VCV000403909.13 - ClinVar

NM_006218.4(PIK3CA):c.1130C>G (p.Pro377Arg)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Uncertain significance
Uncertain significance (3)

3 out of 3 submissions contributed to this classification

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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006218.4(PIK3CA):c.1130C>G (p.Pro377Arg)

Variation ID: 403909 Accession: VCV000403909.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q26.32 3: 179204573 (GRCh38) [ NCBI UCSC ] 3: 178922361 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Oct 10, 2018	Feb 15, 2026	Oct 23, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_006218.4:c.1130C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006209.2:p.Pro377Arg	missense
NM_006218.3:c.1130C>G
NC_000003.12:g.179204573C>G
NC_000003.11:g.178922361C>G
NG_012113.2:g.61051C>G
LRG_310:g.61051C>G
LRG_310t1:c.1130C>G

... more HGVS ... less HGVS

Protein change

P377R

Other names

Canonical SPDI

NC_000003.12:179204572:C:G

Global minor allele frequency (GMAF) Help The 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.

0.00020 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00008

The Genome Aggregation Database (gnomAD), exomes 0.00006

1000 Genomes Project 30x 0.00016

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00017

1000 Genomes Project 0.00020

Exome Aggregation Consortium (ExAC) 0.00007

The Genome Aggregation Database (gnomAD) 0.00009

The Genome Aggregation Database (gnomAD) 0.00010

The Genome Aggregation Database (gnomAD), exomes 0.00013

Links

ClinGen: CA2710648 dbSNP: rs113613074 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help 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.
PIK3CA		No evidence available	No evidence available	GRCh38 GRCh37	1650	1689

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help 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 Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cowden syndrome	Uncertain significance (1)	criteria provided, single submitter	Oct 23, 2025	RCV000461259.13
CLAPO syndrome CLOVES syndrome Carcinoma of colon Congenital macrodactylia Cowden syndrome 5 Epidermal nevus Familial cancer of breast Hepatocellular carcinoma Lung carcinoma Megalencephaly-capillary malformation-polymicrogyria syndrome Neoplasm of stomach Ovarian neoplasm Seborrheic keratosis	Uncertain significance (1)	criteria provided, single submitter	Oct 31, 2018	RCV000764479.3
PIK3CA-related disorder	Uncertain significance (1)	criteria provided, single submitter	Nov 23, 2022	RCV004533141.1

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 Help 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 Help 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.	Expand all rows Collapse all rows Help 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.
Uncertain significance (Oct 31, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Familial cancer of breast Colorectal cancer Hepatocellular carcinoma Congenital macrodactylia Epidermal nevus Ovarian cancer Seborrheic keratosis Lung cancer Megalencephaly-capillary malformation-polymicrogyria syndrome CLOVES syndrome CLAPO syndrome Gastric cancer Cowden syndrome 5	Fulgent Genetics, Fulgent Genetics Accession: SCV000895550.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30 pmc: 4544753 pmc: 4544753 Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Uncertain significance (Oct 23, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Cowden syndrome	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000541312.12 First in ClinVar: Apr 17, 2017 Last updated: Feb 15, 2026	Publications: PubMed (1) PubMed: 28492532 Comment: show This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 377 of the PIK3CA protein (p.Pro377Arg). This variant is present in population databases (rs113613074, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PIK3CA-related conditions. ClinVar contains an entry for this variant (Variation ID: 403909). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PIK3CA protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Nov 23, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	PIK3CA-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV004117348.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: show The PIK3CA c.1130C>G variant is predicted to result in the amino acid substitution p.Pro377Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-178922361-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 377 of the PIK3CA protein (p.Pro377Arg). This variant is present in population databases (rs113613074, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PIK3CA-related conditions. ClinVar contains an entry for this variant (Variation ID: 403909). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PIK3CA protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The PIK3CA c.1130C>G variant is predicted to result in the amino acid substitution p.Pro377Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-178922361-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs113613074 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jul 06, 2026