NM_001009944.3:c.9850T>C (p.Cys3284Arg) is a missense variant in PKD1, associated with autosomal dominant polycystic kidney disease (ADPKD). This variant is absent from gnomAD v4.1 (0/1,562,318 alleles), gnomAD v2.1, and gnomAD-Canada v1.0, meeting PM2 at moderate strength.1 REVEL meta-predictor score of 0.754 supports a deleterious effect, meeting PP3 at supporting strength.2 ClinVar contains a single submission (SCV004239210, Labor Dr. Heidrich & Kollegen MVZ GmbH) classifying this variant as Likely pathogenic, but with no assertion criteria provided; this is insufficient to meet PS5 or PP5.3 With only PM2 (moderate) and PP3 (supporting) met, the variant does not reach the threshold for Likely Pathogenic under generic ACMG/AMP 2015 combination rules (PMID:25741868). PM2 + PP3 alone constitutes a Variant of Uncertain Significance. No benign criteria are met.4
PKD1
Final classification
VUS
PKD1 c.9850T>C · p.Cys3284Arg
PKD1
NM_001009944.3:c.9850T>C (p.Cys3284Arg) is a missense variant in PKD1, associated with autosomal dominant polycystic kidney disease (ADPKD).
ClinGen Kidney Cystic and Ciliopathy Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PKD1 Version 1.0.0 v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate, PP3 supporting; combination = 1 moderate + 1 supporting, which maps to VUS.
Classification rationale
PM2PP3
VUS
PKD1 c.9850T>C
PM2 + PP3
→
VUS
Gene diagram
· NM_001009944.3 · variants mapped to exon structure
PKD1
NM_001009944.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
moderate
Pathogenic
This variant is absent from large population databases. In gnomAD v4.1, it is absent in 1,562,318 alleles (0 homozygotes, AF = 0%), absent in gnomAD v2.1, and absent in gnomAD-Canada v1.0. Using generic ACMG/AMP thresholds (PM2: AF < 0.1% with confirmed absence), this meets moderate evidence for pathogenicity.
gnomAD v4.1: 0/1562318 alleles
✓
PP3
supporting
Pathogenic
REVEL, a meta-predictor integrating multiple computational methods, scores this variant at 0.754, which exceeds the commonly used pathogenic threshold of 0.5 and supports a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.00). BayesDel score (0.242) falls in the uncertain range and does not independently support pathogenicity. REVEL alone provides sufficient computational support for PP3 at the supporting level.
REVEL: 0.754 (deleteriousabove 0.5 threshold)SpliceAI: max delta = 0.00 (no splicing impact)
Assessed · not applied
Pathogenic
PS1
No evidence of a different nucleotide change at codon 3284 with an established pathogenic classification was identified.
PS2
No de novo occurrence data with confirmed maternity and paternity were identified for this variant.
PS3
No well-established in vitro or in vivo functional studies were identified for NM_001009944.3:c.9850T>C (p.Cys3284Arg).
PS4
Insufficient data to assess variant prevalence in affected individuals vs controls.
PM1
The variant does not lie in a statistically significant mutational hotspot per the Cancer Hotspots database.
PM5
No pathogenic missense comparators at codon 3284 were identified through automated ClinVar harvesting.
PM6
No de novo occurrence data (without confirmation of paternity and maternity) were identified for this variant.
PP1
No co-segregation data with disease in multiple affected family members were identified.
PP2
PKD1 is known to harbor pathogenic missense variants in ADPKD, but gene-level missense constraint data (e.g., missense Z-score, HCI prior) were not available to formally assess a low rate of benign missense variation.
PP4
No patient-specific phenotypic data or family history information were available to assess whether the phenotype is highly specific for ADPKD with a single genetic etiology.
PP5
Same as PS5: a single ClinVar submission classifies this variant as Likely pathogenic without assertion criteria, which does not meet the PP5 threshold for a reputable source report.
Benign
BA1
Global minor allele frequency is 0.0% in gnomAD v4.1, far below the 1% threshold for BA1.
BS1
Global minor allele frequency is 0.0%, far below the 0.3% threshold for BS1 in a dominant disorder.
BS2
No data on observation of this variant in healthy adult individuals in the absence of ADPKD.
BS3
No well-established in vitro or in vivo functional studies showing no deleterious effect were identified for this variant.
BS4
No segregation data demonstrating lack of co-segregation with disease were available.
BP2
No observation of this variant in trans with a known pathogenic dominant PKD1 variant was identified.
BP4
REVEL score of 0.754 predicts a deleterious effect, contradicting the requirement for multiple lines of computational evidence suggesting no impact on gene product.
BP5
No case was identified where this variant was found in an individual with an alternate molecular basis for disease.
BP6
ClinVar classifies this variant as Likely pathogenic (1 submitter), not benign.
N/A · 6
PVS1 · PM3 · PM4 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1562318 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73802 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / 1,562,318
0 hom
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory). (ClinVarID = 2690992)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.754. BayesDel score = 0.242292.
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links