id: O43826
gene_symbol: SLC37A4
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  SLC37A4 (glucose-6-phosphate exchanger; G6PT/G6PT1) is a multi-pass endoplasmic
  reticulum membrane transporter of the SLC37 sugar-phosphate/phosphate exchanger
  family (major facilitator superfamily, organophosphate:Pi antiporter clade). It is
  the glucose-6-phosphate:inorganic-phosphate antiporter that translocates cytosolic
  glucose-6-phosphate (G6P) into the ER lumen in exchange for luminal inorganic
  phosphate. By importing G6P into the ER, it delivers the substrate to the luminal
  active site of the glucose-6-phosphatase catalytic subunits (G6PC1 in liver, kidney
  and intestine; G6PC3 ubiquitously, including neutrophils), and thereby carries out
  the terminal, glucose-releasing step shared by gluconeogenesis and glycogenolysis,
  playing a central role in interprandial blood-glucose homeostasis. Two alternatively
  spliced isoforms exist (isoform 2/vG6PT includes an extra exon-7 segment); both are
  active G6P transporters. Loss-of-function variants cause glycogen storage disease
  type Ib (von Gierke type Ib), combining the GSD Ia-like metabolic phenotype (fasting
  hypoglycemia, hepatomegaly, lactic acidemia, hyperlipidemia) with neutropenia,
  neutrophil dysfunction and inflammatory-bowel-disease-like features, reflecting the
  transporter's role in both the hepatic G6PC1 and the neutrophil G6PC3 systems. A
  distinct dominant variant (p.Arg423*) that removes the C-terminal ER-retention signal
  mislocalizes the transporter to the Golgi and causes a congenital disorder of
  glycosylation (CDG-IIw) with liver dysfunction and coagulopathy.
alternative_products:
- name: '1'
  id: O43826-1
- name: '2'
  id: O43826-2
  sequence_note: VSP_006171
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: >-
      Phylogenetic (IBA) annotation placing the active SLC37A4 protein in the ER
      membrane. This is the well-established site of action of the G6P/Pi antiporter and
      is directly supported by experimental localization data.
    action: ACCEPT
    reason: >-
      The ER membrane is the correct, experimentally confirmed compartment for this
      transporter (see the IDA/EXP annotations below), and the phylogenetic inference is
      consistent with orthologs. Retain as a core localization.
    supported_by:
    - reference_id: PMID:21949678
      supporting_text: >-
        The glucose-6-phosphate transporter (G6PT, also known as SLC37A4) is localized in the endoplasmic reticulum (ER) membrane
- term:
    id: GO:0061513
    label: glucose 6-phosphate:phosphate antiporter activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) annotation for the defining molecular function: glucose
      6-phosphate:phosphate antiporter activity. This is the correct, most informative
      MF term and is heavily supported by experimental evidence.
    action: ACCEPT
    reason: >-
      This is the core molecular function of SLC37A4/G6PT, confirmed biochemically in
      reconstituted proteoliposomes as a dual G6P/Pi antiporter. The IBA is at the right
      level of specificity.
    supported_by:
    - reference_id: PMID:18337460
      supporting_text: >-
        our results suggest that G6PT has a dual role as a G6P and a P(i)
    - reference_id: PMID:21949678
      supporting_text: >-
        The primary function of G6PT is to translocate G6P from the cytoplasm into the lumen of the ER for hydrolysis into glucose and Pi
- term:
    id: GO:0015760
    label: glucose-6-phosphate transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation for the biological process of glucose-6-phosphate
      transport, the direct process carried out by this antiporter.
    action: ACCEPT
    reason: >-
      G6P transport across the ER membrane is the direct, core biological process of
      SLC37A4, supported by multiple experimental (IMP/IDA) annotations. Retain as core.
    supported_by:
    - reference_id: PMID:21949678
      supporting_text: >-
        The primary function of G6PT is to translocate G6P from the cytoplasm into the lumen of the ER for hydrolysis into glucose and Pi
- term:
    id: GO:0035435
    label: phosphate ion transmembrane transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation for phosphate ion transmembrane transport. Because
      SLC37A4 is an antiporter, inorganic phosphate is the counter-substrate moved in the
      opposite direction to G6P, so phosphate transport is a genuine part of its activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Phosphate transport is real but is the counter-transport leg of the G6P:Pi
      antiport rather than the physiologically salient function; the G6P-directed terms
      capture the core role. Keep as a non-core aspect.
