VCV000196052.52 - ClinVar

NM_138694.4(PKHD1):c.2854G>A (p.Gly952Arg)

Germline

Classification

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

Pathogenic/Likely pathogenic
Pathogenic (8); Likely pathogenic (1)

9 out of 11 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_138694.4(PKHD1):c.2854G>A (p.Gly952Arg)

Variation ID: 196052 Accession: VCV000196052.52

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p12.2 6: 52043102 (GRCh38) [ NCBI UCSC ] 6: 51907900 (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	Jun 28, 2015	Apr 4, 2026	Dec 24, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_138694.4:c.2854G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_619639.3:p.Gly952Arg	missense
NM_170724.3:c.2854G>A	NP_733842.2:p.Gly952Arg	missense
NC_000006.12:g.52043102C>T
NC_000006.11:g.51907900C>T
NG_008753.1:g.49524G>A

... more HGVS ... less HGVS

Protein change

G952R

Other names

Canonical SPDI

NC_000006.12:52043101:C: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

ClinGen: CA275144 dbSNP: rs773136605 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.
PKHD1		-	-	GRCh38 GRCh37	6627	6937

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.
Autosomal recessive polycystic kidney disease	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 24, 2025	RCV000176777.15
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jun 3, 2022	RCV000724042.10
Polycystic kidney disease 4	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 9, 2024	RCV001198369.5
Autosomal dominant polycystic liver disease	Likely pathogenic (1)	no assertion criteria provided	Sep 1, 2021	RCV001844815.2

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.
Pathogenic (Jul 05, 2018) C Contributing to aggregate classification	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	not provided	Blueprint Genetics Accession: SCV000927782.1 First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 Comment: Patient analyzed with Polycystic Kidney Disease Panel	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (May 21, 2021) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Autosomal recessive polycystic kidney disease	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001737689.1 First in ClinVar: Jun 23, 2021 Last updated: Jun 23, 2021	Publications: PubMed (3) PubMed: 16133180‚ 27225849‚ 33845788 Comment: show Variant summary: PKHD1 c.2854G>A (p.Gly952Arg) results in a non-conservative amino acid change located in the IPT domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250594 control chromosomes. c.2854G>A has been reported in the literature in multiple individuals affected with Polycystic Kidney And Hepatic Disease (Losekoot_2005, Melchionda_2016, Yao_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (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

Pathogenic (Jun 03, 2022) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV002525272.3 First in ClinVar: Jun 10, 2022 Last updated: Mar 04, 2023	Comment: show Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16133180, 27225849, 33845788) (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

Pathogenic (Jan 09, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Polycystic kidney disease 4	Baylor Genetics Accession: SCV004202213.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Dec 01, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	Autosomal recessive polycystic kidney disease	Natera, Inc. Accession: SCV002081012.2 First in ClinVar: Apr 23, 2022 Last updated: Apr 04, 2026	Publications: PubMed (1) PubMed: 16133180 Comment: show The c.2854G>A variant in PKHD1 is a missense variant predicted to cause substitution of glycine to arginine at amino acid 952. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 16133180). Given the available evidence, this variant is classified as Pathogenic. (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

Likely pathogenic (Dec 11, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Polycystic kidney disease 4	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001369281.2 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: show This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP3. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes

Pathogenic (Jun 05, 2014) C Contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015)	not provided	Eurofins Ntd Llc (ga) Accession: SCV000228491.6 First in ClinVar: Jun 28, 2015 Last updated: Apr 13, 2025	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PKHD1 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 Number of individuals with the variant: 1 Zygosity: 1 Single Heterozygote Sex: mixed

Pathogenic (Aug 03, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Polycystic kidney disease 4	Department of Pathology and Laboratory Medicine, Sinai Health System Accession: SCV005912467.1 First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025	Observation: 1 Collection method: research Allele origin: germline Affected status: unknown Observation 1 Collection method: research Allele origin: germline Affected status: unknown

Pathogenic (Dec 24, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Autosomal recessive polycystic kidney disease	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001199787.7 First in ClinVar: Apr 15, 2020 Last updated: Mar 07, 2026	Publications: PubMed (2) PubMed: 16133180‚ 27225849 Comment: show This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 952 of the PKHD1 protein (p.Gly952Arg). This variant is present in population databases (rs773136605, gnomAD 0.01%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 16133180, 27225849). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 196052). 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 PKHD1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (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

Likely pathogenic (Sep 05, 2016) N Not contributing to aggregate classification	no assertion criteria provided	Polycystic kidney disease 4	Division of Human Genetics, Children's Hospital of Philadelphia Study: CSER-PediSeq Accession: SCV000536850.1 First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015	Publications: PubMed (1) PubMed: 16133180 Observation: 1 Collection method: research Allele origin: maternal Affected status: unknown Observation 1 Collection method: research Allele origin: maternal Affected status: unknown

Likely pathogenic (Sep 01, 2021) N Not contributing to aggregate classification	no assertion criteria provided	Autosomal dominant polycystic liver disease	Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center Accession: SCV001876987.2 First in ClinVar: Mar 19, 2022 Last updated: Apr 13, 2025	Observation: 1 Collection method: research Allele origin: germline Affected status: yes more Observation 1 Collection method: research Allele origin: germline Affected status: yes Sex: female Geographic origin: Netherlands

Comment:

Variant summary: PKHD1 c.2854G>A (p.Gly952Arg) results in a non-conservative amino acid change located in the IPT domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250594 control chromosomes. c.2854G>A has been reported in the literature in multiple individuals affected with Polycystic Kidney And Hepatic Disease (Losekoot_2005, Melchionda_2016, Yao_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16133180, 27225849, 33845788)

Comment:

The c.2854G>A variant in PKHD1 is a missense variant predicted to cause substitution of glycine to arginine at amino acid 952. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 16133180). Given the available evidence, this variant is classified as Pathogenic.

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 952 of the PKHD1 protein (p.Gly952Arg). This variant is present in population databases (rs773136605, gnomAD 0.01%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 16133180, 27225849). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 196052). 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 PKHD1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Imaging manifestations of Caroli disease with autosomal recessive polycystic kidney disease: a case report and literature review.	Yao X	BMC pregnancy and childbirth	2021	PMID: 33845788
Expanding the mutation spectrum in 130 probands with ARPKD: identification of 62 novel PKHD1 mutations by sanger sequencing and MLPA analysis.	Melchionda S	Journal of human genetics	2016	PMID: 27225849
Analysis of missense variants in the PKHD1-gene in patients with autosomal recessive polycystic kidney disease (ARPKD).	Losekoot M	Human genetics	2005	PMID: 16133180
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PKHD1	-	-	-	-

Text-mined citations for rs773136605 ...

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