id: O95427
gene_symbol: PIGN
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PIGN (GPI ethanolamine phosphate transferase 1; GPI-ET-I) is a multi-pass
  endoplasmic reticulum membrane protein that acts in glycosylphosphatidylinositol
  (GPI) anchor biosynthesis. It transfers ethanolamine phosphate from
  phosphatidylethanolamine onto the 2-OH of the first alpha-1,4-linked mannose of
  the GPI intermediate, one of three ethanolamine phosphate additions to the trimannosyl
  core (PIGN acts on mannose 1; the paralogs PIGO and PIGG act on mannoses 3 and 2).
  PIGN belongs to the PIGG/PIGN/PIGO family and localizes to the ER membrane, where the
  later steps of GPI assembly occur. Biallelic loss-of-function variants cause multiple
  congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1), an autosomal recessive
  disorder of GPI-anchor biosynthesis characterized by neonatal hypotonia, seizures,
  dysmorphic features, and congenital anomalies.
existing_annotations:
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      PIGN is a multi-pass ER membrane protein that carries out the ethanolamine
      phosphate transfer step of GPI-anchor biosynthesis in the ER; this phylogenetic
      (IBA) location annotation reflects the correct site of action and is a core
      localization.
    action: ACCEPT
    reason: >-
      UniProt records the subcellular location as ER membrane (multi-pass membrane
      protein), consistent with the whole GPI-biosynthetic machinery residing in the
      ER, and the topology has 13 predicted transmembrane helices. This IBA is well
      supported and represents where PIGN functions.
    supported_by:
    - reference_id: file:human/PIGN/PIGN-uniprot.txt
      supporting_text: >-
        Endoplasmic reticulum membrane
    - reference_id: file:human/PIGN/PIGN-uniprot.txt
      supporting_text: >-
        Multi-pass membrane protein
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      PIGN participates in GPI-anchor biosynthesis, transferring ethanolamine phosphate
      onto the first mannose of the GPI intermediate. This phylogenetic annotation
      captures the core biological process.
    action: ACCEPT
    reason: >-
      The UniProt PATHWAY line assigns PIGN to glycosylphosphatidylinositol-anchor
      biosynthesis, and its FUNCTION describes participation in a defined step of GPI
      biosynthesis. The IBA is consistent across orthologs (yeast MCD4, mouse Pign) and
      represents a core process.
    supported_by:
    - reference_id: file:human/PIGN/PIGN-uniprot.txt
      supporting_text: >-
        Glycolipid biosynthesis; glycosylphosphatidylinositol-anchor
    - reference_id: file:human/PIGN/PIGN-uniprot.txt
      supporting_text: >-
        participates in the eighth step of the
- term:
    id: GO:0051377
    label: mannose-ethanolamine phosphotransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      This is PIGN's core molecular function: transfer of ethanolamine phosphate from
      phosphatidylethanolamine onto a mannose of the GPI intermediate. The phylogenetic
      annotation is the correct, appropriately specific catalytic term.
    action: ACCEPT
    reason: >-
      UniProt describes PIGN as an ethanolamine phosphate transferase that transfers
      EtNP from PE to the 2-OH of the first alpha-1,4-linked mannose of the GPI
      intermediate. GO:0051377 (mannose-ethanolamine phosphotransferase activity) is the
      exact catalytic term and is well conserved across the PIGN orthologs used for the
      IBA.
    supported_by:
    - reference_id: file:human/PIGN/PIGN-uniprot.txt
      supporting_text: >-
        Ethanolamine phosphate transferase that catalyzes an
    - reference_id: file:human/PIGN/PIGN-uniprot.txt
      supporting_text: >-
        ethanolamine phosphate (EtNP) transfer from phosphatidylethanolamine
    - reference_id: file:human/PIGN/PIGN-uniprot.txt
      supporting_text: >-
        the first alpha-1,4-linked mannose
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic (InterPro/SubCell) annotation placing PIGN in the ER membrane; agrees
      with the curated UniProt location and the IBA.
    action: ACCEPT
    reason: >-
      The InterPro signatures (IPR007070 GPI EtNP transferase 1, IPR017852) and
      UniProtKB-SubCell SL-0097 map to ER membrane, matching PIGN's curated location as
      a multi-pass ER membrane protein.
    supported_by:
    - reference_id: file:human/PIGN/PIGN-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 annotation assigning PIGN to GPI-anchor biosynthesis via InterPro and
      UniPathway; consistent with the curated pathway and the IBA/TAS.
    action: ACCEPT
    reason: >-
      InterPro GPI EtNP-transferase signatures and UniPathway UPA00196
      (glycosylphosphatidylinositol-anchor biosynthesis) correctly place PIGN in this
      core process.
