# NM_000048.4(ASL):c.446+2T>C

https://sugi.bio/variant/asl-c-446-plus-2t-c

## Summary

**ASL c.446+2T>C** is classified **Pathogenic** in ASL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-19). Very rare (popmax 0.00268%, afr); Associated with argininosuccinic aciduria.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1268519003 · 4 submitters · 1 linked condition · very rare (popmax 0.00268%, afr)

## For patients & families {#patients}

This is a change in the ASL gene that is considered disease-causing, submitted by 4 submitters, 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/) |
| Coding change (HGVS c.) | c.446+2T>C |
| MANE Select transcript | [NM_000048](https://www.ncbi.nlm.nih.gov/nuccore/NM_000048) |
| dbSNP | [rs1268519003](https://www.ncbi.nlm.nih.gov/snp/rs1268519003/) |
| Variant type | single nucleotide variant |
| Location | chr7:66083176-66083176 (GRCh38) |
| ClinVar | [VCV553540](https://www.ncbi.nlm.nih.gov/clinvar/variation/553540/) |

**All HGVS expressions:** `NC_000007.13:g.65548163T>C`, `NC_000007.14:g.66083176T>C`, `NG_009288.1:g.12388T>C`, `NM_000048.3:c.446+2T>C`, `NM_000048.4:c.446+2T>C`, `NM_001024943.2:c.446+2T>C`, `NM_001024944.2:c.446+2T>C`, `NM_001024946.2:c.446+2T>C`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.84) — consistent with the pathogenic call
- Conservation: phyloP 6.194, GERP 1.54, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **canonical splice-site (±1/±2)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.937, pLI 2.6098e-13. *Descriptive; not an applied PVS1 code.*
- 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.*
- Splice region: **canonical splice dinucleotide (donor +2)** — inside the zone ClinGen GN167 excludes from BP7, so this variant must not be called benign merely for being synonymous or intronic.
- Non-coding constraint (Gnocchi): **Z 2.63**, o/e 0.82 (1 kb window 66,083,000–66,084,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.84**, acceptor gain **0.00**, donor gain **0.28**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.84**, acceptor gain **0.00**, donor gain **0.28**.
- Pangolin: Δ**0.75** (loss), gain 0.54 / loss 0.75. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00268%** (afr) · FAF95 0.000445% · FAF99 0.000167% · 2/74,622 in the highest group · 2/1,611,602 alleles overall — very rare (popmax 0.00268%, afr).

*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}


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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-19.

**Submitter consensus:** conflicting (3 Pathogenic, 1 Likely pathogenic).

**Submission history:** 4 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Counsyl | Likely pathogenic | no assertion criteria provided | clinical testing | 2017-08-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-19 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-08-09 |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-23 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related ASL variant pages (same residue, condition, or type): [ASL c.1062+5G>C](/variant/asl-c-1062-plus-5g-c), [ASL c.1143+1G>T](/variant/asl-c-1143-plus-1g-t), [ASL c.13-1G>C](/variant/asl-c-13-minus-1g-c), [ASL c.291+1G>T](/variant/asl-c-291-plus-1g-t), [ASL c.348+1G>A](/variant/asl-c-348-plus-1g-a), [ASL c.349-1G>A](/variant/asl-c-349-minus-1g-a), [ASL c.446+1G>A](/variant/asl-c-446-plus-1g-a), [ASL c.447-1G>A](/variant/asl-c-447-minus-1g-a).

### 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 553540). 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.*