# NM_001171613.2(PREPL):c.1262G>A (p.Arg421Gln)

https://sugi.bio/variant/prepl-p-arg421gln

## Summary

**PREPL p.Arg421Gln (c.1262G>A)** is classified **Uncertain significance** in PREPL (ClinVar, Single submitter, 1 submitter; last evaluated 2018-07-01). AlphaMissense: likely pathogenic (0.6971); Ultra-rare (popmax 0.0166%, mid); Associated with myasthenic syndrome, congenital, 22.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs754572953 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0166%, mid)

## For patients & families {#patients}

This is a change in the PREPL gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Arg421Gln |
| Coding change (HGVS c.) | c.1262G>A |
| MANE Select transcript | [NM_001171613](https://www.ncbi.nlm.nih.gov/nuccore/NM_001171613) |
| dbSNP | [rs754572953](https://www.ncbi.nlm.nih.gov/snp/rs754572953/) |
| Variant type | single nucleotide variant |
| Location | chr2:44328937-44328937 (GRCh38) |
| ClinVar | [VCV650135](https://www.ncbi.nlm.nih.gov/clinvar/variation/650135/) |

**All HGVS expressions:** `NC_000002.11:g.44556076C>T`, `NC_000002.12:g.44328937C>T`, `NG_016429.1:g.37926G>A`, `NM_001042385.2:c.1343G>A`, `NM_001042386.2:c.1331G>A`, `NM_001171603.1:c.1529G>A`, `NM_001171606.2:c.1529G>A`, `NM_001171613.2:c.1262G>A`, `NM_001171617.1:c.1262G>A`, `NM_001374275.1:c.1529G>A`, `NM_001374276.1:c.1529G>A`, `NM_001374277.1:c.1262G>A`, `NM_006036.4:c.1529G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6971)
- REVEL 0.521 (indeterminate)
- SaProt LLR -12.915 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- SpliceAI predicts **donor loss** (Δ 0.34) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.702, GERP 2.79, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **R510Q** vs ClinVar **R421Q**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 35.0**. 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.*
- Regional missense constraint: **o/e 1.29** across the covering region of the MANE Select transcript (44,321,359–44,346,342), spanning 24,983 bp. Chi-square p 1e-15. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.34**, acceptor gain **0.00**, donor gain **0.25**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.25**.
- Pangolin: Δ**0.69** (loss), gain 0.28 / loss 0.69. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0166%** (mid) · FAF95 0.00435% · FAF99 0.00276% · 1/6,032 in the highest group · 39/1,609,218 alleles overall — ultra-rare (popmax 0.0166%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0166% | 6,032 |
| East Asian | 0.0111% | 8,971 |
| Remaining individuals (not grpmax-eligible) | 0.00481% | 20,771 |
| European (non-Finnish) | 0.00246% | 40,628 |
| South Asian | 0.00111% | 89,752 |

*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}

Residue **510** lies in a UniProt-annotated variant site (found in a patient with intellectual disability, short stature, chronic lung disease and failure to thrive; uncertain significance).

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-07-01.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-07-01 |

## 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.

## Same-residue context {#hotspot}

Residue **421** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [PREPL p.Arg421Ter](/variant/prepl-p-arg421ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PREPL variant pages (same residue, condition, or type): [PREPL p.Arg421Ter](/variant/prepl-p-arg421ter), [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).

### 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 650135). 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.*