    supported_by:
    - reference_id: PMID:18337460
      supporting_text: >-
        our results suggest that G6PT has a dual role as a G6P and a P(i)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation (UniProt Subcellular Location mapping) placing SLC37A4 in the
      ER membrane. Correct and consistent with experimental localization.
    action: ACCEPT
    reason: >-
      The UniProt SubCell mapping (SL-0097, ER membrane) is accurate and matches the
      experimentally determined localization. Retain.
    supported_by:
    - reference_id: PMID:32884905
      supporting_text: >-
        The wildtype protein resides in the ER of HepG2 tetoff cells
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: >-
      Electronic (InterPro2GO) annotation to the generic term "membrane". SLC37A4 is
      indeed a membrane protein, but this term is far less specific than the
      experimentally supported ER membrane localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "membrane" is trivially true for a multi-pass transporter but uninformative given
      that the specific compartment (ER membrane) is well established. Over-annotation.
    supported_by:
    - reference_id: PMID:32884905
      supporting_text: >-
        The wildtype protein resides in the ER of HepG2 tetoff cells
- term:
    id: GO:0022857
    label: transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Electronic (InterPro2GO) annotation to the very general MF "transmembrane
      transporter activity". Correct in essence but much broader than the specific G6P:Pi
      antiporter activity that is experimentally established.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The specific antiporter activity (GO:0061513) and the G6P transmembrane transporter
      activity (GO:0015152) are the informative MF terms; the generic parent adds no
      information. Mark as over-annotated rather than removing an InterPro-based root term.
    supported_by:
    - reference_id: PMID:18337460
      supporting_text: >-
        our results suggest that G6PT has a dual role as a G6P and a P(i)
- term:
    id: GO:0055085
    label: transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      Electronic (InterPro2GO) annotation to the general BP "transmembrane transport".
      True but general relative to the specific glucose-6-phosphate transport process.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct high-level process; the specific G6P transport (GO:0015760) is the core
      term. Keep as a valid but non-core parent.
    supported_by:
    - reference_id: PMID:21949678
      supporting_text: >-
        The primary function of G6PT is to translocate G6P from the cytoplasm into the lumen of the ER for hydrolysis into glucose and Pi
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      IPI annotation to the uninformative "protein binding" term, from a high-throughput
      yeast-two-hybrid interactome map (HuRI) reporting an interaction with BIK
      (UniProtKB:Q13323). This is a bare binding annotation with no functional context.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidelines, bare "protein binding" is not informative about molecular
      function. The single high-throughput binary interaction (with BIK) has no
      established functional consequence for the G6P antiporter and should not be treated
      as a core function. Retained but flagged (not removed, per policy on IPI binding
      annotations).
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: >-
        HuRI is a systematic proteome-wide reference that links genomic
- term:
    id: GO:0006094
    label: gluconeogenesis
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70263
  qualifier: involved_in
  review:
    summary: >-
      TAS (Reactome) annotation to gluconeogenesis. SLC37A4 supplies G6P to the ER-luminal
      glucose-6-phosphatase, carrying out the terminal, glucose-releasing step common to
      gluconeogenesis and glycogenolysis, so participation in gluconeogenesis is correct.
    action: KEEP_AS_NON_CORE
    reason: >-
      SLC37A4 contributes to gluconeogenesis by delivering G6P for the final hydrolysis
      step, but its molecular activity is transport, not a gluconeogenic enzymatic step.
