# NM_181882.3(PRX):c.276C>T (p.Val92=)

https://sugi.bio/variant/prx-p-val92

## Summary

**PRX p.Val92= (c.276C>T)** is classified **Likely benign** in PRX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-06). Very rare (popmax 0.00934%, afr); Associated with Charcot-Marie-Tooth disease type 4.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00934%, afr)

## For patients & families {#patients}

This is a change in the PRX gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Charcot-Marie-Tooth disease type 4.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012440/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PRX](https://sugi.bio/atlas/gene/PRX/) |
| Protein change (HGVS p.) | p.Val92= |
| Coding change (HGVS c.) | c.276C>T |
| MANE Select transcript | [NM_181882](https://www.ncbi.nlm.nih.gov/nuccore/NM_181882) |
| Variant type | single nucleotide variant |
| Location | chr19:40398725-40398725 (GRCh38) |
| ClinVar | [VCV4705209](https://www.ncbi.nlm.nih.gov/clinvar/variation/4705209/) |

**All HGVS expressions:** `LRG_265:g.19640C>T`, `LRG_265t1:c.276C>T`, `LRG_265t2:c.276C>T`, `NC_000019.10:g.40398725G>A`, `NC_000019.9:g.40904632G>A`, `NG_007979.1:g.19640C>T`, `NM_001411127.1:c.561C>T`, `NM_020956.2:c.276C>T`, `NM_181882.3:c.276C>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 2.024, GERP 0.056, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 10.94**. 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>T, Δ0.41 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 **0.00934%** (afr) · FAF95 0.00437% · FAF99 0.00309% · 7/74,928 in the highest group · 7/1,613,996 alleles overall — very rare (popmax 0.00934%, 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.*

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

**PRX** population constraint: LOEUF 1.321, pLI 2.7562e-10, missense-Z 0.59052. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Charcot-Marie-Tooth disease type 4** — Definitive (AR)

## Protein context {#protein}

Residue **92** lies in the pdz domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 35.74, 0% of residues very-high.

**1 experimental structure(s)** (PDB): [4CMZ](https://www.rcsb.org/structure/4CMZ).

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

*Describes the biological roles of PRX (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.*


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [EGR2 and SOX10-mediated initiation of Schwann cell myelination](https://reactome.org/content/detail/R-HSA-9619665) | curated |

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-02-06.

**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 | 2025-02-06 |

## Associated conditions {#conditions}

[Charcot-Marie-Tooth disease type 4](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-type-4/).

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease type 4, Charcot-Marie-Tooth, Type 4, Charcot-Marie-Tooth disease, type IV.

## Similar variants {#similar}

Related PRX variant pages (same residue, condition, or type): [PRX c.184+2T>C](/variant/prx-c-184-plus-2t-c), [PRX p.Arg1070Ter](/variant/prx-p-arg1070ter), [PRX p.Arg196Ter](/variant/prx-p-arg196ter), [PRX p.Arg364Ter](/variant/prx-p-arg364ter), [PRX p.Arg368Ter](/variant/prx-p-arg368ter), [PRX p.Arg392Ter](/variant/prx-p-arg392ter), [PRX p.Arg464Ter](/variant/prx-p-arg464ter), [PRX p.Arg897Ter](/variant/prx-p-arg897ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 4705209). 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.*