Is PRRT2 p.Pro216His (c.647C>A) pathogenic?

PRRT2 p.Pro216His (c.647C>A) is classified Likely benign in PRRT2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-07). AlphaMissense: likely benign (0.2334); Rare (popmax 0.131%, sas); Associated with episodic kinesigenic dyskinesia.

What condition is associated with PRRT2 p.Pro216His (c.647C>A)?

PRRT2 p.Pro216His (c.647C>A) is associated with episodic kinesigenic dyskinesia, infantile convulsions and choreoathetosis, seizures, benign familial infantile, 2 (ClinVar).

How common is PRRT2 p.Pro216His (c.647C>A) in the general population?

PRRT2 p.Pro216His (c.647C>A) is rare (popmax 0.131%, 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.Pro216His (c.647C>A)?

AlphaMissense predicts likely benign (score 0.2334) — an in-silico prediction, not a clinical call.

PRRT2 p.Pro216His

c.647C>A · rs76335820 · VCV206689

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2334 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.131%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

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	0.2334	likely benign
REVEL	0.371	indeterminate
SaProt	LLR -7.23	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.6	GERP 1.2, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 785 bp · p 0.003 · regional, not allelic
Overall
CADD	24.2	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 0.131% South Asian · 114/86,804 alleles

Filtering AF 0.112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.104%

Overall 0.0369% 584/1,582,356 alleles · rare exomes 526/1,430,300 · genomes 58/152,056 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.808%	124
South Asiangrpmax	0.131%	761
Middle Eastern	0.102%	984
Remaining individualsnot grpmax-eligible	0.0607%	1,647
East Asian	0.0338%	2,954
European (non-Finnish)	0.0159%	6,289
Admixed American	0.00356%	28,106
African / African-American	0.00271%	36,905
Finnishnot grpmax-eligible	0.0016%	62,506

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro216His
Coding: c.647C>A
MANE Select: NM_145239
dbSNP: rs76335820
Type: single nucleotide variant
Location: chr16:29813701 (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

Also linked: infantile convulsions and choreoathetosis seizures, benign familial infantile, 2 episodic kinesigenic dyskinesia 1

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-pro216his (accessed [today's date]).

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