Is PRRT2 p.Pro215Ser (c.643C>T) pathogenic?

PRRT2 p.Pro215Ser (c.643C>T) is classified Conflicting classifications of pathogenicity in PRRT2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-01). AlphaMissense: likely benign (0.1755); Ultra-rare (popmax 0.0219%, nfe); Associated with episodic kinesigenic dyskinesia.

What condition is associated with PRRT2 p.Pro215Ser (c.643C>T)?

PRRT2 p.Pro215Ser (c.643C>T) is associated with episodic kinesigenic dyskinesia (ClinVar).

How common is PRRT2 p.Pro215Ser (c.643C>T) in the general population?

PRRT2 p.Pro215Ser (c.643C>T) is ultra-rare (popmax 0.0219%, nfe) (gnomAD).

How is Paroxysmal kinesigenic dyskinesia inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PRRT2 p.Pro215Ser (c.643C>T)?

AlphaMissense predicts likely benign (score 0.1755) — an in-silico prediction, not a clinical call.

PRRT2 p.Pro215Ser

c.643C>T · rs374642875 · VCV666144

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1755 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0219%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

episodic kinesigenic dyskinesia

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.1755	likely benign
REVEL	0.121	moderately benign-leaning
SaProt	LLR -6.15	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5	GERP 1.2, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 785 bp · p 0.003 · regional, not allelic
Overall
CADD	23.2	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 0.0219% European (non-Finnish) · 252/1,151,562 alleles

Filtering AF 0.0196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.0164% 257/1,567,220 alleles · ultra-rare exomes 249/1,415,718 · genomes 8/151,502 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0219%	4,570
Remaining individualsnot grpmax-eligible	0.00665%	15,045
African / African-American	0.00137%	73,258

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: PRRT2
Protein: p.Pro215Ser
Coding: c.643C>T
MANE Select: NM_145239
dbSNP: rs374642875
Type: single nucleotide variant
Location: chr16:29813697 (GRCh38)

Full PRRT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

episodic kinesigenic dyskinesia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Paroxysmal kinesigenic dyskinesia (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Worldwide)

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/prrt2-p-pro215ser (accessed [today's date]).

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