Is PLK4 p.Pro593Ser (c.1777C>T) pathogenic?

PLK4 p.Pro593Ser (c.1777C>T) is classified Uncertain significance in PLK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-22). AlphaMissense: ambiguous (0.5031); Very rare (popmax 0.000593%, nfe).

How common is PLK4 p.Pro593Ser (c.1777C>T) in the general population?

PLK4 p.Pro593Ser (c.1777C>T) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about PLK4 p.Pro593Ser (c.1777C>T)?

AlphaMissense predicts ambiguous (score 0.5031) — an in-silico prediction, not a clinical call.

PLK4 p.Pro593Ser

c.1777C>T · VCV4968581

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5031 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5031	ambiguous
REVEL	0.529	indeterminate
SaProt	LLR -9.29	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,488 bp · p 0.44 · regional, not allelic
Overall
CADD	24.5	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 0.000593% European (non-Finnish) · 7/1,179,580 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,490 alleles · very rare exomes 7/1,461,236 · genomes 0/152,254 · 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: PLK4
Protein: p.Pro593Ser
Coding: c.1777C>T
MANE Select: NM_014264
Type: single nucleotide variant
Location: chr4:127890183 (GRCh38)
Gene constraint: LOEUF 0.619 · pLI 0.18 (gnomAD)
Structure: AlphaFold pLDDT 66.31 · 19 PDB
Residue 593: the cryptic polo box 1 (cpb1) domain; an α-helix

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

Similar variants

PLK4 p.Pro593Leu Uncertain significance ★ same residue
PLK4 p.Pro593= Likely benign ★ same residue
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

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-pro593ser (accessed [today's date]).

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