VCV000202000.13 - ClinVar

NM_001005242.3(PKP2):c.1744T>A (p.Tyr582Asn)

Germline

Classification

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

Uncertain significance
Uncertain significance (5)

5 out of 5 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_001005242.3(PKP2):c.1744T>A (p.Tyr582Asn)

Variation ID: 202000 Accession: VCV000202000.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p11.21 12: 32822562 (GRCh38) [ NCBI UCSC ] 12: 32975496 (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	Jul 5, 2015	Feb 15, 2026	Dec 23, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_001005242.3:c.1744T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001005242.2:p.Tyr582Asn	missense
NM_004572.4:c.1876T>A	NP_004563.2:p.Tyr626Asn	missense
NC_000012.12:g.32822562A>T
NC_000012.11:g.32975496A>T
NG_009000.1:g.79285T>A
LRG_398:g.79285T>A
LRG_398t1:c.1876T>A	LRG_398p1:p.Tyr626Asn

... more HGVS ... less HGVS

Protein change

Y626N, Y582N

Other names

p.Y626N:TAT>AAT

Canonical SPDI

NC_000012.12:32822561:A:T

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.

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

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Links

ClinGen: CA011539 dbSNP: rs794729112 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.
PKP2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2359	2419

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.
not provided	Uncertain significance (1)	criteria provided, single submitter	Apr 10, 2018	RCV000183762.1
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Jul 24, 2025	RCV000617549.5
Arrhythmogenic right ventricular dysplasia 9	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 23, 2025	RCV000640019.7
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Nov 15, 2023	RCV006547771.1

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 (Nov 16, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Arrhythmogenic right ventricular dysplasia 9	Fulgent Genetics, Fulgent Genetics Accession: SCV002782079.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	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 (Jul 24, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV000738225.7 First in ClinVar: Apr 14, 2018 Last updated: Oct 05, 2025	Comment: show The p.Y626N variant (also known as c.1876T>A), located in coding exon 9 of the PKP2 gene, results from a T to A substitution at nucleotide position 1876. The tyrosine at codon 626 is replaced by asparagine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (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 (Dec 23, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Arrhythmogenic right ventricular dysplasia 9	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000761606.5 First in ClinVar: May 28, 2018 Last updated: Feb 15, 2026	Comment: show This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 626 of the PKP2 protein (p.Tyr626Asn). This variant is present in population databases (rs794729112, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with PKP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 202000). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 15, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV007441708.1 First in ClinVar: Feb 15, 2026 Last updated: Feb 15, 2026	Comment: show This missense variant replaces tyrosine with asparagine at codon 626 of the PKP2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PKP2-related disorders in the literature. This variant has been identified in 1/251282 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Platform type: NGS

Uncertain significance (Apr 10, 2018) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	not provided	GeneDx Accession: SCV000236243.11 First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015	Comment: show The Y626N variant of uncertain significance in the PKP2 gene has not been published as pathogenic or benign to our knowledge. The Y626N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In addition, Y626N is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Moreover, Y626N has been identified independently and/or in conjunction with additional cardiogenetic variants in other individuals referred for genetic testing at GeneDx; however, segregation data is absent for these individuals due to the lack of clinical information provided and insufficient participation by informative family members. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Comment:

The p.Y626N variant (also known as c.1876T>A), located in coding exon 9 of the PKP2 gene, results from a T to A substitution at nucleotide position 1876. The tyrosine at codon 626 is replaced by asparagine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 626 of the PKP2 protein (p.Tyr626Asn). This variant is present in population databases (rs794729112, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with PKP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 202000). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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:

This missense variant replaces tyrosine with asparagine at codon 626 of the PKP2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PKP2-related disorders in the literature. This variant has been identified in 1/251282 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

The Y626N variant of uncertain significance in the PKP2 gene has not been published as pathogenic or benign to our knowledge. The Y626N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In addition, Y626N is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Moreover, Y626N has been identified independently and/or in conjunction with additional cardiogenetic variants in other individuals referred for genetic testing at GeneDx; however, segregation data is absent for these individuals due to the lack of clinical information provided and insufficient participation by informative family members.

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 rs794729112 ...

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 Feb 15, 2026