Is PLK4 p.Ile703Thr (c.2108T>C) pathogenic?

PLK4 p.Ile703Thr (c.2108T>C) is classified Uncertain significance in PLK4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-23). AlphaMissense: likely pathogenic (0.9543); Very rare (popmax 0.000684%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PLK4 p.Ile703Thr (c.2108T>C)?

PLK4 p.Ile703Thr (c.2108T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PLK4 p.Ile703Thr (c.2108T>C) in the general population?

PLK4 p.Ile703Thr (c.2108T>C) is very rare (popmax 0.000684%, nfe) (gnomAD).

What do computational predictors say about PLK4 p.Ile703Thr (c.2108T>C)?

AlphaMissense predicts likely pathogenic (score 0.9543) — an in-silico prediction, not a clinical call.

PLK4 p.Ile703Thr

c.2108T>C · rs967796334 · VCV1007921

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9543 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000684%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9543	likely pathogenic
REVEL	0.252	benign-leaning
SaProt	LLR -12.18	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 0.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,488 bp · p 0.44 · regional, not allelic
Overall
CADD	23.7	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 0.000684% European (non-Finnish) · 8/1,169,866 alleles

Filtering AF 0.000294% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000213%

Overall 0.000504% 8/1,588,386 alleles · very rare exomes 7/1,436,362 · genomes 1/152,024 · 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.Ile703Thr
Coding: c.2108T>C
MANE Select: NM_014264
dbSNP: rs967796334
Type: single nucleotide variant
Location: chr4:127892434 (GRCh38)
Gene constraint: LOEUF 0.619 · pLI 0.18 (gnomAD)
Structure: AlphaFold pLDDT 66.31 · 19 PDB
Residue 703: the cryptic polo box 2 (cpb2) domain; a β-strand

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.Ile703= Benign/Likely benign ★★ same residue
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

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-ile703thr (accessed [today's date]).

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