# NM_022041.4(GAN):c.993del (p.Phe331fs)

https://sugi.bio/variant/gan-p-phe331fs

## Summary

**GAN p.Phe331fs (c.993del)** is classified **Pathogenic** in GAN (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-08). No gnomAD frequency available for this variant; Associated with giant axonal neuropathy 1.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2150690197 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the GAN gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to giant axonal neuropathy 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) | Childhood, Infancy |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | GAN is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Giant axonal neuropathy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Areflexia — Very frequent (99-80%)
- Generalized hypotonia — Very frequent (99-80%)
- Joint hypermobility — Very frequent (99-80%)
- Pili canaliculi — Very frequent (99-80%)
- Diffuse axonal swelling — Very frequent (99-80%)
- CNS hypomyelination — Very frequent (99-80%)
- Proximal muscle weakness — Very frequent (99-80%)
- Abnormality of the Achilles tendon — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006500/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GAN](https://sugi.bio/atlas/gene/GAN/) |
| Protein change (HGVS p.) | p.Phe331fs |
| Coding change (HGVS c.) | c.993del |
| MANE Select transcript | [NM_022041](https://www.ncbi.nlm.nih.gov/nuccore/NM_022041) |
| dbSNP | [rs2150690197](https://www.ncbi.nlm.nih.gov/snp/rs2150690197/) |
| Variant type | Deletion |
| Location | chr16:81362518-81362518 (GRCh38) |
| ClinVar | [VCV1076942](https://www.ncbi.nlm.nih.gov/clinvar/variation/1076942/) |

**All HGVS expressions:** `LRG_242:g.52553del`, `NC_000016.10:g.81362518del`, `NC_000016.9:g.81396123del`, `NG_009007.1:g.52553del`, `NM_001377486.1:c.354del`, `NM_022041.4:c.993del`

## 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 5.083, GERP 0.809, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.842, pLI 1.5123e-06. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 11**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- 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}

**GAN** population constraint: LOEUF 0.842, pLI 1.5123e-06, missense-Z -2.0202. *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):

- **giant axonal neuropathy 1** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 89.93, 70% of residues very-high.

**2 experimental structure(s)** (PDB): [2PPI](https://www.rcsb.org/structure/2PPI), [3HVE](https://www.rcsb.org/structure/3HVE).

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

*Describes the biological roles of GAN (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}

GAN participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Antigen processing: Ubiquitination & Proteasome degradation](https://reactome.org/content/detail/R-HSA-983168) | other |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | other |

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

**Biological process:** protein ubiquitination.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-07-08.

**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 | 2021-07-08 |

## Associated conditions {#conditions}

[giant axonal neuropathy 1](https://sugi.bio/atlas/disease/giant-axonal-neuropathy-1/).

**Reported phenotype names (ClinVar):** Giant axonal neuropathy 1, GIANT AXONAL NEUROPATHY 1, AUTOSOMAL RECESSIVE, GAN-Related Neurodegeneration.

## Similar variants {#similar}

Related GAN variant pages (same residue, condition, or type): [GAN p.Phe331=](/variant/gan-p-phe331), [GAN p.Ile209fs](/variant/gan-p-ile209fs), [GAN p.Gly333_Asp335del](/variant/gan-p-gly333-asp335del), [GAN p.Ter598GluextTer?](/variant/gan-p-ter598gluextter), [GAN p.Ala204fs](/variant/gan-p-ala204fs), [GAN p.Arg501_Trp502insTer](/variant/gan-p-arg501-trp502inster), [GAN p.Glu260fs](/variant/gan-p-glu260fs), [GAN p.Glu387_Leu388insTer](/variant/gan-p-glu387-leu388inster).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 1076942). 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.*