Is PLK4 p.Trp519Ser (c.1556G>C) pathogenic?

PLK4 p.Trp519Ser (c.1556G>C) is classified Benign in PLK4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1893); Low-frequency (popmax 4.97%, mid).

How common is PLK4 p.Trp519Ser (c.1556G>C) in the general population?

PLK4 p.Trp519Ser (c.1556G>C) is low-frequency (popmax 4.97%, mid) (gnomAD).

What do computational predictors say about PLK4 p.Trp519Ser (c.1556G>C)?

AlphaMissense predicts likely benign (score 0.1893) — an in-silico prediction, not a clinical call.

PLK4 p.Trp519Ser

c.1556G>C · rs56043017 · VCV1164304

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1893 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.97%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1893	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -4.28	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 5.3	GERP 1.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,488 bp · p 0.44 · regional, not allelic
Overall
CADD	23.8	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 4.97% Middle Eastern · 301/6,062 alleles

Filtering AF 4.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.32%

Overall 1.01% 16,378/1,613,908 alleles · low-frequency exomes 15,158/1,461,716 · genomes 1,220/152,192 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	4.97%	20
South Asian	3.11%	32
Ashkenazi Jewishnot grpmax-eligible	2.91%	34
Remaining individualsnot grpmax-eligible	1.24%	81
Admixed American	1.08%	93
European (non-Finnish)	0.911%	110
African / African-American	0.219%	457
Finnishnot grpmax-eligible	0.0641%	1,561
East Asian	0.00891%	11,218

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.Trp519Ser
Coding: c.1556G>C
MANE Select: NM_014264
dbSNP: rs56043017
Type: single nucleotide variant
Location: chr4:127889962 (GRCh38)
Gene constraint: LOEUF 0.619 · pLI 0.18 (gnomAD)
Structure: AlphaFold pLDDT 66.31 · 19 PDB
Residue 519: a UniProt-annotated variant site (in); the 'disordered' region

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

Similar variants

PLK4 p.Trp519Cys Uncertain significance ★★ ⚠ 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
PLK4 p.Arg28Ser 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-trp519ser (accessed [today's date]).

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