# NM_001875.5(CPS1):c.1596del (p.Val533fs)

https://sugi.bio/variant/cps1-p-val533fs

## Summary

**CPS1 p.Val533fs (c.1596del)** is classified **Pathogenic/Likely pathogenic** in CPS1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-15). Very rare (popmax 8.48e-05%, nfe); Associated with carbamoyl phosphate synthetase I deficiency disease.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1698686080 · 3 submitters · 2 linked conditions · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the CPS1 gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to carbamoyl phosphate synthetase I deficiency disease.

*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) | All ages |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CPS1 is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of Carbamoyl-phosphate synthetase 1 deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Seizure — Very frequent (99-80%)
- Hypotonia — Very frequent (99-80%)
- Episodic ammonia intoxication — Very frequent (99-80%)
- Hyperammonemia — Very frequent (99-80%)
- Respiratory insufficiency — Very frequent (99-80%)
- Aminoaciduria — Very frequent (99-80%)
- Hypoargininemia — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007269/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CPS1](https://sugi.bio/atlas/gene/CPS1/) |
| Protein change (HGVS p.) | p.Val533fs |
| Coding change (HGVS c.) | c.1596del |
| MANE Select transcript | [NM_001875](https://www.ncbi.nlm.nih.gov/nuccore/NM_001875) |
| dbSNP | [rs1698686080](https://www.ncbi.nlm.nih.gov/snp/rs1698686080/) |
| Variant type | Deletion |
| Location | chr2:210600599-210600599 (GRCh38) |
| ClinVar | [VCV1968039](https://www.ncbi.nlm.nih.gov/clinvar/variation/1968039/) |

**All HGVS expressions:** `LRG_336:g.127917del`, `LRG_336t1:c.1596del`, `NC_000002.11:g.211465325del`, `NC_000002.12:g.210600601del`, `NG_008285.1:g.127917del`, `NM_001122633.3:c.1596del`, `NM_001369256.1:c.1629del`, `NM_001369257.1:c.1596del`, `NM_001875.5:c.1596del`, `NM_001875.5:c.1596delA`, `NR_161225.1:n.2505del`, `NR_163592.1:n.752del`

## Computational & population evidence {#evidence}

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

- **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 4.282, GERP 0.207, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.764, pLI 1.7622e-19. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 15 of 38**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 33.0**. 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** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,178,892 in the highest group · 1/151,896 alleles overall — very rare (popmax 8.48e-05%, nfe).

*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}

**CPS1** population constraint: LOEUF 0.764, pLI 1.7622e-19, missense-Z 1.7456. *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):

- **carbamoyl phosphate synthetase I deficiency disease** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 93.80, 88% of residues very-high.

**14 experimental structure(s)** (PDB): [2YVQ](https://www.rcsb.org/structure/2YVQ), [4UTR](https://www.rcsb.org/structure/4UTR), [4UTV](https://www.rcsb.org/structure/4UTV), [4UTX](https://www.rcsb.org/structure/4UTX), [4UTZ](https://www.rcsb.org/structure/4UTZ), [4UU7](https://www.rcsb.org/structure/4UU7).

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

*Describes the biological roles of CPS1 (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:** CPS1's established molecular role includes carbamoyl-phosphate synthase (ammonia) activity. In Reactome, CPS1 is annotated in disease pathway(s) including **CPS1 variants cause CPS1 deficiency**.

**Disease mechanism (Reactome):** CPS1 loss or alteration is curated in [CPS1 variants cause CPS1 deficiency](https://reactome.org/content/detail/R-HSA-9955542).

### Pathways affected {#pathways}

CPS1 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [CPS1 variants cause CPS1 deficiency](https://reactome.org/content/detail/R-HSA-9955542) | other |
| [Negative transcriptional regulation of urea cycle enzymes](https://reactome.org/content/detail/R-HSA-9988426) | curated |
| [Urea cycle](https://reactome.org/content/detail/R-HSA-70635) | other |

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

**Molecular function:** carbamoyl-phosphate synthase (ammonia) activity, potassium ion binding, small molecule binding, metal ion binding, modified amino acid binding.

**Biological process:** triglyceride catabolic process, response to lipopolysaccharide, vasodilation, nitric oxide metabolic process, homocysteine metabolic process, carbamoyl phosphate biosynthetic process.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-06-15.

**Submitter consensus:** conflicting (2 Pathogenic, 1 Likely pathogenic).

**Submission history:** 3 submissions (2023–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-05-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-05-19 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-06-15 |

## Associated conditions {#conditions}

[carbamoyl phosphate synthetase I deficiency disease](https://sugi.bio/atlas/disease/carbamoyl-phosphate-synthetase-i-deficiency-disease/), [pulmonary hypertension, neonatal, susceptibility to](https://sugi.bio/atlas/disease/pulmonary-hypertension-neonatal-susceptibility-to/).

**Reported phenotype names (ClinVar):** Congenital hyperammonemia, type I, Pulmonary hypertension, neonatal, susceptibility to, CPS I DEFICIENCY, Carbamoyl phosphate synthetase 1 deficiency, Hyperammonemia due to carbamoyl phosphate synthetase 1 deficiency, CPS 1 deficiency, Carbamyl phosphate synthetase (CPS) deficiency, Carbamoyl phosphate synthetase I deficiency disease, Carbamoyl-phosphate synthase I deficiency.

## Similar variants {#similar}

Related CPS1 variant pages (same residue, condition, or type): [CPS1 p.Ala907fs](/variant/cps1-p-ala907fs), [CPS1 p.Arg1228fs](/variant/cps1-p-arg1228fs), [CPS1 p.Arg932_Leu933insTer](/variant/cps1-p-arg932-leu933inster), [CPS1 p.Asp1304fs](/variant/cps1-p-asp1304fs), [CPS1 p.Asp642fs](/variant/cps1-p-asp642fs), [CPS1 p.Cys644fs](/variant/cps1-p-cys644fs), [CPS1 p.Glu455fs](/variant/cps1-p-glu455fs), [CPS1 p.Glu842fs](/variant/cps1-p-glu842fs).

### 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 1968039). 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.*