# NM_002726.5(PREP):c.579G>C (p.Gln193His)

https://sugi.bio/variant/prep-p-gln193his

## Summary

**PREP p.Gln193His (c.579G>C)** is classified **Uncertain significance** in PREP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-30). AlphaMissense: ambiguous (0.4442); Very rare (popmax 0.00267%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the PREP gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [PREP](https://sugi.bio/atlas/gene/PREP/) |
| Protein change (HGVS p.) | p.Gln193His |
| Coding change (HGVS c.) | c.579G>C |
| MANE Select transcript | [NM_014889](https://www.ncbi.nlm.nih.gov/nuccore/NM_014889) (variant reported on NM_002726) |
| Variant type | single nucleotide variant |
| Location | chr6:105373385-105373385 (GRCh38) |
| ClinVar | [VCV3424826](https://www.ncbi.nlm.nih.gov/clinvar/variation/3424826/) |

**All HGVS expressions:** `NC_000006.11:g.105821260C>G`, `NC_000006.12:g.105373385C>G`, `NG_011472.1:g.34710G>C`, `NM_002726.5:c.579G>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this tolerated; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.4442) — no call either way
- REVEL 0.096 (moderately benign-leaning)
- SaProt LLR -9.321 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense makes no call
- Conservation: phyloP 0.415, GERP -1.84, phastCons 0.995 — weakly conserved position
- CADD: **PHRED 20.9**. 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 assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00267%** (afr) · FAF95 0.000442% · FAF99 0.000166% · 2/75,016 in the highest group · 2/1,461,796 alleles overall — very rare (popmax 0.00267%, afr).

*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.*

## Protein context {#protein}

Residue **193** lies in a disulfide bond; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 94.44, 93% of residues very-high.

**8 experimental structure(s)** (PDB): [4L3T](https://www.rcsb.org/structure/4L3T), [4NGE](https://www.rcsb.org/structure/4NGE), [4RPU](https://www.rcsb.org/structure/4RPU), [6XOS](https://www.rcsb.org/structure/6XOS), [6XOT](https://www.rcsb.org/structure/6XOT), [6XOU](https://www.rcsb.org/structure/6XOU).

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

*Describes the biological roles of PREP (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:** PREP's established molecular role includes metalloendopeptidase activity.


### Pathways affected {#pathways}

PREP participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial protein import](https://reactome.org/content/detail/R-HSA-1268020) | curated |

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

**Molecular function:** metalloendopeptidase activity, metallopeptidase activity, zinc ion binding.

**Biological process:** proteolysis.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-09-30.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-30 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related PREP variant pages (same residue, condition, or type): [PITRM1 p.Thr931Met](/variant/pitrm1-p-thr931met), [PITRM1 p.Ala1003Thr](/variant/pitrm1-p-ala1003thr), [PITRM1 p.Ala559Val](/variant/pitrm1-p-ala559val), [PITRM1 p.Ala887Val](/variant/pitrm1-p-ala887val), [PITRM1 p.Ala942Val](/variant/pitrm1-p-ala942val), [PITRM1 p.Ala965Thr](/variant/pitrm1-p-ala965thr), [PITRM1 p.Arg32Trp](/variant/pitrm1-p-arg32trp), [PITRM1 p.Arg545Gln](/variant/pitrm1-p-arg545gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 3424826). 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.*