# NM_001905.4(CTPS1):c.1311A>G (p.Pro437=)

https://sugi.bio/variant/ctps1-p-pro437

## Summary

**CTPS1 p.Pro437= (c.1311A>G)** is classified **Likely benign** in CTPS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-29). Very rare (popmax 0.0011%, sas); Associated with combined immunodeficiency due to CTPS1 deficiency.

**At a glance:** Likely benign · review: Single submitter · rsID rs781599785 · 1 submitter · 1 linked condition · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the CTPS1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to combined immunodeficiency due to CTPS1 deficiency.

*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 recessive |
| Age of onset (of this condition) | Childhood, Infancy, Neonatal |
| Diagnostic panels | CTPS1 is a diagnostic-grade gene on 2 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017696/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CTPS1](https://sugi.bio/atlas/gene/CTPS1/) |
| Protein change (HGVS p.) | p.Pro437= |
| Coding change (HGVS c.) | c.1311A>G |
| MANE Select transcript | [NM_001905](https://www.ncbi.nlm.nih.gov/nuccore/NM_001905) |
| dbSNP | [rs781599785](https://www.ncbi.nlm.nih.gov/snp/rs781599785/) |
| Variant type | single nucleotide variant |
| Location | chr1:41007463-41007463 (GRCh38) |
| ClinVar | [VCV755385](https://www.ncbi.nlm.nih.gov/clinvar/variation/755385/) |

**All HGVS expressions:** `LRG_1229:g.33165A>G`, `LRG_1229t1:c.1311A>G`, `NC_000001.10:g.41473135A>G`, `NC_000001.11:g.41007463A>G`, `NG_034208.1:g.33165A>G`, `NM_001301237.2:c.843A>G`, `NM_001905.4:c.1311A>G`, `NR_125440.2:n.1458A>G`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.23) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -1.466, GERP -5.21 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 5.844**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.23**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.23**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · FAF95 0.000124% · FAF99 9e-05% · 1/91,086 in the highest group · 6/1,461,760 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 91,086 |
| European (non-Finnish) | 0.000424% | 236,006 |

*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}

**CTPS1** population constraint: LOEUF 0.423, pLI 0.99986, missense-Z 3.885. *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):

- **severe combined immunodeficiency due to CTPS1 deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **437** lies in the glutamine amidotransferase type-1 domain.

AlphaFold model confidence (whole protein): pLDDT 91.46, 83% of residues very-high.

**7 experimental structure(s)** (PDB): [2VO1](https://www.rcsb.org/structure/2VO1), [5U03](https://www.rcsb.org/structure/5U03), [7MGZ](https://www.rcsb.org/structure/7MGZ), [7MH0](https://www.rcsb.org/structure/7MH0), [7MIF](https://www.rcsb.org/structure/7MIF), [7MIG](https://www.rcsb.org/structure/7MIG).

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

*Describes the biological roles of CTPS1 (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:** CTPS1's established molecular role includes CTP synthase activity. p.Pro437= falls in the glutamine amidotransferase type-1 domain.


### Pathways affected {#pathways}

CTPS1 participates in **1 Reactome pathway** (⚕ = disease pathway):

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

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

**Molecular function:** CTP synthase activity, identical protein binding, histone H1N76/N77 asparagine deamidase activity.

**Biological process:** CTP biosynthetic process, T cell proliferation, B cell proliferation, DNA repair-dependent chromatin remodeling, negative regulation of chromosome condensation.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-07-29.

**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 | 2023-07-29 |

## Associated conditions {#conditions}

[combined immunodeficiency due to CTPS1 deficiency](https://sugi.bio/atlas/disease/combined-immunodeficiency-due-to-ctps1-deficiency/).

**Reported phenotype names (ClinVar):** Combined immunodeficiency due to CTPS1 deficiency, Immunodeficiency 24, Severe combined immunodeficiency due to CTPS1 deficiency.

## Similar variants {#similar}

Related CTPS1 variant pages (same residue, condition, or type): [CTPS1 c.1692-1G>C](/variant/ctps1-c-1692-minus-1g-c), [CTPS1 c.1095-5T>G](/variant/ctps1-c-1095-minus-5t-g), [CTPS1 p.Ala471Thr](/variant/ctps1-p-ala471thr), [CTPS1 p.Arg102Trp](/variant/ctps1-p-arg102trp), [CTPS1 p.Arg294His](/variant/ctps1-p-arg294his), [CTPS1 p.Arg376Gln](/variant/ctps1-p-arg376gln), [CTPS1 p.Arg550Gln](/variant/ctps1-p-arg550gln), [CTPS1 p.Asn412Ser](/variant/ctps1-p-asn412ser).

### 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 755385). 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.*