ClinVar Genomic variation as it relates to human health
NM_002576.5(PAK1):c.1225G>A (p.Gly409Arg)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002576.5(PAK1):c.1225G>A (p.Gly409Arg)
Variation ID: 985490 Accession: VCV000985490.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.5 11: 77336274 (GRCh38) [ NCBI UCSC ] 11: 77047319 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Nov 21, 2020 May 1, 2024 Jun 29, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002576.5:c.1225G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002567.3:p.Gly409Arg missense NM_001128620.2:c.1225G>A NP_001122092.1:p.Gly409Arg missense NM_001376268.1:c.1225G>A NP_001363197.1:p.Gly409Arg missense NM_001376269.1:c.1225G>A NP_001363198.1:p.Gly409Arg missense NM_001376270.1:c.1225G>A NP_001363199.1:p.Gly409Arg missense NM_001376271.1:c.1225G>A NP_001363200.1:p.Gly409Arg missense NM_001376272.1:c.1246G>A NP_001363201.1:p.Gly416Arg missense NM_001376273.1:c.1225G>A NP_001363202.1:p.Gly409Arg missense NM_001376274.1:c.1225G>A NP_001363203.1:p.Gly409Arg missense NM_001376275.1:c.1225G>A NP_001363204.1:p.Gly409Arg missense NM_001376276.1:c.1225G>A NP_001363205.1:p.Gly409Arg missense NM_001376277.1:c.1225G>A NP_001363206.1:p.Gly409Arg missense NM_001376278.1:c.1225G>A NP_001363207.1:p.Gly409Arg missense NM_001376279.1:c.1225G>A NP_001363208.1:p.Gly409Arg missense NM_001376280.1:c.1225G>A NP_001363209.1:p.Gly409Arg missense NM_001376281.1:c.1225G>A NP_001363210.1:p.Gly409Arg missense NM_001376282.1:c.1225G>A NP_001363211.1:p.Gly409Arg missense NM_001376283.1:c.1225G>A NP_001363212.1:p.Gly409Arg missense NM_001376284.1:c.1225G>A NP_001363213.1:p.Gly409Arg missense NM_001376285.1:c.1225G>A NP_001363214.1:p.Gly409Arg missense NM_001376286.1:c.1225G>A NP_001363215.1:p.Gly409Arg missense NM_001376287.1:c.1225G>A NP_001363216.1:p.Gly409Arg missense NM_001376288.1:c.1225G>A NP_001363217.1:p.Gly409Arg missense NM_001376289.1:c.1225G>A NP_001363218.1:p.Gly409Arg missense NM_001376290.1:c.1117-15G>A intron variant NM_001376291.1:c.1117-15G>A intron variant NM_001376292.1:c.1225G>A NP_001363221.1:p.Gly409Arg missense NM_001376293.1:c.1225G>A NP_001363222.1:p.Gly409Arg missense NM_001376294.1:c.1216G>A NP_001363223.1:p.Gly406Arg missense NM_001376295.1:c.1048G>A NP_001363224.1:p.Gly350Arg missense NM_001376301.1:c.976G>A NP_001363230.1:p.Gly326Arg missense NM_001376302.1:c.931G>A NP_001363231.1:p.Gly311Arg missense NM_001376303.1:c.937G>A NP_001363232.1:p.Gly313Arg missense NM_001376304.1:c.931G>A NP_001363233.1:p.Gly311Arg missense NM_001376305.1:c.931G>A NP_001363234.1:p.Gly311Arg missense NR_164797.1:n.1441G>A non-coding transcript variant NR_164798.1:n.1444G>A non-coding transcript variant NC_000011.10:g.77336274C>T NC_000011.9:g.77047319C>T NG_029900.2:g.142790G>A - Protein change
- G311R, G313R, G326R, G350R, G406R, G409R, G416R
- Other names
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- Canonical SPDI
- NC_000011.10:77336273:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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PAK1 | - | - |
GRCh38 GRCh37 |
93 | 102 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (1) |
criteria provided, single submitter
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Jun 29, 2022 | RCV001266426.4 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Jun 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001444600.4
First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024 |
Comment:
The c.1225G>A (p.G409R) alteration is located in exon 13 (coding exon 12) of the PAK1 gene. This alteration results from a G to A substitution … (more)
The c.1225G>A (p.G409R) alteration is located in exon 13 (coding exon 12) of the PAK1 gene. This alteration results from a G to A substitution at nucleotide position 1225, causing the glycine (G) at amino acid position 409 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. The p.G409 amino acid is located within the activation loop in the kinase catalytic core (Lei, 2000). PAK1 exists as an autoinhibited homodimer until its kinase activity is activated by binding to the GTP-bound forms of Rho GTPases, CDC42 and RAC1 (reviewed in Harms, 2018). The activation loop is bound by the N-terminal kinase inhibitory (KI) segment in the autoinhibited conformation of the PAK1 dimer. Upon binding of the dimer to CDC42 or RAC1, a conformational change releases the activation loop from the KI segment followed by phosphorylation to activate the PAK1 kinase enzyme (Lei, 2000). This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Activating Mutations in PAK1, Encoding p21-Activated Kinase 1, Cause a Neurodevelopmental Disorder. | Harms FL | American journal of human genetics | 2018 | PMID: 30290153 |
Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch. | Lei M | Cell | 2000 | PMID: 10975528 |
Text-mined citations for rs1942667410 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.