Is PRRT2 p.Met280Thr (c.839T>C) pathogenic?

PRRT2 p.Met280Thr (c.839T>C) is classified Uncertain significance in PRRT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-04-23). AlphaMissense: likely pathogenic (0.9439); Very rare (popmax 0.00017%, nfe); Associated with seizures, benign familial infantile, 2.

What condition is associated with PRRT2 p.Met280Thr (c.839T>C)?

PRRT2 p.Met280Thr (c.839T>C) is associated with seizures, benign familial infantile, 2 (ClinVar).

How common is PRRT2 p.Met280Thr (c.839T>C) in the general population?

PRRT2 p.Met280Thr (c.839T>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Self-limited infantile epilepsy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PRRT2 p.Met280Thr (c.839T>C)?

AlphaMissense predicts likely pathogenic (score 0.9439) — an in-silico prediction, not a clinical call.

PRRT2 p.Met280Thr

c.839T>C · rs1419914220 · VCV953068

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9439 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

seizures, benign familial infantile, 2

⚠ 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	0.9439	likely pathogenic
REVEL	0.445	indeterminate
SaProt	LLR -10.08	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 6.1	GERP 0.72, phastCons 1
Regional constraint	o/e 0.46	unconstrained · MANE · 84 bp · p 0.0007 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,178,204 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,610,454 alleles · very rare exomes 1/1,458,318 · genomes 1/152,136 · 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.Met280Thr
Coding: c.839T>C
MANE Select: NM_145239
dbSNP: rs1419914220
Type: single nucleotide variant
Location: chr16:29813893 (GRCh38)

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

Disease context

seizures, benign familial infantile, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Self-limited infantile epilepsy (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

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-met280thr (accessed [today's date]).

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