Is PLK4 p.Ser421fs (c.1261_1264del) pathogenic?

PLK4 p.Ser421fs (c.12611264del) is classified Pathogenic in PLK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-27). Very rare (popmax 0.00017%, nfe).

How common is PLK4 p.Ser421fs (c.1261_1264del) in the general population?

PLK4 p.Ser421fs (c.1261_1264del) is very rare (popmax 0.00017%, nfe) (gnomAD).

PLK4 p.Ser421fs

c.1261_1264del · rs1306520020 · VCV2788633

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.9	GERP -2.8, phastCons 0.012

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,174,922 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,608,522 alleles · very rare exomes 2/1,456,264 · genomes 0/152,258 · 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.Ser421fs
Coding: c.1261_1264del
MANE Select: NM_014264
dbSNP: rs1306520020
Type: Deletion
Location: chr4:127886629 (GRCh38)
Gene constraint: LOEUF 0.619 · pLI 0.18 (gnomAD)
Structure: AlphaFold pLDDT 66.31 · 19 PDB
Residue 421: the 'disordered' region

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

Similar variants

PLK4 p.Asn450fs Pathogenic/Likely pathogenic ★★ same type
PLK4 p.Pro553fs Pathogenic/Likely pathogenic ★★ same type
PLK4 c.1359-11del Benign/Likely benign ★★ same type
PLK4 p.Asn652fs Pathogenic ★ same type
PLK4 p.Cys560fs Pathogenic ★ same type
PLK4 p.Gly21fs Pathogenic ★ same type
PLK4 p.Leu139_Ser140insTer Pathogenic ★ same type
PLK4 p.Lys572fs Likely pathogenic ★ 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-ser421fs (accessed [today's date]).

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