# NM_145239.3(PRRT2):c.133C>T (p.Pro45Ser)

https://sugi.bio/variant/prrt2-p-pro45ser

## Summary

**PRRT2 p.Pro45Ser (c.133C>T)** is classified **Conflicting classifications of pathogenicity** in PRRT2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0894); Rare (popmax 0.336%, afr); Associated with episodic kinesigenic dyskinesia.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs11556732 · 7 submitters · 1 linked condition · AlphaMissense likely benign · rare (popmax 0.336%, 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 of uncertain or conflicting significance (submitters disagree on it), submitted by 7 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.Pro45Ser |
| Coding change (HGVS c.) | c.133C>T |
| MANE Select transcript | [NM_145239](https://www.ncbi.nlm.nih.gov/nuccore/NM_145239) |
| dbSNP | [rs11556732](https://www.ncbi.nlm.nih.gov/snp/rs11556732/) |
| Variant type | single nucleotide variant |
| Location | chr16:29813187-29813187 (GRCh38) |
| ClinVar | [VCV206678](https://www.ncbi.nlm.nih.gov/clinvar/variation/206678/) |

**All HGVS expressions:** `NC_000016.10:g.29813187C>T`, `NC_000016.9:g.29824508C>T`, `NG_032039.1:g.6100C>T`, `NM_001256442.1:c.133C>T`, `NM_001256442.2:c.133C>T`, `NM_001256443.2:c.133C>T`, `NM_145239.3:c.133C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0894)
- REVEL 0.124 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.954 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.048, GERP 1.4, phastCons 1 — weakly conserved position
- CADD: **PHRED 19.75**. 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.*
- Regional missense constraint: **o/e 1.16** across the covering region of the MANE Select transcript (29,813,055–29,813,840), spanning 785 bp. Chi-square p 0.003. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.336%** (afr) · FAF95 0.302% · FAF99 0.289% · 252/75,028 in the highest group · 310/1,613,974 alleles overall — rare (popmax 0.336%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.336% | 298 |
| Admixed American | 0.045% | 2,223 |
| Remaining individuals (not grpmax-eligible) | 0.0432% | 2,315 |
| Middle Eastern | 0.033% | 3,028 |
| South Asian | 0.0011% | 91,088 |
| European (non-Finnish) | 8.47e-05% | 1,179,994 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-02.

**Submitter consensus:** conflicting (5 Likely benign, 1 Benign, 1 Uncertain significance).

**Submission history:** 6 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Likely benign | criteria provided, single submitter | clinical testing | 2017-08-15 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2020-11-27 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-07-13 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-07-23 |
| Eurofins Ntd Llc (ga) | Likely benign | criteria provided, single submitter | clinical testing | 2016-08-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-02 |

## Associated conditions {#conditions}

[episodic kinesigenic dyskinesia](https://sugi.bio/atlas/disease/episodic-kinesigenic-dyskinesia/).

**Reported phenotype names (ClinVar):** Episodic kinesigenic dyskinesia, not specified, not provided, Inborn genetic diseases, PRRT2-Related Disorder, PRRT2-related disorders, Paroxysmal kinesigenic dyskinesia, AllHighlyPenetrant, none provided.

### 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 206678). 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.*