      Retain as a valid contributory (non-core) process annotation.
    supported_by:
    - reference_id: PMID:21949678
      supporting_text: >-
        Together, the G6PT/G6Pase-α complex maintains interprandial glucose homeostasis
- term:
    id: GO:0061513
    label: glucose 6-phosphate:phosphate antiporter activity
  evidence_type: EXP
  original_reference_id: PMID:18337460
  qualifier: enables
  review:
    summary: >-
      Experimental annotation for the G6P:Pi antiporter activity, based on reconstituted
      proteoliposome transport assays demonstrating the dual G6P/Pi antiport function.
    action: ACCEPT
    reason: >-
      Direct biochemical demonstration of the defining molecular function in
      proteoliposomes; a null mutant (p.R28H) abolished transport. Core function.
    supported_by:
    - reference_id: PMID:18337460
      supporting_text: >-
        our results suggest that G6PT has a dual role as a G6P and a P(i)
- term:
    id: GO:0061513
    label: glucose 6-phosphate:phosphate antiporter activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3229118
  qualifier: enables
  review:
    summary: >-
      TAS (Reactome) annotation for the G6P:Pi antiporter activity across the ER membrane.
      Consistent with the experimental evidence.
    action: ACCEPT
    reason: >-
      Correct, well-supported core molecular function; duplicate of the EXP/IDA/IBA
      antiporter annotations with an authoritative source.
    supported_by:
    - reference_id: PMID:18337460
      supporting_text: >-
        our results suggest that G6PT has a dual role as a G6P and a P(i)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:32884905
  qualifier: located_in
  review:
    summary: >-
      Experimental localization to the ER membrane; wild-type SLC37A4 resides in the ER
      (contrasted with the Golgi-mislocalizing R423* CDG variant).
    action: ACCEPT
    reason: >-
      Direct experimental support for ER membrane localization of the wild-type protein.
      Core localization.
    supported_by:
    - reference_id: PMID:32884905
      supporting_text: >-
        The wildtype protein resides in the ER of HepG2 tetoff cells
- term:
    id: GO:0061513
    label: glucose 6-phosphate:phosphate antiporter activity
  evidence_type: EXP
  original_reference_id: PMID:10026167
  qualifier: enables
  review:
    summary: >-
      Experimental annotation for the antiporter activity based on functional
      characterization of the recombinant G6P transporter and the demonstration that
      GSD-1b mutations disrupt G6P transport.
    action: ACCEPT
    reason: >-
      Foundational functional characterization establishing the molecular activity of the
      transporter and its loss in disease mutants. Core function.
    supported_by:
    - reference_id: PMID:10026167
      supporting_text: >-
        mutations uncovered in GSD-1b patients disrupt G6P
- term:
    id: GO:0061513
    label: glucose 6-phosphate:phosphate antiporter activity
  evidence_type: EXP
  original_reference_id: PMID:33964207
  qualifier: enables
  review:
    summary: >-
      Experimental annotation for the antiporter activity; SLC37A4 is required for
      transporting glucose-6-phosphate into the ER, where it is hydrolyzed to glucose and
      phosphate.
    action: ACCEPT
    reason: >-
      Supports the transport/antiport function of the ER-localized transporter. Core
      molecular function.
    supported_by:
    - reference_id: PMID:33964207
      supporting_text: >-
        required for transporting glucose-6-phosphate (Glc-6P) into the ER
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:33964207
  qualifier: located_in
  review:
    summary: >-
      IDA localization of SLC37A4 to the ER membrane (wild-type protein), consistent with
      other experimental localization data.
    action: ACCEPT
    reason: >-
      Directly observed ER localization of the wild-type transporter. Core localization.
    supported_by:
    - reference_id: PMID:33964207
      supporting_text: >-
        SLC37A4 encodes an endoplasmic reticulum (ER)-localized multitransmembrane
- term:
    id: GO:0015760
    label: glucose-6-phosphate transport
  evidence_type: IMP
  original_reference_id: PMID:10026167
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation for glucose-6-phosphate transport; GSD-1b mutations were shown to
      disrupt G6P transport, implicating SLC37A4 in this process.
    action: ACCEPT
    reason: >-
      Mutational evidence directly links SLC37A4 to the G6P transport process. Core.
    supported_by:
    - reference_id: PMID:10026167
      supporting_text: >-
        mutations uncovered in GSD-1b patients disrupt G6P
- term:
    id: GO:0015760
    label: glucose-6-phosphate transport
  evidence_type: IMP
  original_reference_id: PMID:33964207
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation for glucose-6-phosphate transport, from characterization of the
      SLC37A4 R423* variant and the transporter's role in importing G6P into the ER.