    supported_by:
    - reference_id: file:human/PIGN/PIGN-uniprot.txt
      supporting_text: >-
        Glycolipid biosynthesis; glycosylphosphatidylinositol-anchor
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: >-
      Generic InterPro-derived membrane localization. True but uninformative given the
      more specific ER membrane annotation that pinpoints where PIGN acts.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      PIGN is a multi-pass membrane protein, so a bare 'membrane' term is not wrong, but
      it is subsumed by the more specific and functionally correct GO:0005789 ER
      membrane annotation. The specific term should carry the localization.
    supported_by:
    - reference_id: file:human/PIGN/PIGN-uniprot.txt
      supporting_text: >-
        Multi-pass membrane protein
- term:
    id: GO:0016740
    label: transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Generic InterPro parent term for PIGN's transferase activity. Correct but far less
      informative than the specific mannose-ethanolamine phosphotransferase activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0016740 is a high-level ancestor of PIGN's actual catalytic term GO:0051377.
      It is not wrong, but the specific EtNP-transferase term should represent the
      molecular function; the parent adds no additional information.
    supported_by:
    - reference_id: file:human/PIGN/PIGN-uniprot.txt
      supporting_text: >-
        Ethanolamine phosphate transferase that catalyzes an
- term:
    id: GO:0051377
    label: mannose-ethanolamine phosphotransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Electronic (InterPro) assignment of PIGN's specific catalytic activity, matching
      the IBA/ISS/TAS and the curated UniProt function.
    action: ACCEPT
    reason: >-
      InterPro GPI EtNP-transferase 1 signatures (IPR007070, IPR037671) correctly
      predict the mannose-ethanolamine phosphotransferase activity that is PIGN's core
      molecular function.
    supported_by:
    - reference_id: file:human/PIGN/PIGN-uniprot.txt
      supporting_text: >-
        ethanolamine phosphate (EtNP) transfer from phosphatidylethanolamine
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162710
  qualifier: involved_in
  review:
    summary: >-
      Reactome traceable-author annotation placing PIGN in the human GPI synthesis
      pathway. Consistent with the core biological process.
    action: ACCEPT
    reason: >-
      Reactome pathway R-HSA-162710 (Synthesis of glycosylphosphatidylinositol) includes
      the EtNP-transfer reaction catalyzed by PIGN as one step of GPI-anchor biosynthesis;
      this is a well-established core process annotation.
    supported_by:
    - reference_id: Reactome:R-HSA-162710
      supporting_text: >-
        GPI is synthesized in the endoplasmic reticulum
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      HPA immunofluorescence-based cytosolic localization. PIGN is a multi-pass ER
      membrane protein that functions on the lumenal/ER-membrane face during GPI
      assembly; a cytosolic pool is not its site of function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This is a high-throughput HPA IF annotation. PIGN's curated location is the ER
      membrane, and its 13-TM topology and role in GPI-anchor synthesis place its
      activity in the ER, not the bulk cytosol. A cytosolic signal most likely reflects
      antibody background or over-expression and is not the functional site. Retained
      (not removed) per policy, but flagged as over-annotated relative to the ER
      localization.
    supported_by:
    - reference_id: file:human/PIGN/PIGN-uniprot.txt
      supporting_text: >-
        Endoplasmic reticulum membrane
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      HPA immunofluorescence-based plasma membrane localization. PIGN acts in the ER
      membrane during GPI-anchor biosynthesis; the plasma membrane is where mature
      GPI-anchored proteins end up, not where PIGN itself functions.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      A plasma-membrane signal for an ER-resident biosynthetic enzyme is not its
      functional location. This HPA IF annotation likely reflects staining of the
      broader secretory/membrane compartment or antibody cross-reactivity; PIGN's
      curated and functional location is the ER membrane. Retained (not removed) per
      policy, but marked over-annotated.
    supported_by:
    - reference_id: file:human/PIGN/PIGN-uniprot.txt
      supporting_text: >-
        Endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence-similarity transfer of the ER membrane location from the mouse ortholog
      (Q9R1S3). Matches the curated location and other evidence.
    action: ACCEPT
    reason: >-
      ISS from mouse Pign (UniProtKB:Q9R1S3) correctly assigns the ER membrane location;
      this is PIGN's core site of action and is corroborated by IBA, IEA, and TAS
      evidence.
    supported_by:
    - reference_id: file:human/PIGN/PIGN-uniprot.txt
      supporting_text: >-
        Endoplasmic reticulum membrane
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence-similarity transfer of the GPI-anchor biosynthetic process from mouse
      Pign. Consistent with PIGN's core role.
    action: ACCEPT
    reason: >-
      ISS from mouse Pign (UniProtKB:Q9R1S3) assigns the GPI-anchor biosynthetic process,
      matching the curated pathway and PIGN's function as the EtNP transferase for the
      first mannose.
