Is PLK4 p.Pro164Ser (c.490C>T) pathogenic?

PLK4 p.Pro164Ser (c.490C>T) is classified Uncertain significance in PLK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-24). AlphaMissense: likely pathogenic (0.7388); Very rare (popmax 0.00237%, nfe).

How common is PLK4 p.Pro164Ser (c.490C>T) in the general population?

PLK4 p.Pro164Ser (c.490C>T) is very rare (popmax 0.00237%, nfe) (gnomAD).

What do computational predictors say about PLK4 p.Pro164Ser (c.490C>T)?

AlphaMissense predicts likely pathogenic (score 0.7388) — an in-silico prediction, not a clinical call.

PLK4 p.Pro164Ser

c.490C>T · rs753397524 · VCV951429

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7388 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7388	likely pathogenic
REVEL	0.406	indeterminate
SaProt	LLR -6.96	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 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 4,902 bp · p 1.5e-05 · regional, not allelic
Overall
CADD	25.7	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 0.00237% European (non-Finnish) · 28/1,179,974 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00186% 30/1,613,922 alleles · very rare exomes 28/1,461,830 · genomes 2/152,092 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00237%	42,142
Remaining individualsnot grpmax-eligible	0.0016%	62,490
African / African-American	0.00134%	74,882

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.Pro164Ser
Coding: c.490C>T
MANE Select: NM_014264
dbSNP: rs753397524
Type: single nucleotide variant
Location: chr4:127885860 (GRCh38)
Gene constraint: LOEUF 0.619 · pLI 0.18 (gnomAD)
Structure: AlphaFold pLDDT 66.31 · 19 PDB
Residue 164: the protein kinase domain

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

Similar variants

PLK4 c.1358+1G>C Likely pathogenic ★★ same type
PLK4 p.Arg185Ter Pathogenic/Likely pathogenic ★★ same type
PLK4 c.126+5G>C Uncertain significance ★★ same type
PLK4 c.1935+4A>T Uncertain significance ★★ same type
PLK4 p.Arg185Gln Uncertain significance ★★ same type
PLK4 p.Arg247His Uncertain significance ★★ ⚠ same type
PLK4 p.Arg28Ser Uncertain significance ★★ ⚠ same type
PLK4 p.Arg371Gln 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/plk4-p-pro164ser (accessed [today's date]).

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