity in vitro
  - reference_id: PMID:16162815
    supporting_text: the catalytic subunit PIG-A
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10944123
  title: Initial enzyme for glycosylphosphatidylinositol biosynthesis requires PIG-P
    and is regulated by DPM2.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only cache. Defines the GPI-GnT complex as PIG-A, PIG-H, PIG-C and
      GPI1 plus PIG-P, with DPM2 associating through PIG-A, PIG-C and GPI1; supports
      PIGC complex membership and the PIGC-DPM2 IntAct interaction.
- id: PMID:16162815
  title: The initial enzyme for glycosylphosphatidylinositol biosynthesis requires
    PIG-Y, a seventh component.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only cache. Characterizes the seven-component GPI-GnT complex and
      explicitly names PIG-A as the catalytic subunit, confirming PIGC is an accessory
      (non-catalytic) subunit.
- id: PMID:27694521
  title: Mutations in the phosphatidylinositol glycan C (PIGC) gene are associated
    with epilepsy and intellectual disability.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only cache. Patient and engineered PIGC variants reduce surface
      expression of GPI-anchored proteins, establishing PIGC deficiency as a GPI
      biosynthesis defect (GPIBD16) with developmental delay and seizures.
- id: PMID:8806613
  title: PIG-C, one of the three human genes involved in the first step of glycosylphosphatidylinositol
    biosynthesis is a homologue of Saccharomyces cerevisiae GPI2.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only cache. Original cloning of human PIG-C as a homologue of yeast
      GPI2; places PIG-C in the first step of GPI biosynthesis and as an ER membrane
      protein.
- id: PMID:9463366
  title: The first step of glycosylphosphatidylinositol biosynthesis is mediated by
    a complex of PIG-A, PIG-H, PIG-C and GPI1.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full abstract cached. Demonstrates that PIG-A, PIG-H, PIG-C and GPI1 form an
      ER-membrane complex with GPI-GlcNAc transferase activity; supports PIGC complex
      membership and the PIGC-PIGQ(GPI1) interaction.
- id: Reactome:R-HSA-162730
  title: phosphatidylinositol + UDP-N-acetyl-D-glucosamine -> N-acetylglucosaminyl-PI
    + UDP
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Reactome reaction for the first GPI step in the ER membrane, catalyzed by the
      multimeric enzyme that includes PIGC. Supports the ER-membrane localization.
- id: file:human/PIGC/PIGC-uniprot.txt
  title: UniProtKB entry PIGC_HUMAN (Q92535)
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      UniProt record: FUNCTION (part of the GPI-GnT complex catalyzing GlcNAc transfer
      to PI, first step of GPI biosynthesis), SUBCELLULAR LOCATION (ER membrane,
      multi-pass), SUBUNIT (PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY, DPM2) and disease
      (GPIBD16).