Is PRRT2 p.Asn335Ser (c.1004A>G) pathogenic?

PRRT2 p.Asn335Ser (c.1004A>G) is classified Uncertain significance in PRRT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-24). AlphaMissense: ambiguous (0.5275); Very rare (popmax 0.000255%, nfe); Associated with PRRT2-Related Disorder.

What condition is associated with PRRT2 p.Asn335Ser (c.1004A>G)?

PRRT2 p.Asn335Ser (c.1004A>G) is associated with PRRT2-Related Disorder, episodic kinesigenic dyskinesia (ClinVar).

How common is PRRT2 p.Asn335Ser (c.1004A>G) in the general population?

PRRT2 p.Asn335Ser (c.1004A>G) is very rare (popmax 0.000255%, nfe) (gnomAD).

What do computational predictors say about PRRT2 p.Asn335Ser (c.1004A>G)?

AlphaMissense predicts ambiguous (score 0.5275) — an in-silico prediction, not a clinical call.

PRRT2 p.Asn335Ser

c.1004A>G · rs774242702 · VCV2632527

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5275 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Conditions

PRRT2-Related Disorder

⚠ 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	0.5275	ambiguous
REVEL	0.334	indeterminate
SaProt	LLR -11.11	damaging
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 709 bp · p 0.39 · regional, not allelic
Overall
CADD	26.7	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 0.000255% European (non-Finnish) · 3/1,174,602 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000187% 3/1,603,640 alleles · very rare exomes 3/1,451,556 · genomes 0/152,084 · 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.Asn335Ser
Coding: c.1004A>G
MANE Select: NM_145239
dbSNP: rs774242702
Type: single nucleotide variant
Location: chr16:29814457 (GRCh38)

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

Disease context

Also linked: episodic kinesigenic dyskinesia

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-asn335ser (accessed [today's date]).

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