Is PLK4 p.Pro508Ser (c.1522C>T) pathogenic?

PLK4 p.Pro508Ser (c.1522C>T) is classified Uncertain significance in PLK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-16). AlphaMissense: likely benign (0.0782); Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

What condition is associated with PLK4 p.Pro508Ser (c.1522C>T)?

PLK4 p.Pro508Ser (c.1522C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PLK4 p.Pro508Ser (c.1522C>T) in the general population?

PLK4 p.Pro508Ser (c.1522C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about PLK4 p.Pro508Ser (c.1522C>T)?

AlphaMissense predicts likely benign (score 0.0782) — an in-silico prediction, not a clinical call.

PLK4 p.Pro508Ser

c.1522C>T · rs369019607 · VCV2250775

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0782 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0782	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -4.94	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 0.11	GERP -3.1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,488 bp · p 0.44 · regional, not allelic
Overall
CADD	5.435	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 0.005% Admixed American · 3/59,956 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00062% 10/1,613,548 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,985
European (non-Finnish)	0.000593%	168,537

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.Pro508Ser
Coding: c.1522C>T
MANE Select: NM_014264
dbSNP: rs369019607
Type: single nucleotide variant
Location: chr4:127889928 (GRCh38)
Gene constraint: LOEUF 0.619 · pLI 0.18 (gnomAD)
Structure: AlphaFold pLDDT 66.31 · 19 PDB
Residue 508: the 'disordered' region

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.Arg247His Uncertain significance ★★ ⚠ same condition
PLK4 p.Arg28Ser 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-pro508ser (accessed [today's date]).

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