# NM_001875.5(CPS1):c.209_216dup (p.Phe73fs)

https://sugi.bio/variant/cps1-p-phe73fs

## Summary

**CPS1 p.Phe73fs (c.209_216dup)** is classified **Likely pathogenic** in CPS1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2016-06-21). No gnomAD frequency available for this variant; Associated with carbamoyl phosphate synthetase I deficiency disease.

**At a glance:** Likely pathogenic · review: No assertion criteria · rsID rs1553509010 · 1 submitter · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CPS1 gene that is considered likely disease-causing, submitted by 1 submitter, 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.Phe73fs |
| Coding change (HGVS c.) | c.209_216dup |
| MANE Select transcript | [NM_001875](https://www.ncbi.nlm.nih.gov/nuccore/NM_001875) |
| dbSNP | [rs1553509010](https://www.ncbi.nlm.nih.gov/snp/rs1553509010/) |
| Variant type | Duplication |
| Location | chr2:210573379-210573380 (GRCh38) |
| ClinVar | [VCV417895](https://www.ncbi.nlm.nih.gov/clinvar/variation/417895/) |

**All HGVS expressions:** `LRG_336:g.100696_100703dup`, `NC_000002.11:g.211438104_211438111dup`, `NC_000002.12:g.210573380_210573387dup`, `NG_008285.1:g.100696_100703dup`, `NM_001122633.3:c.209_216dup`, `NM_001369256.1:c.242_249dup`, `NM_001369257.1:c.209_216dup`, `NM_001875.5:c.209_216dup`, `NR_161225.1:n.1121_1128dup`

## 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 11.895, GERP 2.73, 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 2 of 38**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

Residue **73** lies in a β-strand; the 'anthranilate phosphoribosyltransferase homolog' region.

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. p.Phe73fs falls in the anthranilate phosphoribosyltransferase homolog region. 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}

**Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2016-06-21.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Division of Human Genetics, Children's Hospital of Philadelphia | Likely pathogenic | no assertion criteria provided | research | 2016-06-21 |

## 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, Carbamoyl phosphate synthetase I deficiency disease, Carbamoyl phosphate synthetase 1 deficiency, Hyperammonemia due to carbamoyl phosphate synthetase 1 deficiency, CPS 1 deficiency, Carbamyl phosphate synthetase (CPS) deficiency, Carbamoyl-phosphate synthase I deficiency, CPS I DEFICIENCY.

## Similar variants {#similar}

Related CPS1 variant pages (same residue, condition, or type): [CPS1 p.Asn103_Gly104dup](/variant/cps1-p-asn103-gly104dup), [CPS1 p.Asp442Ter](/variant/cps1-p-asp442ter), [CPS1 p.Gly802fs](/variant/cps1-p-gly802fs), [CPS1 p.Leu290fs](/variant/cps1-p-leu290fs), [CPS1 c.3666+77dup](/variant/cps1-c-3666-plus-77dup), [CPS1 c.3928-8dup](/variant/cps1-c-3928-minus-8dup), [CPS1 p.Ala1102fs](/variant/cps1-p-ala1102fs), [CPS1 p.Asn472fs](/variant/cps1-p-asn472fs).

### 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 417895). 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.*