    action: ACCEPT
    reason: >-
      Supports the core G6P transport process of SLC37A4. Core.
    supported_by:
    - reference_id: PMID:33964207
      supporting_text: >-
        required for transporting glucose-6-phosphate (Glc-6P) into the ER
- term:
    id: GO:0061513
    label: glucose 6-phosphate:phosphate antiporter activity
  evidence_type: IDA
  original_reference_id: PMID:18337460
  qualifier: enables
  review:
    summary: >-
      IDA annotation for the G6P:Pi antiporter activity from proteoliposome transport
      assays (MGI-assigned; same primary paper as the EXP annotation).
    action: ACCEPT
    reason: >-
      Direct assay of the dual G6P/Pi antiport function. Core molecular function.
    supported_by:
    - reference_id: PMID:18337460
      supporting_text: >-
        our results suggest that G6PT has a dual role as a G6P and a P(i)
- term:
    id: GO:0015760
    label: glucose-6-phosphate transport
  evidence_type: NAS
  original_reference_id: PMID:9428641
  qualifier: involved_in
  review:
    summary: >-
      NAS annotation for glucose-6-phosphate transport based on the original cDNA cloning,
      identifying the protein as the glucose-6-phosphate translocase functionally
      associated with glucose-6-phosphatase.
    action: ACCEPT
    reason: >-
      The founding paper assigns the G6P translocase role; concordant with later
      experimental evidence for the core transport process.
    supported_by:
    - reference_id: PMID:9428641
      supporting_text: >-
        most likely the glucose 6-phosphate translocase that is
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:21949678
  qualifier: located_in
  review:
    summary: >-
      IDA localization to the ER membrane, based on immunofluorescence co-localization
      with the ER marker calreticulin.
    action: ACCEPT
    reason: >-
      Direct experimental support for ER membrane localization. Core localization.
    supported_by:
    - reference_id: PMID:21949678
      supporting_text: >-
        The glucose-6-phosphate transporter (G6PT, also known as SLC37A4) is localized in the endoplasmic reticulum (ER) membrane
- term:
    id: GO:0015760
    label: glucose-6-phosphate transport
  evidence_type: IDA
  original_reference_id: PMID:21949678
  qualifier: involved_in
  review:
    summary: >-
      IDA annotation for glucose-6-phosphate transport from reconstituted proteoliposome
      G6P uptake assays for G6PT/SLC37A4.
    action: ACCEPT
    reason: >-
      Direct functional demonstration of G6P transport; core process.
    supported_by:
    - reference_id: PMID:21949678
      supporting_text: >-
        The primary function of G6PT is to translocate G6P from the cytoplasm into the lumen of the ER for hydrolysis into glucose and Pi
- term:
    id: GO:0035435
    label: phosphate ion transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:21949678
  qualifier: involved_in
  review:
    summary: >-
      IDA annotation for phosphate ion transmembrane transport, from proteoliposome assays
      showing Pi uptake as the counter-substrate of the G6P:Pi antiport.
    action: KEEP_AS_NON_CORE
    reason: >-
      Pi transport is directly measured but represents the counter-transport leg of the
      antiporter; the G6P-directed function is the physiologically core role. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:18337460
      supporting_text: >-
        our results suggest that G6PT has a dual role as a G6P and a P(i)
- term:
    id: GO:0061513
    label: glucose 6-phosphate:phosphate antiporter activity
  evidence_type: IDA
  original_reference_id: PMID:21949678
  qualifier: enables
  review:
    summary: >-
      IDA annotation for the G6P:Pi antiporter activity from reconstituted proteoliposomes;
      G6PT is the physiological ER G6P antiporter that couples to glucose-6-phosphatase-α.
    action: ACCEPT
    reason: >-
      Direct biochemical demonstration of the defining antiporter activity, including CHA
      sensitivity and coupling to G6Pase-α that distinguishes G6PT from other SLC37
      members. Core function.
    supported_by:
    - reference_id: PMID:21949678
      supporting_text: >-
        Taken together these findings suggest that only SCL37A4 contributes to interprandial blood glucose homeostasis
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: >-
      High-throughput direct assay (membrane proteomics of an NK-like cell line) detecting
      SLC37A4 in the membrane fraction. Confirms membrane association but is unspecific.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      A proteomics hit to the generic "membrane" term adds nothing beyond the specific,
      experimentally established ER membrane localization. Over-annotation (kept, not
      removed).
