# NM_054012.4(ASS1):c.381del (p.Phe128fs)

https://sugi.bio/variant/ass1-p-phe128fs

## Summary

**ASS1 p.Phe128fs (c.381del)** is classified **Likely pathogenic** in ASS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-22). Associated with citrullinemia type I.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the ASS1 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to citrullinemia type I.

*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 |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 7 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ASS1 is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Citrullinemia type I** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hyperammonemia — Very frequent (99-80%)
- Elevated plasma citrulline — Very frequent (99-80%)
- Hepatic failure — Frequent (79-30%)
- Abnormality of the nervous system — Occasional (29-5%)
- Seizure — Occasional (29-5%)
- Lethargy — Occasional (29-5%)
- Spasticity — Occasional (29-5%)
- Failure to thrive — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006114/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ASS1](https://sugi.bio/atlas/gene/ASS1/) |
| Protein change (HGVS p.) | p.Phe128fs |
| Coding change (HGVS c.) | c.381del |
| MANE Select transcript | [NM_054012](https://www.ncbi.nlm.nih.gov/nuccore/NM_054012) |
| Variant type | Deletion |
| Location | chr9:130464127-130464127 (GRCh38) |
| ClinVar | [VCV3362551](https://www.ncbi.nlm.nih.gov/clinvar/variation/3362551/) |

**All HGVS expressions:** `NC_000009.11:g.133339515del`, `NC_000009.12:g.130464128del`, `NG_011542.1:g.24422del`, `NM_000050.4:c.381del`, `NM_054012.4:c.381del`

## 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 7.607, GERP 1.1, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.14, pLI 1.4303e-18. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 5 of 15**, so the transcript is predicted to undergo NMD.
- 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.

*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}

**ASS1** population constraint: LOEUF 1.14, pLI 1.4303e-18, missense-Z 1.8142. *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):

- **citrullinemia type I** — Definitive (AR)

## Protein context {#protein}

Residue **128** lies in an α-helix; a UniProt-annotated variant site (in ctln1).

AlphaFold model confidence (whole protein): pLDDT 95.64, 91% of residues very-high.

**1 experimental structure(s)** (PDB): [2NZ2](https://www.rcsb.org/structure/2NZ2).

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

*Describes the biological roles of ASS1 (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:** ASS1's established molecular role includes RNA binding. In Reactome, ASS1 is annotated in disease pathway(s) including **ASS1 variants cause citrullinemia**.

**Disease mechanism (Reactome):** ASS1 loss or alteration is curated in [ASS1 variants cause citrullinemia](https://reactome.org/content/detail/R-HSA-9956520).

### Pathways affected {#pathways}

ASS1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [ASS1 variants cause citrullinemia](https://reactome.org/content/detail/R-HSA-9956520) | curated |
| [Urea cycle](https://reactome.org/content/detail/R-HSA-70635) | curated |

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

**Molecular function:** RNA binding, argininosuccinate synthase activity, amino acid binding, identical protein binding.

**Biological process:** urea cycle, obsolete citrulline metabolic process, obsolete argininosuccinate metabolic process, L-arginine biosynthetic process, aspartate metabolic process, circadian rhythm.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-09-22.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-09-22 |

## Associated conditions {#conditions}

[citrullinemia type I](https://sugi.bio/atlas/disease/citrullinemia-type-i/).

**Reported phenotype names (ClinVar):** Citrullinemia type I, argininosuccinate synthetase deficiency, ASS DEFICIENCY.

## Similar variants {#similar}

Related ASS1 variant pages (same residue, condition, or type): [ASS1 p.Arg95fs](/variant/ass1-p-arg95fs), [ASS1 p.Gln107fs](/variant/ass1-p-gln107fs), [ASS1 p.Gln350fs](/variant/ass1-p-gln350fs), [ASS1 p.Glu283fs](/variant/ass1-p-glu283fs), [ASS1 p.Glu298fs](/variant/ass1-p-glu298fs), [ASS1 p.Phe150fs](/variant/ass1-p-phe150fs), [ASS1 p.Phe154fs](/variant/ass1-p-phe154fs), [ASS1 p.Phe317fs](/variant/ass1-p-phe317fs).

### 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 3362551). 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.*