# NM_001673.5(ASNS):c.399_400del (p.Phe134fs)

https://sugi.bio/variant/asns-p-phe134fs

## Summary

**ASNS p.Phe134fs (c.399_400del)** is classified **Pathogenic** in ASNS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-16). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2484682215 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ASNS gene that is reported as disease-causing, but on limited review, 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.Phe134fs |
| Coding change (HGVS c.) | c.399_400del |
| MANE Select transcript | [NM_001673](https://www.ncbi.nlm.nih.gov/nuccore/NM_001673) |
| dbSNP | [rs2484682215](https://www.ncbi.nlm.nih.gov/snp/rs2484682215/) |
| Variant type | Microsatellite |
| Location | chr7:97864346-97864347 (GRCh38) |
| ClinVar | [VCV2846241](https://www.ncbi.nlm.nih.gov/clinvar/variation/2846241/) |

**All HGVS expressions:** `NC_000007.13:g.97493658AC[1]`, `NC_000007.14:g.97864346AC[1]`, `NG_033870.2:g.69214GT[1]`, `NM_001178075.2:c.336_337del`, `NM_001178076.2:c.150_151del`, `NM_001178077.1:c.150_151del`, `NM_001352496.2:c.399_400del`, `NM_001673.5:c.399_400del`, `NM_133436.3:c.399_400del`, `NM_183356.4:c.399_400del`, `NR_147989.1:n.2026GT[1]`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 9.124, GERP 1.69, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.745, pLI 9.1235e-06. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 13**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Repeat context: **segmental_duplication** (chr8:46572685, chr14_GL000194v1_random:35866, chr9:64051997). Short reads may not map uniquely here, so both the call and its population frequency are less reliable. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- 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}

**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 **134** lies in the glutamine amidotransferase type-2 domain; a β-strand.

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.Phe134fs falls in the glutamine amidotransferase type-2 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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-03-16.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-03-16 |

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

## Similar variants {#similar}

Related ASNS variant pages (same residue, condition, or type): [ASNS p.Phe134=](/variant/asns-p-phe134), [ASNS p.Asp250fs](/variant/asns-p-asp250fs), [ASNS p.Leu393fs](/variant/asns-p-leu393fs), [ASNS p.Val231fs](/variant/asns-p-val231fs), [ASNS c.1239-15_1239-13del](/variant/asns-c-1239-minus-15-1239-minus-13del), [ASNS c.487+2TAA[2]](/variant/asns-c-487-plus-2taa-2), [ASNS c.903+15_903+16del](/variant/asns-c-903-plus-15-903-plus-16del), [ASNS p.Glu389del](/variant/asns-p-glu389del).

### 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 2846241). 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.*