# NM_001673.5(ASNS):c.1440C>T (p.Ser480=)

https://sugi.bio/variant/asns-p-ser480

## Summary

**ASNS p.Ser480= (c.1440C>T)** is classified **Likely benign** in ASNS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-25). Absent from gnomAD v4.1.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ASNS gene that is classified as likely benign — not considered disease-causing, 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 | [ASNS](https://sugi.bio/atlas/gene/ASNS/) |
| Protein change (HGVS p.) | p.Ser480= |
| Coding change (HGVS c.) | c.1440C>T |
| MANE Select transcript | [NM_001673](https://www.ncbi.nlm.nih.gov/nuccore/NM_001673) |
| Variant type | single nucleotide variant |
| Location | chr7:97853096-97853096 (GRCh38) |
| ClinVar | [VCV3687924](https://www.ncbi.nlm.nih.gov/clinvar/variation/3687924/) |

**All HGVS expressions:** `NC_000007.13:g.97482408G>A`, `NC_000007.14:g.97853096G>A`, `NG_033870.2:g.80467C>T`, `NM_001178075.2:c.1377C>T`, `NM_001178076.2:c.1191C>T`, `NM_001178077.1:c.1191C>T`, `NM_001352496.2:c.1440C>T`, `NM_001673.5:c.1440C>T`, `NM_133436.3:c.1440C>T`, `NM_183356.4:c.1440C>T`, `NR_147989.1:n.3143C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.27) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.755, GERP -0.06, phastCons 1 — weakly conserved position
- CADD: **PHRED 14.15**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.27**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.27**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**ASNS** population constraint: LOEUF 0.745, pLI 9.1235e-06, missense-Z 2.4057. *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):

- **congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome** — Definitive (AR)

## Protein context {#protein}

Residue **480** lies in the asparagine synthetase domain.

AlphaFold model confidence (whole protein): pLDDT 94.36, 89% of residues very-high.

**3 experimental structure(s)** (PDB): [6GQ3](https://www.rcsb.org/structure/6GQ3), [8SUE](https://www.rcsb.org/structure/8SUE), [9B6C](https://www.rcsb.org/structure/9B6C) — incl. mutant structure 9B6C.

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

*Describes the biological roles of ASNS (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:** ASNS's established molecular role includes asparagine synthase (glutamine-hydrolyzing) activity. p.Ser480= falls in the asparagine synthetase domain.


### Pathways affected {#pathways}

ASNS participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Aspartate and asparagine metabolism](https://reactome.org/content/detail/R-HSA-8963693) | curated |
| [ATF4 activates genes in response to endoplasmic reticulum  stress](https://reactome.org/content/detail/R-HSA-380994) | electronic |
| [Response of EIF2AK1 (HRI) to heme deficiency](https://reactome.org/content/detail/R-HSA-9648895) | electronic |
| [Response of EIF2AK4 (GCN2) to amino acid deficiency](https://reactome.org/content/detail/R-HSA-9633012) | electronic |

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

**Molecular function:** asparagine synthase (glutamine-hydrolyzing) activity.

**Biological process:** cellular response to glucose starvation, negative regulation of apoptotic process, positive regulation of mitotic cell cycle, L-asparagine biosynthetic process.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-25.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-01-25 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ASNS variant pages (same residue, condition, or type): [ASNS p.Ser480Phe](/variant/asns-p-ser480phe), [ASNS c.1030+1G>A](/variant/asns-c-1030-plus-1g-a), [ASNS c.1138-1G>A](/variant/asns-c-1138-minus-1g-a), [ASNS c.1239-2A>T](/variant/asns-c-1239-minus-2a-t), [ASNS c.1320+1G>C](/variant/asns-c-1320-plus-1g-c), [ASNS c.1320+1G>T](/variant/asns-c-1320-plus-1g-t), [ASNS c.1321-1G>A](/variant/asns-c-1321-minus-1g-a), [ASNS c.1476+1G>A](/variant/asns-c-1476-plus-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 3687924). 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.*