# NM_178557.4(ASPNAT):c.176C>G (p.Pro59Arg)

https://sugi.bio/variant/aspnat-p-pro59arg

## Summary

**ASPNAT p.Pro59Arg (c.176C>G)** is classified **Uncertain significance** in ASPNAT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely benign (0.1185); Very rare (popmax 0.000348%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.000348%, nfe)

## For patients & families {#patients}

This is a change in the ASPNAT gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [ASPNAT](https://sugi.bio/atlas/gene/ASPNAT/) |
| Protein change (HGVS p.) | p.Pro59Arg |
| Coding change (HGVS c.) | c.176C>G |
| MANE Select transcript | [NM_178557](https://www.ncbi.nlm.nih.gov/nuccore/NM_178557) |
| Variant type | single nucleotide variant |
| Location | chr4:2059687-2059687 (GRCh38) |
| ClinVar | [VCV3917341](https://www.ncbi.nlm.nih.gov/clinvar/variation/3917341/) |

**All HGVS expressions:** `NC_000004.11:g.2061414C>G`, `NC_000004.12:g.2059687C>G`, `NG_027961.1:g.5176C>G`, `NM_178557.4:c.176C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1185)
- REVEL 0.051 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.214 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.62, GERP -1.56, phastCons 0.001 — weakly conserved position
- CADD: **PHRED 14.46**. 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 1.01** across the covering region of the MANE Select transcript (2,059,512–2,061,046), spanning 1,534 bp. Chi-square p 0.84. 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 (C>A, Δ0.23 donor 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 **0.000348%** (nfe) · FAF95 9.3e-05% · FAF99 2.6e-05% · 3/861,846 in the highest group · 4/1,031,134 alleles overall — very rare (popmax 0.000348%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00307% | 32,522 |
| European (non-Finnish) (grpmax) | 0.000348% | 287,282 |

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}

**ASPNAT** population constraint: 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):

- **N-acetylaspartate deficiency** — Limited (AR)

## Protein context {#protein}

Residue **59** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 81.36, 72% of residues very-high.

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

*Describes the biological roles of ASPNAT (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:** ASPNAT's established molecular role includes L-aspartate N-acetyltransferase activity. p.Pro59Arg falls in the disordered region.


### Pathways affected {#pathways}

ASPNAT participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Aspartate and asparagine metabolism](https://reactome.org/content/detail/R-HSA-8963693) | curated |

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

**Molecular function:** L-aspartate N-acetyltransferase activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-07.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-07 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related ASPNAT variant pages (same residue, condition, or type): [ASPNAT p.Pro59Leu](/variant/aspnat-p-pro59leu), [ASPNAT p.Pro59Ser](/variant/aspnat-p-pro59ser), [ASPNAT c.541+8C>T](/variant/aspnat-c-541-plus-8c-t), [ASPNAT p.Ala35=](/variant/aspnat-p-ala35), [ASPNAT p.Gly263=](/variant/aspnat-p-gly263), [ASPNAT p.Pro56=](/variant/aspnat-p-pro56), [ASPNAT p.Ala125Thr](/variant/aspnat-p-ala125thr), [ASPNAT p.Ala225Thr](/variant/aspnat-p-ala225thr).

### 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 3917341). 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.*