# NM_001171613.2(PREPL):c.539_540dup (p.Met181fs)

https://sugi.bio/variant/prepl-p-met181fs

## Summary

**PREPL p.Met181fs (c.539_540dup)** is classified **Likely pathogenic** in PREPL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-02). No gnomAD frequency available for this variant; Associated with PREPL-related disorder.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1057523690 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PREPL gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to PREPL-related disorder.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PREPL](https://sugi.bio/atlas/gene/PREPL/) |
| Protein change (HGVS p.) | p.Met181fs |
| Coding change (HGVS c.) | c.539_540dup |
| MANE Select transcript | [NM_001171613](https://www.ncbi.nlm.nih.gov/nuccore/NM_001171613) |
| dbSNP | [rs1057523690](https://www.ncbi.nlm.nih.gov/snp/rs1057523690/) |
| Variant type | Duplication |
| Location | chr2:44339308-44339309 (GRCh38) |
| ClinVar | [VCV2635506](https://www.ncbi.nlm.nih.gov/clinvar/variation/2635506/) |

**All HGVS expressions:** `NC_000002.11:g.44566448_44566449dup`, `NC_000002.12:g.44339309_44339310dup`, `NG_016429.1:g.27553_27554dup`, `NM_001042385.2:c.806_807dup`, `NM_001042386.2:c.806_807dup`, `NM_001171603.1:c.806_807dup`, `NM_001171606.2:c.806_807dup`, `NM_001171613.2:c.539_540dup`, `NM_001171617.1:c.539_540dup`, `NM_001374275.1:c.806_807dup`, `NM_001374276.1:c.806_807dup`, `NM_001374277.1:c.539_540dup`, `NM_006036.4:c.806_807dup`, `NM_006036.4:c.806_807dupTT`

## 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 6.201, GERP 2.55, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.247, pLI 2.1658e-24. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 14**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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.*

## Gene constraint & dosage {#gene-context}

**PREPL** population constraint: LOEUF 1.247, pLI 2.1658e-24, missense-Z -2.4297; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 82.46, 64% of residues very-high.

**2 experimental structure(s)** (PDB): [7OBM](https://www.rcsb.org/structure/7OBM), [8RFB](https://www.rcsb.org/structure/8RFB) — incl. mutant structure 8RFB.

## What this gene does {#gene-function}

*Describes the biological roles of PREPL (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** PREPL's established molecular role includes peptidase activity.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** peptidase activity.

**Biological process:** regulation of synaptic vesicle exocytosis.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-01-02.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-01-02 |

## Associated conditions {#conditions}

[PREPL-related disorder](https://sugi.bio/atlas/disease/prepl-related-disorder/).

**Reported phenotype names (ClinVar):** PREPL-related disorder, PREPL-related condition.

## Similar variants {#similar}

Related PREPL variant pages (same residue, condition, or type): [PREPL p.Gln14Ter](/variant/prepl-p-gln14ter), [SLC3A1 p.Arg567fs](/variant/slc3a1-p-arg567fs), [PREPL p.Tyr53Ter](/variant/prepl-p-tyr53ter), [PREPL p.Gly391Glu](/variant/prepl-p-gly391glu), [PREPL c.1480-5T>C](/variant/prepl-c-1480-minus-5t-c), [PREPL c.1827+4T>C](/variant/prepl-c-1827-plus-4t-c), [PREPL c.-49+1660A>G](/variant/prepl-c-minus-49-plus-1660a-g), [PREPL p.Arg293=](/variant/prepl-p-arg293).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2635506). 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.*