Is PKD2 p.Arg496Pro (c.1487G>C) pathogenic?

PKD2 p.Arg496Pro (c.1487G>C) is classified Uncertain significance in PKD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-17). AlphaMissense: likely pathogenic (0.8805); Absent from gnomAD v4.1; Associated with polycystic kidney disease 2.

What condition is associated with PKD2 p.Arg496Pro (c.1487G>C)?

PKD2 p.Arg496Pro (c.1487G>C) is associated with polycystic kidney disease 2 (ClinVar).

How common is PKD2 p.Arg496Pro (c.1487G>C) in the general population?

PKD2 p.Arg496Pro (c.1487G>C) is absent from gnomAD v4.1 (gnomAD).

How is Autosomal dominant polycystic kidney disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PKD2 p.Arg496Pro (c.1487G>C)?

AlphaMissense predicts likely pathogenic (score 0.8805) — an in-silico prediction, not a clinical call.

PKD2 p.Arg496Pro

c.1487G>C · VCV4056734

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8805 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

polycystic kidney disease 2

Computational evidence

Protein change
AlphaMissense	0.8805	likely pathogenic
REVEL	0.828	moderately pathogenic-leaning
SaProt	LLR -12.98	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP -2, phastCons 1
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PKD2
Protein: p.Arg496Pro
Coding: c.1487G>C
MANE Select: NM_000297
Type: single nucleotide variant
Location: chr4:88046809 (GRCh38)
Structure: AlphaFold pLDDT 69.85 · 4 PDB
Residue 496: the ph domain; a UniProt-annotated variant site (in); an α-helix

Full PKD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

polycystic kidney disease 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant polycystic kidney disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

PKD2 p.Arg496Cys Uncertain significance ★★ ⚠ same residue
PKD2 p.Arg496His Uncertain significance ★★ ⚠ same residue
PKD2 p.Arg496Leu Uncertain significance ★ ⚠ same residue
PKD2 c.1094+1G>A Pathogenic ★★ same condition
PKD2 c.1094+1G>C Pathogenic ★★ same condition
PKD2 c.1319+1G>A Pathogenic/Likely pathogenic ★★ same condition
PKD2 c.1320-2A>C Pathogenic/Likely pathogenic ★★ same condition
PKD2 c.1548+1G>A Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pkd2-p-arg496pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown