# NM_000048.4(ASL):c.803del (p.Phe268fs)

https://sugi.bio/variant/asl-p-phe268fs

## Summary

**ASL p.Phe268fs (c.803del)** is classified **Likely pathogenic** in ASL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-04). No gnomAD frequency available for this variant; Associated with argininosuccinic aciduria.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1584031242 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ASL gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to argininosuccinic aciduria.

*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 / 1 000 000 (United States) |
| Clinical trials | 8 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ASL is a diagnostic-grade gene on 13 Genomics England panels |

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

- Hyperammonemia — Very frequent (99-80%)
- Hyperglutaminemia — Very frequent (99-80%)
- Aminoaciduria — Very frequent (99-80%)
- Hypoargininemia — Very frequent (99-80%)
- Hypertension — Frequent (79-30%)
- Intellectual disability — Frequent (79-30%)
- Seizure — Frequent (79-30%)
- Ataxia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005843/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ASL](https://sugi.bio/atlas/gene/ASL/) |
| Protein change (HGVS p.) | p.Phe268fs |
| Coding change (HGVS c.) | c.803del |
| MANE Select transcript | [NM_000048](https://www.ncbi.nlm.nih.gov/nuccore/NM_000048) |
| dbSNP | [rs1584031242](https://www.ncbi.nlm.nih.gov/snp/rs1584031242/) |
| Variant type | Deletion |
| Location | chr7:66088890-66088890 (GRCh38) |
| ClinVar | [VCV2678804](https://www.ncbi.nlm.nih.gov/clinvar/variation/2678804/) |

**All HGVS expressions:** `NC_000007.13:g.65553878del`, `NC_000007.14:g.66088891del`, `NG_009288.1:g.18103del`, `NM_000048.4:c.803del`, `NM_001024943.2:c.803del`, `NM_001024944.2:c.803del`, `NM_001024946.2:c.725del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -0.513, GERP -3.38 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.937, pLI 2.6098e-13. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 11 of 17**, 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.
- 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}

**ASL** population constraint: LOEUF 0.937, pLI 2.6098e-13, missense-Z 1.3965; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **argininosuccinic aciduria** — Definitive (AR)

## Protein context {#protein}

Residue **268** lies in a turn.

AlphaFold model confidence (whole protein): pLDDT 96.51, 95% of residues very-high.

**2 experimental structure(s)** (PDB): [1AOS](https://www.rcsb.org/structure/1AOS), [1K62](https://www.rcsb.org/structure/1K62) — incl. mutant structure 1K62.

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

*Describes the biological roles of ASL (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:** ASL's established molecular role includes argininosuccinate lyase activity. In Reactome, ASL is annotated in disease pathway(s) including **ASL variants cause argininosuccinate aciduria**.

**Disease mechanism (Reactome):** ASL loss or alteration is curated in [ASL variants cause argininosuccinate aciduria](https://reactome.org/content/detail/R-HSA-9956529).

### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [ASL variants cause argininosuccinate aciduria](https://reactome.org/content/detail/R-HSA-9956529) | curated |
| [Urea cycle](https://reactome.org/content/detail/R-HSA-70635) | curated |

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

**Molecular function:** argininosuccinate lyase activity, identical protein binding.

**Biological process:** arginine metabolic process, L-arginine biosynthetic process, positive regulation of nitric oxide biosynthetic process.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-11-04.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-11-04 |

## Associated conditions {#conditions}

[argininosuccinic aciduria](https://sugi.bio/atlas/disease/argininosuccinic-aciduria/).

**Reported phenotype names (ClinVar):** Argininosuccinate lyase deficiency, Argininosuccinic aciduria, ARGININOSUCCINIC ACID LYASE DEFICIENCY, ASL DEFICIENCY.

## Similar variants {#similar}

Related ASL variant pages (same residue, condition, or type): [ASL c.1045_1062+7del](/variant/asl-c-1045-1062-plus-7del), [ASL c.1143+1del](/variant/asl-c-1143-plus-1del), [ASL p.Asp38fs](/variant/asl-p-asp38fs), [ASL p.Leu325fs](/variant/asl-p-leu325fs), [ASL p.Leu419fs](/variant/asl-p-leu419fs), [ASL p.Val211fs](/variant/asl-p-val211fs), [ASL p.Val349fs](/variant/asl-p-val349fs), [ASL p.Val403fs](/variant/asl-p-val403fs).

### 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 2678804). 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.*