Is PLK4 p.Arg28Ser (c.84A>T) pathogenic?

PLK4 p.Arg28Ser (c.84A>T) is classified Uncertain significance in PLK4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-02). AlphaMissense: likely pathogenic (0.9703); Very rare (popmax 0.00051%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PLK4 p.Arg28Ser (c.84A>T)?

PLK4 p.Arg28Ser (c.84A>T) is associated with Inborn genetic diseases (ClinVar).

How common is PLK4 p.Arg28Ser (c.84A>T) in the general population?

PLK4 p.Arg28Ser (c.84A>T) is very rare (popmax 0.00051%, nfe) (gnomAD).

What do computational predictors say about PLK4 p.Arg28Ser (c.84A>T)?

AlphaMissense predicts likely pathogenic (score 0.9703) — an in-silico prediction, not a clinical call.

PLK4 p.Arg28Ser

c.84A>T · rs756460506 · VCV1462765

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9703 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00051%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9703	likely pathogenic · top 10% in PLK4
REVEL	0.364	indeterminate
SaProt	LLR -9.10	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.11, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 4,902 bp · p 1.5e-05 · regional, not allelic
Overall
CADD	24.2	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 0.00051% European (non-Finnish) · 6/1,176,040 alleles

Filtering AF 0.000184% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000412% 6/1,457,464 alleles · very rare

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: PLK4
Protein: p.Arg28Ser
Coding: c.84A>T
MANE Select: NM_014264
dbSNP: rs756460506
Type: single nucleotide variant
Location: chr4:127881884 (GRCh38)
Gene constraint: LOEUF 0.619 · pLI 0.18 (gnomAD)
Structure: AlphaFold pLDDT 66.31 · 19 PDB
Residue 28: the protein kinase domain; a β-strand

Full PLK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PLK4 p.Arg28= Likely benign ★ same residue
PLK4 p.Arg247His Uncertain significance ★★ ⚠ same condition
PLK4 p.Arg371Gln Uncertain significance ★★ ⚠ same condition
PLK4 p.Arg410Ile Uncertain significance ★★ ⚠ same condition
PLK4 p.Arg684Gln Uncertain significance ★★ ⚠ same condition
PLK4 p.Arg777His Uncertain significance ★★ ⚠ same condition
PLK4 p.Arg794Lys Uncertain significance ★★ ⚠ same condition
PLK4 p.Asn449Asp Uncertain significance ★★ ⚠ 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/plk4-p-arg28ser (accessed [today's date]).

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