Is PKN2 p.Trp437Arg (c.1309T>C) pathogenic?

PKN2 p.Trp437Arg (c.1309T>C) is classified Uncertain significance in PKN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-25). AlphaMissense: likely pathogenic (0.998); Very rare (popmax 0.00892%, eas).

How common is PKN2 p.Trp437Arg (c.1309T>C) in the general population?

PKN2 p.Trp437Arg (c.1309T>C) is very rare (popmax 0.00892%, eas) (gnomAD).

What do computational predictors say about PKN2 p.Trp437Arg (c.1309T>C)?

AlphaMissense predicts likely pathogenic (score 0.998) — an in-silico prediction, not a clinical call.

PKN2 p.Trp437Arg

c.1309T>C · VCV3307068

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.998 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.998	likely pathogenic
REVEL	0.54	indeterminate
SaProt	LLR -15.57	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 64 kb · p 1e-12 · regional, not allelic
Overall
CADD	33.0	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

Grpmax group 0.00892% East Asian · 4/44,848 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000372% 6/1,612,996 alleles · very rare exomes 4/1,460,812 · genomes 2/152,184 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00892%	11,212
South Asian	0.0022%	45,460

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: PKN2
Protein: p.Trp437Arg
Coding: c.1309T>C
MANE Select: NM_006256
Type: single nucleotide variant
Location: chr1:88804418 (GRCh38)
Gene constraint: LOEUF 0.428 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.06 · 4 PDB
Residue 437: the c2 domain; the 'necessary to rescue apical junction formation' region

Full PKN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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PKN2 p.Arg130Leu Uncertain significance ★ ⚠ same type
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PKN2 p.Arg223Lys Uncertain significance ★ ⚠ same type
PKN2 p.Arg223Ser Uncertain significance ★ ⚠ same type

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/pkn2-p-trp437arg (accessed [today's date]).

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