# NM_002764.4(PRPS1):c.826C>T (p.Pro276Ser)

https://sugi.bio/variant/prps1-p-pro276ser

## Summary

**PRPS1 p.Pro276Ser (c.826C>T)** is classified **Likely pathogenic** in PRPS1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-03-01). AlphaMissense: likely pathogenic (0.8223); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease X-linked recessive 5.

**At a glance:** Likely pathogenic · review: No assertion criteria · rsID rs2521349816 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PRPS1 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Charcot-Marie-Tooth disease X-linked recessive 5.

*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) | X-linked recessive |
| Age of onset (of this condition) | Childhood, Infancy |
| Prevalence | <1 / 1 000 000 (Worldwide) |
| Diagnostic panels | PRPS1 is a diagnostic-grade gene on 12 Genomics England panels |

**Commonly reported features of X-linked Charcot-Marie-Tooth disease type 5** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hearing impairment — Very frequent (99-80%)
- Optic atrophy — Very frequent (99-80%)
- Sensory neuropathy — Very frequent (99-80%)
- Areflexia — Very frequent (99-80%)
- Muscle weakness — Very frequent (99-80%)
- Pes cavus — Very frequent (99-80%)
- Skeletal muscle hypertrophy — Very frequent (99-80%)
- Peripheral neuropathy — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000114/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PRPS1](https://sugi.bio/atlas/gene/PRPS1/) |
| Protein change (HGVS p.) | p.Pro276Ser |
| Coding change (HGVS c.) | c.826C>T |
| MANE Select transcript | [NM_002764](https://www.ncbi.nlm.nih.gov/nuccore/NM_002764) |
| dbSNP | [rs2521349816](https://www.ncbi.nlm.nih.gov/snp/rs2521349816/) |
| Variant type | single nucleotide variant |
| Location | chrX:107647727-107647727 (GRCh38) |
| ClinVar | [VCV1710220](https://www.ncbi.nlm.nih.gov/clinvar/variation/1710220/) |

**All HGVS expressions:** `LRG_264:g.24304C>T`, `LRG_264t1:c.826C>T`, `NC_000023.10:g.106890957C>T`, `NC_000023.11:g.107647727C>T`, `NG_008407.1:g.24304C>T`, `NM_001204402.2:c.214C>T`, `NM_002764.4:c.826C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.8223) — concordant with the pathogenic call
- REVEL 0.826 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.257 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.615, GERP 2.25, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.8**. 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 0.37** across the covering region of the MANE Select transcript (107,645,245–107,647,742), spanning 2,497 bp. Chi-square p 1.3e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}


Curated gene–disease validity (ClinGen):

- **phosphoribosylpyrophosphate synthetase superactivity** — Limited (XL)
- **PRPS1 deficiency disorder** — Definitive (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 94.77, 90% of residues very-high.

**27 experimental structure(s)** (PDB): [2H06](https://www.rcsb.org/structure/2H06), [2H07](https://www.rcsb.org/structure/2H07), [2H08](https://www.rcsb.org/structure/2H08), [2HCR](https://www.rcsb.org/structure/2HCR), [3EFH](https://www.rcsb.org/structure/3EFH), [3S5J](https://www.rcsb.org/structure/3S5J) — incl. mutant structure 2H07.

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

*Describes the biological roles of PRPS1 (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:** PRPS1's established molecular role includes ribose phosphate diphosphokinase activity.


### Pathways affected {#pathways}

PRPS1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [5-Phosphoribose 1-diphosphate biosynthesis](https://reactome.org/content/detail/R-HSA-73843) | curated |

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

**Molecular function:** ribose phosphate diphosphokinase activity, ATP binding, identical protein binding, protein homodimerization activity.

**Biological process:** purine nucleobase metabolic process, purine nucleotide biosynthetic process, nervous system development, urate biosynthetic process, hypoxanthine biosynthetic process.

## Clinical significance {#significance}

**Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2022-03-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Likely pathogenic | no assertion criteria provided | clinical testing | 2022-03-01 |

## Associated conditions {#conditions}

[Charcot-Marie-Tooth disease X-linked recessive 5](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-x-linked-recessive-5/).

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease X-linked recessive 5, Optic atrophy, neural deafness, and distal neurogenic amyotrophy, OPTIC ATROPHY, POLYNEUROPATHY, AND DEAFNESS, ROSENBERG-CHUTORIAN SYNDROME, Charcot-Marie-Tooth Neuropathy X Type 5 (CMTX5).

## Same-residue context {#hotspot}

Residue **276** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [PRPS1 p.Pro276Ala](/variant/prps1-p-pro276ala), [PRPS1 p.Pro276Leu](/variant/prps1-p-pro276leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PRPS1 variant pages (same residue, condition, or type): [PRPS1 p.Pro276Ala](/variant/prps1-p-pro276ala), [PRPS1 p.Pro276Leu](/variant/prps1-p-pro276leu), [PRPS1 p.Pro276His](/variant/prps1-p-pro276his), [PRPS1 p.Ile107Val](/variant/prps1-p-ile107val), [PRPS1 p.Met115Thr](/variant/prps1-p-met115thr), [PRPS1 p.Met115Val](/variant/prps1-p-met115val), [PRPS1 c.306+5G>T](/variant/prps1-c-306-plus-5g-t), [PRPS1 p.Arg204His](/variant/prps1-p-arg204his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 1710220). 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.*