    supported_by:
    - reference_id: file:human/PIGN/PIGN-uniprot.txt
      supporting_text: >-
        participates in the eighth step of the
- term:
    id: GO:0051377
    label: mannose-ethanolamine phosphotransferase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Sequence-similarity transfer of the EtNP-transferase activity from mouse Pign;
      this is PIGN's core molecular function and the UniProt EC/catalytic-activity block
      is itself inferred by similarity to the mouse enzyme.
    action: ACCEPT
    reason: >-
      ISS from mouse Pign (UniProtKB:Q9R1S3) assigns mannose-ethanolamine
      phosphotransferase activity, matching PIGN's curated catalytic activity (EtNP
      transfer from PE to the first mannose of the GPI intermediate).
    supported_by:
    - reference_id: file:human/PIGN/PIGN-uniprot.txt
      supporting_text: >-
        Ethanolamine phosphate transferase that catalyzes an
- term:
    id: GO:0051377
    label: mannose-ethanolamine phosphotransferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162798
  qualifier: enables
  review:
    summary: >-
      Reactome traceable-author annotation of the specific EtNP-transfer reaction
      catalyzed by PIGN (phosphoethanolamine from PE onto the first mannose of the GPI
      precursor). Directly supports the core molecular function.
    action: ACCEPT
    reason: >-
      Reactome reaction R-HSA-162798 describes the transfer of a phosphoethanolamine
      group from phosphatidylethanolamine onto the first mannose of the GPI precursor,
      the reaction PIGN catalyzes, mapping to GO:0051377.
    supported_by:
    - reference_id: Reactome:R-HSA-162798
      supporting_text: >-
        a phosphoethanolamine group is transferred from phosphatidylethanolamine onto
        the first mannose of the GPI precursor
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: >-
      High-throughput mass-spectrometry detection of PIGN in an NK-cell membrane
      proteome. Confirms PIGN is a membrane protein but gives only a generic membrane
      location, not its functional ER-membrane site.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The cited study is a bulk membrane-proteome MS survey of the YTS NK-like cell line
      that identified ~1843 proteins; detection in a crude membrane fraction supports
      only a generic 'membrane' term and is subsumed by the specific ER membrane
      annotation that reflects where PIGN acts.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: >-
        Mass spectrometric analysis identified 1843 proteins with high confidence scores.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162798
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author annotation placing the PIGN-catalyzed EtNP-transfer
      reaction in the ER. Consistent with the core localization.
    action: ACCEPT
    reason: >-
      Reactome annotates GPI synthesis, including the PIGN reaction R-HSA-162798, as
      occurring in the endoplasmic reticulum, matching PIGN's curated ER membrane
      location.
    supported_by:
    - reference_id: Reactome:R-HSA-162710
      supporting_text: >-
        GPI is synthesized in the endoplasmic reticulum
core_functions:
- description: >-
    PIGN transfers ethanolamine phosphate from phosphatidylethanolamine onto the 2-OH of
    the first alpha-1,4-linked mannose of the GPI intermediate in the ER membrane, an
    essential step of glycosylphosphatidylinositol-anchor biosynthesis.
  molecular_function:
    id: GO:0051377
    label: mannose-ethanolamine phosphotransferase activity
  directly_involved_in:
  - id: GO:0006506
    label: GPI anchor biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/PIGN/PIGN-uniprot.txt
    supporting_text: >-
      Ethanolamine phosphate transferase that catalyzes an ethanolamine phosphate (EtNP)
      transfer from phosphatidylethanolamine
  - reference_id: file:human/PIGN/PIGN-uniprot.txt
    supporting_text: >-
      Glycolipid biosynthesis; glycosylphosphatidylinositol-anchor
  - reference_id: Reactome:R-HSA-162798
    supporting_text: >-
      a phosphoethanolamine group is transferred from phosphatidylethanolamine onto the
      first mannose of the GPI precursor
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Bulk NK-cell membrane-proteome MS study; supports only generic membrane detection
      of PIGN (HDA), not its functional ER-membrane localization.
- id: Reactome:R-HSA-162710
  title: Synthesis of glycosylphosphatidylinositol (GPI)
  findings: []
- id: Reactome:R-HSA-162798
  title: mannose(a1-4)glucosaminyl-acyl-PI + phosphatidylethanolamine -> (ethanolamineP)
    mannose(al1-4)glucosaminyl-acyl-PI + diacylglycerol
  findings: []
- id: file:human/PIGN/PIGN-uniprot.txt
  title: UniProt entry O95427 (PIGN_HUMAN), GPI ethanolamine phosphate transferase 1
  findings: []