# NM_175859.3(CTPS2):c.632C>T (p.Pro211Leu)

https://sugi.bio/variant/ctps2-p-pro211leu

## Summary

**CTPS2 p.Pro211Leu (c.632C>T)** is classified **Uncertain significance** in CTPS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-06). AlphaMissense: likely pathogenic (0.8438); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2518674822 · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CTPS2 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 | [CTPS2](https://sugi.bio/atlas/gene/CTPS2/) |
| Protein change (HGVS p.) | p.Pro211Leu |
| Coding change (HGVS c.) | c.632C>T |
| MANE Select transcript | [NM_175859](https://www.ncbi.nlm.nih.gov/nuccore/NM_175859) |
| dbSNP | [rs2518674822](https://www.ncbi.nlm.nih.gov/snp/rs2518674822/) |
| Variant type | single nucleotide variant |
| Location | chrX:16693148-16693148 (GRCh38) |
| ClinVar | [VCV2533899](https://www.ncbi.nlm.nih.gov/clinvar/variation/2533899/) |

**All HGVS expressions:** `NC_000023.10:g.16711271G>A`, `NC_000023.11:g.16693148G>A`, `NG_013229.1:g.24789C>T`, `NG_013229.2:g.24762C>T`, `NM_001144002.2:c.632C>T`, `NM_019857.5:c.632C>T`, `NM_175859.3:c.632C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8438)
- REVEL 0.599 (indeterminate)
- SaProt LLR -14.154 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- SpliceAI predicts **donor loss** (Δ 0.20) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.493, GERP 2.04, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.7**. 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 0.64** across the covering region of the MANE Select transcript (16,590,796–16,702,902), spanning 112,106 bp. Chi-square p 2.2e-14. 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 **0.20**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.20**, acceptor gain **0.00**, donor gain **0.00**.
- 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.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 91.79, 84% of residues very-high.

**8 experimental structure(s)** (PDB): [2V4U](https://www.rcsb.org/structure/2V4U), [2VKT](https://www.rcsb.org/structure/2VKT), [3IHL](https://www.rcsb.org/structure/3IHL), [6PK4](https://www.rcsb.org/structure/6PK4), [6PK7](https://www.rcsb.org/structure/6PK7), [7MH1](https://www.rcsb.org/structure/7MH1).

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

*Describes the biological roles of CTPS2 (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:** CTPS2's established molecular role includes CTP synthase activity.


### Pathways affected {#pathways}

CTPS2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Interconversion of nucleotide di- and triphosphates](https://reactome.org/content/detail/R-HSA-499943) | other |

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

**Molecular function:** CTP synthase activity, identical protein binding.

**Biological process:** CTP biosynthetic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-04-06.

**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 | 2023-04-06 |

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

## Similar variants {#similar}

Related CTPS2 variant pages (same residue, condition, or type): [CTPS2 p.Gly542=](/variant/ctps2-p-gly542), [CTPS2 p.Ala315Thr](/variant/ctps2-p-ala315thr), [CTPS2 p.Ala428Val](/variant/ctps2-p-ala428val), [CTPS2 p.Ala546Thr](/variant/ctps2-p-ala546thr), [CTPS2 p.Arg202Cys](/variant/ctps2-p-arg202cys), [CTPS2 p.Arg217Gln](/variant/ctps2-p-arg217gln), [CTPS2 p.Arg481Gln](/variant/ctps2-p-arg481gln), [CTPS2 p.Arg481Trp](/variant/ctps2-p-arg481trp).

### 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 2533899). 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.*