Is PLK4 p.Phe433fs (c.1299_1303del) pathogenic?

PLK4 p.Phe433fs (c.12991303del) is classified Conflicting classifications of pathogenicity in PLK4 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-04-10). Ultra-rare (popmax 0.0187%, afr); Associated with microcephaly and chorioretinopathy 2.

What condition is associated with PLK4 p.Phe433fs (c.1299_1303del)?

PLK4 p.Phe433fs (c.1299_1303del) is associated with microcephaly and chorioretinopathy 2 (ClinVar).

How common is PLK4 p.Phe433fs (c.1299_1303del) in the general population?

PLK4 p.Phe433fs (c.1299_1303del) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

PLK4 p.Phe433fs

c.1299_1303del · rs724159996 · VCV162401

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Conditions

microcephaly and chorioretinopathy 2

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 3.2	GERP 0.4, phastCons 1
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% African / African-American · 14/74,906 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.00143% 23/1,613,184 alleles · ultra-rare exomes 14/1,461,010 · genomes 9/152,174 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,350
Admixed American	0.00167%	59,926
Remaining individualsnot grpmax-eligible	0.0016%	62,446
European (non-Finnish)	0.000593%	168,505

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.Phe433fs
Coding: c.1299_1303del
MANE Select: NM_014264
dbSNP: rs724159996
Type: Deletion
Location: chr4:127886669 (GRCh38)
Gene constraint: LOEUF 0.619 · pLI 0.18 (gnomAD)
Structure: AlphaFold pLDDT 66.31 · 19 PDB
Residue 433: the 'disordered' region

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

Disease context

microcephaly and chorioretinopathy 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PLK4 p.Pro553fs Pathogenic/Likely pathogenic ★★ same condition
PLK4 p.Thr393fs Likely pathogenic ★ same condition
PLK4 p.Gln388fs Pathogenic/Likely pathogenic ★★ same condition
PLK4 c.1935+4A>T Uncertain significance ★★ same condition
PLK4 p.Glu790Lys Uncertain significance ★★ ⚠ same condition
PLK4 p.Val54Ile Uncertain significance ★★ ⚠ same condition
PLK4 p.Ile703= Benign/Likely benign ★★ same condition
PLK4 p.Ser232Thr Benign ★★ 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-phe433fs (accessed [today's date]).

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