# NM_015046.7(SETX):c.3212_3213del (p.Phe1071fs)

https://sugi.bio/variant/setx-p-phe1071fs

## Summary

**SETX p.Phe1071fs (c.3212_3213del)** is classified **Pathogenic** in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-25). Very rare (popmax 0.000254%, nfe); Associated with spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 2 linked conditions · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the SETX gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2.

*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) | Adolescent, Adult, Childhood |
| Prevalence | 1-9 / 1 000 000 (France) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | SETX is a diagnostic-grade gene on 16 Genomics England panels |

**Commonly reported features of Spinocerebellar ataxia with axonal neuropathy type 2** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Ataxia — Very frequent (99-80%)
- Areflexia — Very frequent (99-80%)
- Cerebellar vermis atrophy — Very frequent (99-80%)
- Sensorimotor neuropathy — Very frequent (99-80%)
- Gaze-evoked nystagmus — Frequent (79-30%)
- Oculomotor apraxia — Frequent (79-30%)
- Saccadic smooth pursuit — Frequent (79-30%)
- Gait imbalance — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012860/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SETX](https://sugi.bio/atlas/gene/SETX/) |
| Protein change (HGVS p.) | p.Phe1071fs |
| Coding change (HGVS c.) | c.3212_3213del |
| MANE Select transcript | [NM_015046](https://www.ncbi.nlm.nih.gov/nuccore/NM_015046) |
| Variant type | Deletion |
| Location | chr9:132328385-132328386 (GRCh38) |
| ClinVar | [VCV3751911](https://www.ncbi.nlm.nih.gov/clinvar/variation/3751911/) |

**All HGVS expressions:** `LRG_268:g.31600_31601del`, `LRG_268t1:c.3209_3210del`, `NC_000009.11:g.135203775_135203776del`, `NC_000009.12:g.132328388_132328389del`, `NG_007946.1:g.31600_31601del`, `NM_001351527.2:c.3212_3213del`, `NM_001351528.2:c.3212_3213del`, `NM_015046.7:c.3212_3213del`

## 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 -0.051, GERP -2.97 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.442, pLI 0.99995), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 10 of 26**, 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 (gnomAD v4.1): grpmax **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,179,900 in the highest group · 3/1,613,684 alleles overall — very rare (popmax 0.000254%, nfe).

*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}

**SETX** population constraint: LOEUF 0.442, pLI 0.99995, missense-Z 1.7846. *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):

- **distal hereditary motor neuropathy** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 52.93, 11% of residues very-high.

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

*Describes the biological roles of SETX (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:** SETX's established molecular role includes transcription termination site sequence-specific DNA binding.


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

**Molecular function:** transcription termination site sequence-specific DNA binding, DNA/RNA helicase activity, identical protein binding.

**Biological process:** double-strand break repair, DNA-templated transcription termination, mRNA splice site recognition, DNA damage response, positive regulation of neuron projection development, positive regulation of RNA splicing.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-25.

**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 | 2025-07-25 |

## Associated conditions {#conditions}

[spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2](https://sugi.bio/atlas/disease/spinocerebellar-ataxia-autosomal-recessive-with-axonal-neuropathy-2/), [amyotrophic lateral sclerosis type 4](https://sugi.bio/atlas/disease/amyotrophic-lateral-sclerosis-type-4/).

**Reported phenotype names (ClinVar):** Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, Amyotrophic lateral sclerosis type 4, ATAXIA-OCULOMOTOR APRAXIA 2, Ataxia with Oculomotor Apraxia Type 2, Ataxia-ocular apraxia-2, Ataxia with Oculomotor Apraxia, NEURONOPATHY, DISTAL HEREDITARY MOTOR, WITH PYRAMIDAL FEATURES, AMYOTROPHIC LATERAL SCLEROSIS 4, JUVENILE.

## Similar variants {#similar}

Related SETX variant pages (same residue, condition, or type): [SETX c.6843-3_6843-1del](/variant/setx-c-6843-minus-3-6843-minus-1del), [SETX p.Asp2332fs](/variant/setx-p-asp2332fs), [SETX p.Gln1864fs](/variant/setx-p-gln1864fs), [SETX p.Lys796fs](/variant/setx-p-lys796fs), [SETX p.Thr1755fs](/variant/setx-p-thr1755fs), [SETX p.Arg2529fs](/variant/setx-p-arg2529fs), [SETX p.His476_Leu477del](/variant/setx-p-his476-leu477del), [SETX p.Ile664_Glu665del](/variant/setx-p-ile664-glu665del).

### 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 3751911). 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.*