Is PRRT2 p.Val333Ile (c.997G>A) pathogenic?

PRRT2 p.Val333Ile (c.997G>A) is classified Likely benign in PRRT2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-03-03). AlphaMissense: likely benign (0.103); Ultra-rare (popmax 0.0256%, sas); Associated with episodic kinesigenic dyskinesia.

What condition is associated with PRRT2 p.Val333Ile (c.997G>A)?

PRRT2 p.Val333Ile (c.997G>A) is associated with episodic kinesigenic dyskinesia (ClinVar).

How common is PRRT2 p.Val333Ile (c.997G>A) in the general population?

PRRT2 p.Val333Ile (c.997G>A) is ultra-rare (popmax 0.0256%, sas) (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.Val333Ile (c.997G>A)?

AlphaMissense predicts likely benign (score 0.103) — an in-silico prediction, not a clinical call.

PRRT2 p.Val333Ile

c.997G>A · rs749851660 · VCV536486

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.103 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0256%, sas)

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	0.103	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -6.83	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 -2.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 709 bp · p 0.39 · regional, not allelic
Overall
CADD	25.8	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 0.0256% South Asian · 23/89,724 alleles

Filtering AF 0.0174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0148%

Overall 0.0115% 185/1,603,776 alleles · ultra-rare exomes 182/1,451,730 · genomes 3/152,046 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0256%	3,901
Middle Eastern	0.0166%	6,038
European (non-Finnish)	0.0129%	7,781
Remaining individualsnot grpmax-eligible	0.00806%	12,404
Finnishnot grpmax-eligible	0.00475%	21,065
East Asian	0.00223%	44,754
African / African-American	0.00134%	74,666

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.Val333Ile
Coding: c.997G>A
MANE Select: NM_145239
dbSNP: rs749851660
Type: single nucleotide variant
Location: chr16:29814450 (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-val333ile (accessed [today's date]).

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