# NM_001171613.2(PREPL):c.312C>T (p.Pro104=)

https://sugi.bio/variant/prepl-p-pro104

## Summary

**PREPL p.Pro104= (c.312C>T)** is classified **Likely benign** in PREPL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-28). Very rare (popmax 0.00223%, eas); Associated with myasthenic syndrome, congenital, 22.

**At a glance:** Likely benign · review: Single submitter · rsID rs11542603 · 1 submitter · 1 linked condition · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the PREPL gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to myasthenic syndrome, congenital, 22.

*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, Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Diagnostic panels | PREPL is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Congenital myasthenic syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Neck muscle weakness — Very frequent (99-80%)
- Ptosis — Very frequent (99-80%)
- Dysphagia — Very frequent (99-80%)
- Poor suck — Very frequent (99-80%)
- Sudden episodic apnea — Very frequent (99-80%)
- Fatigable weakness — Very frequent (99-80%)
- Proximal muscle weakness — Very frequent (99-80%)
- Frontalis muscle weakness — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025886/index) · [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.Pro104= |
| Coding change (HGVS c.) | c.312C>T |
| MANE Select transcript | [NM_001171613](https://www.ncbi.nlm.nih.gov/nuccore/NM_001171613) |
| dbSNP | [rs11542603](https://www.ncbi.nlm.nih.gov/snp/rs11542603/) |
| Variant type | single nucleotide variant |
| Location | chr2:44343782-44343782 (GRCh38) |
| ClinVar | [VCV765092](https://www.ncbi.nlm.nih.gov/clinvar/variation/765092/) |

**All HGVS expressions:** `NC_000002.11:g.44570921G>A`, `NC_000002.12:g.44343782G>A`, `NG_016429.1:g.23081C>T`, `NM_001042385.2:c.579C>T`, `NM_001042386.2:c.579C>T`, `NM_001171603.1:c.579C>T`, `NM_001171606.2:c.579C>T`, `NM_001171613.2:c.312C>T`, `NM_001171617.1:c.312C>T`, `NM_001374275.1:c.579C>T`, `NM_001374276.1:c.579C>T`, `NM_001374277.1:c.312C>T`, `NM_006036.4:c.579C>T`

## Computational & population evidence {#evidence}

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

- **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 0.479, GERP 0.183, phastCons 0.001 — weakly conserved position
- CADD: **PHRED 10.95**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.32 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · FAF95 0.000247% · FAF99 0.000159% · 1/44,862 in the highest group · 10/1,613,896 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,862 |
| African / African-American | 0.00133% | 75,034 |
| South Asian | 0.0011% | 91,074 |
| European (non-Finnish) | 0.000593% | 168,546 |

*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 benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-28.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-01-28 |

## Associated conditions {#conditions}

[myasthenic syndrome, congenital, 22](https://sugi.bio/atlas/disease/myasthenic-syndrome-congenital-22/).

**Reported phenotype names (ClinVar):** Myasthenic syndrome, congenital, 22, PREPL DEFICIENCY.

## Similar variants {#similar}

Related PREPL variant pages (same residue, condition, or type): [PREPL c.1262+1G>A](/variant/prepl-c-1262-plus-1g-a), [PREPL c.1263-1G>C](/variant/prepl-c-1263-minus-1g-c), [PREPL c.-49+1734C>T](/variant/prepl-c-minus-49-plus-1734c-t), [PREPL p.Arg206Ter](/variant/prepl-p-arg206ter), [PREPL p.Gln14Ter](/variant/prepl-p-gln14ter), [PREPL p.Gln456Ter](/variant/prepl-p-gln456ter), [PREPL p.Glu577Ter](/variant/prepl-p-glu577ter), [PREPL c.1629+30C>T](/variant/prepl-c-1629-plus-30c-t).

### 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 765092). 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.*