Is PRRT2 p.Ser4Arg (c.12C>A) pathogenic?

PRRT2 p.Ser4Arg (c.12C>A) is classified Uncertain significance in PRRT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-12). AlphaMissense: ambiguous (0.5061); Very rare (popmax 0.000426%, nfe); Associated with episodic kinesigenic dyskinesia.

What condition is associated with PRRT2 p.Ser4Arg (c.12C>A)?

PRRT2 p.Ser4Arg (c.12C>A) is associated with episodic kinesigenic dyskinesia (ClinVar).

How common is PRRT2 p.Ser4Arg (c.12C>A) in the general population?

PRRT2 p.Ser4Arg (c.12C>A) is very rare (popmax 0.000426%, 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.Ser4Arg (c.12C>A)?

AlphaMissense predicts ambiguous (score 0.5061) — an in-silico prediction, not a clinical call.

PRRT2 p.Ser4Arg

c.12C>A · rs757148846 · VCV1381913

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5061 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000426%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

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	0.5061	ambiguous
REVEL	0.133	moderately benign-leaning
SaProt	LLR -8.68	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.1	GERP -0.91, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 785 bp · p 0.003 · regional, not allelic
Overall
CADD	18.16	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 0.000426% European (non-Finnish) · 5/1,174,062 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000312% 5/1,600,758 alleles · very rare exomes 5/1,448,428 · genomes 0/152,330 · 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: PRRT2
Protein: p.Ser4Arg
Coding: c.12C>A
MANE Select: NM_145239
dbSNP: rs757148846
Type: single nucleotide variant
Location: chr16:29813066 (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-ser4arg (accessed [today's date]).

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