# NM_144772.3(NAXE):c.399_400del (p.Phe134fs)

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

## Summary

**NAXE p.Phe134fs (c.399_400del)** is classified **Likely pathogenic** in NAXE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-13). Very rare (popmax 0.0011%, sas); Associated with encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the NAXE gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1.

*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) | Infancy |
| Diagnostic panels | NAXE is a diagnostic-grade gene on 12 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017991/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NAXE](https://sugi.bio/atlas/gene/NAXE/) |
| Protein change (HGVS p.) | p.Phe134fs |
| Coding change (HGVS c.) | c.399_400del |
| MANE Select transcript | [NM_144772](https://www.ncbi.nlm.nih.gov/nuccore/NM_144772) |
| Variant type | Microsatellite |
| Location | chr1:156592470-156592471 (GRCh38) |
| ClinVar | [VCV4856332](https://www.ncbi.nlm.nih.gov/clinvar/variation/4856332/) |

**All HGVS expressions:** `NC_000001.10:g.156562262CT[1]`, `NC_000001.11:g.156592470CT[1]`, `NG_052542.1:g.5705CT[1]`, `NG_092384.1:g.641CT[1]`, `NG_092384.2:g.879CT[1]`, `NM_144772.3:c.399_400del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 0.174, GERP -3.28, phastCons 0.184 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.079, pLI 2.1985e-07. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 6**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 35.0**. 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.*
- 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.
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · 1/91,056 in the highest group · 1/1,613,398 alleles overall — very rare (popmax 0.0011%, sas).

*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}

**NAXE** population constraint: LOEUF 1.079, pLI 2.1985e-07, missense-Z 0.54628. *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):

- **mitochondrial disease** — Definitive (AR)
- **Leigh syndrome** — Limited (AR)

## Protein context {#protein}

Residue **134** lies in a UniProt-annotated variant site (found in a patient with progressive myoclonus epilepsy and developmental delay; uncertain significance); the yjef n-terminal domain.

AlphaFold model confidence (whole protein): pLDDT 86.71, 79% of residues very-high.

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

*Describes the biological roles of NAXE (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.*


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Nicotinate metabolism](https://reactome.org/content/detail/R-HSA-196807) | curated |

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

**Biological process:** sprouting angiogenesis, regulation of cholesterol efflux, negative regulation of angiogenesis, membrane raft distribution, nicotinamide nucleotide metabolic process.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-13.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 3billion | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-10-13 |

## Associated conditions {#conditions}

[encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1](https://sugi.bio/atlas/disease/encephalopathy-progressive-early-onset-with-brain-edema-and-or-leukoencephalopathy-1/).

**Reported phenotype names (ClinVar):** Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, NAD(P)HX epimerase deficiency.

## Similar variants {#similar}

Related NAXE variant pages (same residue, condition, or type): [NAXE c.664+2T>A](/variant/naxe-c-664-plus-2t-a), [NAXE p.Ser43Ter](/variant/naxe-p-ser43ter), [NAXE p.Arg254Cys](/variant/naxe-p-arg254cys), [NAXE c.291+7G>A](/variant/naxe-c-291-plus-7g-a), [NAXE c.292-14G>A](/variant/naxe-c-292-minus-14g-a), [NAXE c.664+28G>A](/variant/naxe-c-664-plus-28g-a), [NAXE c.*22T>C](/variant/naxe-c-star-22t-c), [NAXE p.Glu268=](/variant/naxe-p-glu268).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 4856332). 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.*