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: >-
        approximately 40% of
        the identified proteins were predicted as plausible membrane proteins
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3229118
  qualifier: located_in
  review:
    summary: >-
      TAS (Reactome) annotation for ER membrane localization, consistent with all
      experimental localization data.
    action: ACCEPT
    reason: >-
      Correct core localization from an authoritative pathway source.
    supported_by:
    - reference_id: PMID:21949678
      supporting_text: >-
        The glucose-6-phosphate transporter (G6PT, also known as SLC37A4) is localized in the endoplasmic reticulum (ER) membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-198513
  qualifier: located_in
  review:
    summary: >-
      TAS (Reactome) annotation for ER membrane localization (G6P/Pi exchange reaction
      across the ER membrane).
    action: ACCEPT
    reason: >-
      Correct core localization; concordant with experimental data.
    supported_by:
    - reference_id: PMID:21949678
      supporting_text: >-
        The glucose-6-phosphate transporter (G6PT, also known as SLC37A4) is localized in the endoplasmic reticulum (ER) membrane
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: NAS
  original_reference_id: PMID:212064
  qualifier: located_in
  review:
    summary: >-
      NAS annotation to the general "endoplasmic reticulum" term, from an early
      description of a GSD type I variant attributed to a defect in the G6P transport
      system.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct compartment but less specific than the well-supported ER membrane term; the
      transporter is an integral membrane protein, so ER membrane is preferred. Keep as
      non-core / less specific.
    supported_by:
    - reference_id: PMID:212064
      supporting_text: >-
        A new variant of glycogen storage disease type I probably due to a defect in the
        glucose-6-phosphate transport system
- term:
    id: GO:0006006
    label: glucose metabolic process
  evidence_type: NAS
  original_reference_id: PMID:9428641
  qualifier: involved_in
  review:
    summary: >-
      NAS annotation to the broad "glucose metabolic process" term. SLC37A4 participates in
      glucose metabolism by supplying G6P for hydrolysis to glucose, but this is a very
      general process term.
    action: KEEP_AS_NON_CORE
    reason: >-
      True but broad; the specific G6P transport and glucose homeostasis terms capture the
      informative process roles. Keep as non-core parent.
    supported_by:
    - reference_id: PMID:9428641
      supporting_text: >-
        most likely the glucose 6-phosphate translocase that is
- term:
    id: GO:0015152
    label: glucose-6-phosphate transmembrane transporter activity
  evidence_type: IMP
  original_reference_id: PMID:12560945
  qualifier: enables
  review:
    summary: >-
      IMP annotation for glucose-6-phosphate transmembrane transporter activity; mutations
      in the transporter's signature motif abolish microsomal G6P uptake, showing the
      motif is required for G6P transport.
    action: ACCEPT
    reason: >-
      Mutational evidence directly supports G6P transmembrane transporter activity. This
      is a correct, informative MF term (a close, slightly less specific companion to the
      G6P:Pi antiporter term). Core function.
    supported_by:
    - reference_id: PMID:12560945
      supporting_text: >-
        the signature motif is a
- term:
    id: GO:0015152
    label: glucose-6-phosphate transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:11140953
  qualifier: enables
  isoform: O43826-2
  review:
    summary: >-
      IDA annotation (on isoform 2, the variant vG6PT) for glucose-6-phosphate
      transmembrane transporter activity; vG6PT is active in microsomal G6P transport. The
      isoform field records what was assayed, not an isoform-unique function.
    action: ACCEPT
    reason: >-
      Direct demonstration that isoform 2 also transports G6P confirms the MF and shows the
      exon-7 luminal-loop insertion does not impair transport. Core function (isoform 2).
    supported_by:
    - reference_id: PMID:11140953
      supporting_text: >-
        vG6PT is also active in microsomal G6P
- term:
    id: GO:0015760
    label: glucose-6-phosphate transport
  evidence_type: IMP
  original_reference_id: PMID:12560945
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation for glucose-6-phosphate transport; signature-motif mutants lack
      microsomal G6P uptake, implicating SLC37A4 in the transport process.
