# NM_000048.4(ASL):c.452G>A (p.Arg151His)

https://sugi.bio/variant/asl-p-arg151his

## Summary

**ASL p.Arg151His (c.452G>A)** is classified **Uncertain significance** in ASL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-13). AlphaMissense: likely benign (0.0956); Ultra-rare (popmax 0.0495%, mid); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs758359291 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0495%, mid)

## For patients & families {#patients}

This is a change in the ASL gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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.*

**Support & next steps:** [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.Arg151His |
| Coding change (HGVS c.) | c.452G>A |
| MANE Select transcript | [NM_000048](https://www.ncbi.nlm.nih.gov/nuccore/NM_000048) |
| dbSNP | [rs758359291](https://www.ncbi.nlm.nih.gov/snp/rs758359291/) |
| Variant type | single nucleotide variant |
| Location | chr7:66086590-66086590 (GRCh38) |
| ClinVar | [VCV2139158](https://www.ncbi.nlm.nih.gov/clinvar/variation/2139158/) |

**All HGVS expressions:** `NC_000007.13:g.65551577G>A`, `NC_000007.14:g.66086590G>A`, `NG_009288.1:g.15802G>A`, `NG_111325.1:g.387G>A`, `NM_000048.3:c.452G>A`, `NM_000048.4:c.452G>A`, `NM_001024943.2:c.452G>A`, `NM_001024944.2:c.452G>A`, `NM_001024946.2:c.452G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0956)
- REVEL 0.348 (indeterminate)
- SaProt LLR -9.014 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 0.998, GERP 1.69 — weakly conserved position
- CADD: **PHRED 21.1**. 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 0.87** across the covering region of the MANE Select transcript (66,076,082–66,092,909), spanning 16,827 bp. Chi-square p 0.00078. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.20 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0495%** (mid) · FAF95 0.0166% · FAF99 0.0137% · 3/6,064 in the highest group · 62/1,613,576 alleles overall — ultra-rare (popmax 0.0495%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0495% | 2,021 |
| Finnish (not grpmax-eligible) | 0.0409% | 2,447 |
| African / African-American | 0.0254% | 3,944 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,620 |
| South Asian | 0.00329% | 30,361 |
| East Asian | 0.00223% | 44,872 |
| Admixed American | 0.00167% | 59,994 |
| European (non-Finnish) | 0.000424% | 236,005 |

*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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-02-13.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-03-15 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-13 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [argininosuccinic aciduria](https://sugi.bio/atlas/disease/argininosuccinic-aciduria/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, 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.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.446+2T>C](/variant/asl-c-446-plus-2t-c).

### 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 2139158). 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.*