# NM_015459.5(ATL3):c.650del (p.Phe217fs)

https://sugi.bio/variant/atl3-p-phe217fs

## Summary

**ATL3 p.Phe217fs (c.650del)** is classified **Uncertain significance** in ATL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-19). No gnomAD frequency available for this variant; Associated with neuropathy, hereditary sensory, type 1F.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1939792135 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ATL3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to neuropathy, hereditary sensory, type 1F.

*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 dominant |
| Age of onset (of this condition) | All ages |
| Diagnostic panels | ATL3 is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Hereditary sensory and autonomic neuropathy type 1** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Muscle weakness — Very frequent (99-80%)
- Gait imbalance — Very frequent (99-80%)
- Abnormality of the autonomic nervous system — Very frequent (99-80%)
- Distal sensory impairment — Very frequent (99-80%)
- Decreased amplitude of sensory action potentials — Very frequent (99-80%)
- Impaired ability to dress oneself — Very frequent (99-80%)
- Hyperkeratosis — Frequent (79-30%)
- Penetrating foot ulcers — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015995/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ATL3](https://sugi.bio/atlas/gene/ATL3/) |
| Protein change (HGVS p.) | p.Phe217fs |
| Coding change (HGVS c.) | c.650del |
| MANE Select transcript | [NM_015459](https://www.ncbi.nlm.nih.gov/nuccore/NM_015459) |
| dbSNP | [rs1939792135](https://www.ncbi.nlm.nih.gov/snp/rs1939792135/) |
| Variant type | Deletion |
| Location | chr11:63644230-63644230 (GRCh38) |
| ClinVar | [VCV939592](https://www.ncbi.nlm.nih.gov/clinvar/variation/939592/) |

**All HGVS expressions:** `NC_000011.10:g.63644232del`, `NC_000011.9:g.63411704del`, `NG_033985.1:g.32745del`, `NM_001290048.2:c.596del`, `NM_015459.5:c.650del`

## 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 1.469, GERP 0.475, phastCons 1 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.891, pLI 1.991e-09. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 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 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}

**ATL3** population constraint: LOEUF 0.891, pLI 1.991e-09, missense-Z 0.69424. *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):

- **neuropathy, hereditary sensory, type 1F** — Moderate (AD)

## Protein context {#protein}

Residue **217** lies in the gb1/rhd3-type g domain.

AlphaFold model confidence (whole protein): pLDDT 87.30, 61% of residues very-high.

**2 experimental structure(s)** (PDB): [5VGR](https://www.rcsb.org/structure/5VGR), [6XJO](https://www.rcsb.org/structure/6XJO).

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

*Describes the biological roles of ATL3 (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:** ATL3's established molecular role includes identical protein binding. p.Phe217fs falls in the gb1/rhd3-type g domain.


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

**Molecular function:** identical protein binding, GTPase-dependent fusogenic activity.

**Biological process:** endoplasmic reticulum membrane fusion, endoplasmic reticulum tubular network membrane organization.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-07-19.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-19 |

## Associated conditions {#conditions}

[neuropathy, hereditary sensory, type 1F](https://sugi.bio/atlas/disease/neuropathy-hereditary-sensory-type-1f/).

**Reported phenotype names (ClinVar):** Neuropathy, hereditary sensory, type 1F, HSN IF, Hereditary sensory neuropathy type IF.

## Similar variants {#similar}

Related ATL3 variant pages (same residue, condition, or type): [ATL3 p.Glu129del](/variant/atl3-p-glu129del), [ATL3 c.405+4del](/variant/atl3-c-405-plus-4del), [ATL3 c.850+3del](/variant/atl3-c-850-plus-3del), [ATL3 p.Gly334del](/variant/atl3-p-gly334del), [ATL3 p.Gly488fs](/variant/atl3-p-gly488fs), [ATL3 p.Gly501del](/variant/atl3-p-gly501del), [ATL3 p.Pro380fs](/variant/atl3-p-pro380fs), [ATL3 c.1108-8_1108-4del](/variant/atl3-c-1108-minus-8-1108-minus-4del).

### 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 939592). 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.*