    action: ACCEPT
    reason: >-
      Mutational evidence supports the core G6P transport process. Core.
    supported_by:
    - reference_id: PMID:12560945
      supporting_text: >-
        required for microsomal glucose-6-phosphate transport
- term:
    id: GO:0015760
    label: glucose-6-phosphate transport
  evidence_type: IDA
  original_reference_id: PMID:11140953
  qualifier: involved_in
  isoform: O43826-2
  review:
    summary: >-
      IDA annotation (on isoform 2/vG6PT) for glucose-6-phosphate transport; the variant
      isoform is active in microsomal G6P transport.
    action: ACCEPT
    reason: >-
      Direct evidence that isoform 2 carries out G6P transport. Core process (isoform 2);
      not a unique isoform function.
    supported_by:
    - reference_id: PMID:11140953
      supporting_text: >-
        vG6PT is also active in microsomal G6P
- term:
    id: GO:0016020
    label: membrane
  evidence_type: NAS
  original_reference_id: PMID:9428641
  qualifier: located_in
  review:
    summary: >-
      NAS annotation to the generic "membrane" term based on the original cloning of a
      transmembrane protein with a C-terminal ER retention motif.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The generic membrane term is subsumed by the specific ER membrane localization
      (the same paper notes the ER retention motif). Over-annotation.
    supported_by:
    - reference_id: PMID:9428641
      supporting_text: >-
        presents at its carboxy terminus the consensus motif for retention in the
- term:
    id: GO:0042593
    label: glucose homeostasis
  evidence_type: IDA
  original_reference_id: PMID:11140953
  qualifier: involved_in
  isoform: O43826-2
  review:
    summary: >-
      IDA annotation (on isoform 2/vG6PT) for glucose homeostasis; the G6P transporter
      works together with glucose-6-phosphatase to maintain glucose homeostasis.
    action: ACCEPT
    reason: >-
      SLC37A4/G6PT has a central, experimentally supported role in interprandial
      blood-glucose homeostasis by supplying G6P for hydrolysis to glucose. A core
      physiological process for this gene.
    supported_by:
    - reference_id: PMID:11140953
      supporting_text: >-
        which works together with glucose-6-phosphatase to maintain glucose homeostasis
core_functions:
- description: >-
    Glucose-6-phosphate:inorganic-phosphate antiport across the endoplasmic reticulum
    membrane, moving cytosolic glucose-6-phosphate into the ER lumen in exchange for
    luminal inorganic phosphate.
  molecular_function:
    id: GO:0061513
    label: glucose 6-phosphate:phosphate antiporter activity
  directly_involved_in:
  - id: GO:0015760
    label: glucose-6-phosphate transport
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:18337460
    supporting_text: >-
      our results suggest that G6PT has a dual role as a G6P and a P(i)
  - reference_id: PMID:21949678
    supporting_text: >-
      The primary function of G6PT is to translocate G6P from the cytoplasm into the lumen of the ER for hydrolysis into glucose and Pi
- description: >-
    Glucose-6-phosphate transmembrane transport into the ER, delivering G6P substrate to
    the luminal glucose-6-phosphatase catalytic subunits and thereby supporting
    interprandial blood-glucose homeostasis (terminal step of gluconeogenesis and
    glycogenolysis).
  molecular_function:
    id: GO:0015152
    label: glucose-6-phosphate transmembrane transporter activity
  directly_involved_in:
  - id: GO:0042593
    label: glucose homeostasis
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:12560945
    supporting_text: >-
      required for microsomal glucose-6-phosphate transport
  - reference_id: PMID:21949678
    supporting_text: >-
      Together, the G6PT/G6Pase-α complex maintains interprandial glucose homeostasis
proposed_new_terms: []
suggested_questions:
- question: >-
    Beyond the hepatic G6PC1 axis, how does G6PT (with the ubiquitous G6PC3) support
    neutrophil function, and what molecular mechanism links the transporter defect to
    neutropenia and neutrophil dysfunction in GSD Ib?
