# NM_145239.3(PRRT2):c.718C>T (p.Arg240Ter)

https://sugi.bio/variant/prrt2-p-arg240ter

## Summary

**PRRT2 p.Arg240Ter (c.718C>T)** is classified **Pathogenic** in PRRT2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-04-23). Very rare (popmax 0.00269%, afr); Associated with episodic kinesigenic dyskinesia.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs387907126 · 8 submitters · 4 linked conditions · very rare (popmax 0.00269%, afr)

> **Built without this gene's context.** ClinVar files this variant under an overlapping gene, so its own gene's record set does not contain it and this page is assembled from the variant alone. Gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up — absent from this page, not from the data.

## For patients & families {#patients}

This is a change in the PRRT2 gene that is considered disease-causing, submitted by 8 submitters, and is linked to episodic kinesigenic dyskinesia.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Not applicable |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy |
| Prevalence | 1-9 / 1 000 000 (Worldwide) |

**Commonly reported features of Paroxysmal kinesigenic dyskinesia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Dystonia — Very frequent (99-80%)
- Chorea — Very frequent (99-80%)
- Athetosis — Very frequent (99-80%)
- Involuntary movements — Very frequent (99-80%)
- Dyskinesia — Very frequent (99-80%)
- Focal sensory seizure — Frequent (79-30%)
- Seizure — Occasional (29-5%)
- Migraine — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0008721/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PRRT2](https://sugi.bio/atlas/gene/PRRT2/) |
| Protein change (HGVS p.) | p.Arg240Ter |
| Coding change (HGVS c.) | c.718C>T |
| MANE Select transcript | [NM_145239](https://www.ncbi.nlm.nih.gov/nuccore/NM_145239) |
| dbSNP | [rs387907126](https://www.ncbi.nlm.nih.gov/snp/rs387907126/) |
| Variant type | single nucleotide variant |
| Location | chr16:29813772-29813772 (GRCh38) |
| ClinVar | [VCV31174](https://www.ncbi.nlm.nih.gov/clinvar/variation/31174/) |

**All HGVS expressions:** `NC_000016.10:g.29813772C>T`, `NC_000016.9:g.29825093C>T`, `NG_032039.1:g.6685C>T`, `NM_001256442.2:c.718C>T`, `NM_001256443.2:c.718C>T`, `NM_145239.3:c.718C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 2.796, GERP 0.123, phastCons 0.998 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. For a truncating variant the loss-of-function impact is position-dependent — C-terminal / last-exon truncations may escape nonsense-mediated decay. *Descriptive; not an applied PVS1 code.*
- CADD: **PHRED 37.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.00269%** (afr) · FAF95 0.000446% · FAF99 0.000167% · 2/74,462 in the highest group · 5/1,599,774 alleles overall — very rare (popmax 0.00269%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00353% | 28,300 |
| African / African-American (grpmax) | 0.00269% | 37,231 |
| European (non-Finnish) | 0.000171% | 586,424 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. 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.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-04-23.

**Submitter consensus:** unanimous (8/8 Pathogenic).

**Submission history:** 8 submissions (2012–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2024-01-01 |
| Mendelics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-04 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2012-01-26 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2024-01-19 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2015-03-24 |
| MGZ Medical Genetics Center | Pathogenic | criteria provided, single submitter | clinical testing | 2021-09-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-01-18 |
| Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service | Pathogenic | criteria provided, single submitter | clinical testing | 2026-04-23 |

## Associated conditions {#conditions}

[episodic kinesigenic dyskinesia](https://sugi.bio/atlas/disease/episodic-kinesigenic-dyskinesia/), [infantile convulsions and choreoathetosis](https://sugi.bio/atlas/disease/infantile-convulsions-and-choreoathetosis/), [seizures, benign familial infantile, 2](https://sugi.bio/atlas/disease/seizures-benign-familial-infantile-2/), [episodic kinesigenic dyskinesia 1](https://sugi.bio/atlas/disease/episodic-kinesigenic-dyskinesia-1/).

**Reported phenotype names (ClinVar):** Episodic kinesigenic dyskinesia, Infantile convulsions and choreoathetosis, not provided, Episodic kinesigenic dyskinesia 1, Seizures, benign familial infantile, 2, Paroxysmal central nervous system disorders, Paroxysmal kinesigenic dyskinesia, none provided, CONVULSIONS, BENIGN FAMILIAL INFANTILE, 2, PRRT2-Related Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions (PKD/IC).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 31174). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*