Is PLK4 p.Pro651Ser (c.1951C>T) pathogenic?

PLK4 p.Pro651Ser (c.1951C>T) is classified Uncertain significance in PLK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-08-06). AlphaMissense: likely pathogenic (0.911); Very rare (popmax 0.00552%, afr); Associated with PLK4-related microcephaly and growth failure with or without ocular features.

What condition is associated with PLK4 p.Pro651Ser (c.1951C>T)?

PLK4 p.Pro651Ser (c.1951C>T) is associated with PLK4-related microcephaly and growth failure with or without ocular features (ClinVar).

How common is PLK4 p.Pro651Ser (c.1951C>T) in the general population?

PLK4 p.Pro651Ser (c.1951C>T) is very rare (popmax 0.00552%, afr) (gnomAD).

What do computational predictors say about PLK4 p.Pro651Ser (c.1951C>T)?

AlphaMissense predicts likely pathogenic (score 0.911) — an in-silico prediction, not a clinical call.

PLK4 p.Pro651Ser

c.1951C>T · rs1305291662 · VCV989336

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.911 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00552%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

PLK4-related microcephaly and growth failure with or without ocular features

Computational evidence

Protein change
AlphaMissense	0.911	likely pathogenic
REVEL	0.494	indeterminate
SaProt	LLR -10.42	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,488 bp · p 0.44 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00552% African / African-American · 4/72,466 alleles

Filtering AF 0.00179% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00107%

Overall 0.000264% 4/1,513,438 alleles · very rare

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.Pro651Ser
Coding: c.1951C>T
MANE Select: NM_014264
dbSNP: rs1305291662
Type: single nucleotide variant
Location: chr4:127891594 (GRCh38)
Gene constraint: LOEUF 0.619 · pLI 0.18 (gnomAD)
Structure: AlphaFold pLDDT 66.31 · 19 PDB
Residue 651: the cryptic polo box 1 (cpb1) domain; an α-helix

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

Disease context

PLK4-related microcephaly and growth failure with or without ocular features

Similar variants

PLK4 p.Pro651= Likely benign ★★ same residue
PLK4 p.Arg185Ter Pathogenic/Likely pathogenic ★★ same condition
PLK4 c.126+1G>A Likely pathogenic ★ same condition
PLK4 c.1831-2A>G Likely pathogenic ★ same condition
PLK4 p.Ser884Ter Likely pathogenic ★ same condition
PLK4 c.2322+6T>C Likely benign same condition
PLK4 p.Lys572fs Likely pathogenic ★ same condition
PLK4 p.Trp898fs Likely pathogenic ★ 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-pro651ser (accessed [today's date]).

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