- question: >-
    Do the two SLC37A4 isoforms (canonical vs vG6PT) differ in tissue-specific
    regulation or kinetics despite both being active G6P transporters?
suggested_experiments:
- description: >-
    Cryo-EM/functional dissection of the G6P:Pi antiport cycle to define the
    stoichiometry and the residues gating G6P entry versus Pi counter-transport (building
    on the 2025 structures), and test how GSD Ib missense variants perturb each half-cycle.
- description: >-
    Cell-based assays coupling G6PT with G6PC1 versus G6PC3 to quantify how the
    transporter partitions between the hepatic gluconeogenic and the neutrophil
    (energy/1,5-anhydroglucitol-6-phosphate detox) systems.
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: PMID:10026167
  title: Inactivation of the glucose 6-phosphate transporter causes glycogen storage
    disease type 1b.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Foundational functional characterization of recombinant G6PT; establishes that
      GSD-1b mutations disrupt G6P transport. Directly supports the antiporter/transport
      annotations.
- id: PMID:11140953
  title: Human variant glucose-6-phosphate transporter is active in microsomal transport.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Shows isoform 2 (vG6PT) is an active microsomal G6P transporter working with
      glucose-6-phosphatase for glucose homeostasis; source of the isoform-2 annotations.
- id: PMID:12560945
  title: The signature motif in human glucose-6-phosphate transporter is essential
    for microsomal transport of glucose-6-phosphate.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Signature-motif mutants lack microsomal G6P uptake; supports G6P transmembrane
      transporter activity and the G6P transport process.
- id: PMID:18337460
  title: The glucose-6-phosphate transporter is a phosphate-linked antiporter deficient
    in glycogen storage disease type Ib and Ic.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reconstituted-proteoliposome demonstration of the dual G6P/Pi antiport function and
      that GSD-Ib and GSD-Ic map to the same G6PT gene. Primary support for GO:0061513.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput membrane proteomics of an NK-like cell line; only supports the
      generic "membrane" term, which is subsumed by the specific ER membrane localization.
- id: PMID:212064
  title: A new variant of glycogen storage disease type I probably due to a defect
    in the glucose-6-phosphate transport system.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Early clinical description of a GSD type I variant attributed to defective G6P
      transport; historical support for the ER/transport role.
- id: PMID:21949678
  title: SLC37A1 and SLC37A2 are phosphate-linked, glucose-6-phosphate antiporters.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Although the title foregrounds SLC37A1/A2, the full text extensively characterizes
      G6PT/SLC37A4 as the physiological ER G6P:Pi antiporter (positive control), including
      CHA sensitivity, coupling to G6Pase-α, and ER localization. Strongly supports the
      SLC37A4 MF, BP and CC annotations.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI high-throughput Y2H interactome; source of the bare "protein binding" (BIK)
      IPI. No established functional consequence for the antiporter; flagged as
      over-annotated.
- id: PMID:32884905
  title: 'SLC37A4-CDG: Mislocalization of the glucose-6-phosphate transporter to the
    Golgi causes a new congenital disorder of glycosylation.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes ER localization of wild-type SLC37A4 and that the dominant R423*
      variant mislocalizes to the Golgi causing CDG-IIw. Supports ER membrane localization.
- id: PMID:33964207
  title: A mutation in SLC37A4 causes a dominantly inherited congenital disorder of
    glycosylation characterized by liver dysfunction.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Describes SLC37A4 as an ER-localized multitransmembrane protein required for
      transporting G6P into the ER; the dominant CDG variant. Supports transport and ER
      membrane annotations.
- id: PMID:9428641
  title: Sequence of a putative glucose 6-phosphate translocase, mutated in glycogen
    storage disease type Ib.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Original cDNA cloning; identifies the protein as the G6P translocase functionally
      associated with glucose-6-phosphatase, with a C-terminal ER retention motif.
- id: Reactome:R-HSA-198513
  title: 'SLC7A4 exchanges G6P for Pi across the ER membrane '
  findings: []
- id: Reactome:R-HSA-3229118
  title: Defective SLC37A4 does not exchange G6P and Pi across the ER membrane
  findings: []
- id: Reactome:R-HSA-70263
  title: Gluconeogenesis
  findings: []