Is PLK2 p.Ile441Thr (c.1322T>C) pathogenic?

PLK2 p.Ile441Thr (c.1322T>C) is classified Uncertain significance in PLK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: likely benign (0.0643); Very rare (popmax 0.0011%, sas).

How common is PLK2 p.Ile441Thr (c.1322T>C) in the general population?

PLK2 p.Ile441Thr (c.1322T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about PLK2 p.Ile441Thr (c.1322T>C)?

AlphaMissense predicts likely benign (score 0.0643) — an in-silico prediction, not a clinical call.

PLK2 p.Ile441Thr

c.1322T>C · VCV4569570

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0643 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0643	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -4.54	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2.5, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 1,312 bp · p 0.031 · regional, not allelic
Overall
CADD	17.98	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0011% South Asian · 1/91,082 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000558% 9/1,613,684 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,082
European (non-Finnish)	0.000678%	147,478

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: PLK2
Protein: p.Ile441Thr
Coding: c.1322T>C
MANE Select: NM_006622
Type: single nucleotide variant
Location: chr5:58456088 (GRCh38)
Gene constraint: LOEUF 0.471 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.64 · 7 PDB

Full PLK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLK2 p.Ile595Thr Likely benign ★★ same type
PLK2 p.Ala12Thr Uncertain significance ★ ⚠ same type
PLK2 p.Ala12Val Uncertain significance ★ ⚠ same type
PLK2 p.Ala434Thr Uncertain significance ★ ⚠ same type
PLK2 p.Ala54Val Uncertain significance ★ ⚠ same type
PLK2 p.Ala55Val Uncertain significance ★ ⚠ same type
PLK2 p.Arg183Ter Uncertain significance ★ same type
PLK2 p.Arg596Gln 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/plk2-p-ile441thr (accessed [today's date]).

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