# NM_001875.5(CPS1):c.1145C>T (p.Pro382Leu)

https://sugi.bio/variant/cps1-p-pro382leu

## Summary

**CPS1 p.Pro382Leu (c.1145C>T)** is classified **Pathogenic/Likely pathogenic** in CPS1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-04-17). AlphaMissense: likely benign (0.275); Very rare (popmax 0.00288%, nfe); Associated with pulmonary hypertension, neonatal, susceptibility to.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs201407486 · 7 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00288%, nfe)

## For patients & families {#patients}

This is a change in the CPS1 gene that is considered likely disease-causing, submitted by 7 submitters, and is linked to pulmonary hypertension, neonatal, susceptibility to.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [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.Pro382Leu |
| Coding change (HGVS c.) | c.1145C>T |
| MANE Select transcript | [NM_001875](https://www.ncbi.nlm.nih.gov/nuccore/NM_001875) |
| dbSNP | [rs201407486](https://www.ncbi.nlm.nih.gov/snp/rs201407486/) |
| Variant type | single nucleotide variant |
| Location | chr2:210592937-210592937 (GRCh38) |
| ClinVar | [VCV550641](https://www.ncbi.nlm.nih.gov/clinvar/variation/550641/) |

**All HGVS expressions:** `LRG_336:g.120253C>T`, `LRG_336t1:c.1145C>T`, `NC_000002.11:g.211457661C>T`, `NC_000002.12:g.210592937C>T`, `NG_008285.1:g.120253C>T`, `NM_001122633.3:c.1145C>T`, `NM_001369256.1:c.1178C>T`, `NM_001369257.1:c.1145C>T`, `NM_001875.5:c.1145C>T`, `NR_161225.1:n.2057C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.275) — ⚠ discordant with the pathogenic call
- REVEL 0.692 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -4.52 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- Conservation: phyloP 7.66, GERP 2.89, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 32.0**. 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.*
- Regional missense constraint: **o/e 0.93** across the covering region of the MANE Select transcript (210,556,734–210,677,982), spanning 121,248 bp. Chi-square p 0.0019. 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 (gnomAD v4.1): grpmax **0.00288%** (nfe) · FAF95 0.00208% · FAF99 0.00183% · 34/1,178,824 in the highest group · 39/1,460,358 alleles overall — very rare (popmax 0.00288%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00481% | 20,794 |
| European (non-Finnish) (grpmax) | 0.00288% | 34,671 |
| African / African-American | 0.00134% | 74,810 |
| South Asian | 0.0011% | 91,026 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **382** lies in a UniProt-annotated variant site (in cps1d); the glutamine amidotransferase type-1 domain; a β-strand.

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.Pro382Leu falls in the glutamine amidotransferase type-1 domain. 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 2025-04-17.

**Submitter consensus:** conflicting (5 Likely pathogenic, 1 Uncertain significance, 1 Pathogenic).

**Submission history:** 7 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2017-02-14 |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-02-20 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-04-30 |
| The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital | Likely pathogenic | criteria provided, single submitter | research | 2021-03-06 |
| Laboratoire Génétique Moléculaire, CHRU TOURS | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-02-21 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-02-26 |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-17 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related CPS1 variant pages (same residue, condition, or type): [CPS1 p.Pro382=](/variant/cps1-p-pro382), [CPS1 c.1086+1G>A](/variant/cps1-c-1086-plus-1g-a), [CPS1 c.1087-1G>T](/variant/cps1-c-1087-minus-1g-t), [CPS1 c.1165-2A>G](/variant/cps1-c-1165-minus-2a-g), [CPS1 c.1263+5G>C](/variant/cps1-c-1263-plus-5g-c), [CPS1 c.1549+1G>A](/variant/cps1-c-1549-plus-1g-a), [CPS1 c.1549+1G>T](/variant/cps1-c-1549-plus-1g-t), [CPS1 c.1837-8A>G](/variant/cps1-c-1837-minus-8a-g).

### 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 550641). 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.*