Is PKD2 p.Arg440Ser (c.1320G>T) pathogenic?

PKD2 p.Arg440Ser (c.1320G>T) is classified Pathogenic/Likely pathogenic in PKD2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2025-04-02). AlphaMissense: likely pathogenic (0.7221); Very rare (popmax 0.000263%, nfe); Associated with PKD2-related disorder.

What condition is associated with PKD2 p.Arg440Ser (c.1320G>T)?

PKD2 p.Arg440Ser (c.1320G>T) is associated with PKD2-related disorder, autosomal dominant polycystic kidney disease, polycystic kidney disease 2 (ClinVar).

How common is PKD2 p.Arg440Ser (c.1320G>T) in the general population?

PKD2 p.Arg440Ser (c.1320G>T) is very rare (popmax 0.000263%, nfe) (gnomAD).

What do computational predictors say about PKD2 p.Arg440Ser (c.1320G>T)?

AlphaMissense predicts likely pathogenic (score 0.7221) — an in-silico prediction, not a clinical call.

PKD2 p.Arg440Ser

c.1320G>T · rs886041114 · VCV811865

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.7221 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000263%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

PKD2-related disorder

Computational evidence

Protein change
AlphaMissense	0.7221	likely pathogenic ✓ concordant with ClinVar
REVEL	0.553	indeterminate
SaProt	LLR -8.02	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.67	acceptor loss at this position · masked 0 · deltas
Pangolin	Δ0.67	loss · gain 0.08 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.5	GERP 1, phastCons 1
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000263% European (non-Finnish) · 3/1,139,734 alleles

Filtering AF 7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000191% 3/1,569,828 alleles · very rare exomes 3/1,417,544 · genomes 0/152,284 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PKD2
Protein: p.Arg440Ser
Coding: c.1320G>T
MANE Select: NM_000297
dbSNP: rs886041114
Type: single nucleotide variant
Location: chr4:88046642 (GRCh38)
Structure: AlphaFold pLDDT 69.85 · 4 PDB
Residue 440: the ph domain; a β-strand

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

Disease context

PKD2-related disorder

Also linked: autosomal dominant polycystic kidney disease polycystic kidney disease 2

Similar variants

PKD2 p.Arg440= Uncertain significance ★★ same residue
PKD2 p.Arg440fs Pathogenic ★ 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
PKD2 c.1549-1G>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-arg440ser (accessed [today's date]).

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