# NM_015046.7(SETX):c.5929C>T (p.Leu1977Phe)

https://sugi.bio/variant/setx-p-leu1977phe

## Summary

**SETX p.Leu1977Phe (c.5929C>T)** is classified **Conflicting classifications of pathogenicity** in SETX (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2023-11-15). AlphaMissense: likely pathogenic (0.8042); Very rare (popmax 0.00119%, nfe); Associated with amyotrophic lateral sclerosis type 4.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs121434380 · 5 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00119%, nfe)

## For patients & families {#patients}

This is a change in the SETX gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 submitters, and is linked to amyotrophic lateral sclerosis type 4.

*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) | Adolescent, Childhood |
| 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 Amyotrophic lateral sclerosis type 4** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Distal muscle weakness — Frequent (79-30%)
- Skeletal muscle atrophy — Frequent (79-30%)
- Babinski sign — Frequent (79-30%)
- Abnormal pyramidal sign — Frequent (79-30%)
- Spastic paraplegia — Occasional (29-5%)
- Gait disturbance — Occasional (29-5%)
- Pes cavus — Occasional (29-5%)
- Somatic sensory dysfunction — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010502/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.Leu1977Phe |
| Coding change (HGVS c.) | c.5929C>T |
| MANE Select transcript | [NM_015046](https://www.ncbi.nlm.nih.gov/nuccore/NM_015046) |
| dbSNP | [rs121434380](https://www.ncbi.nlm.nih.gov/snp/rs121434380/) |
| Variant type | single nucleotide variant |
| Location | chr9:132296907-132296907 (GRCh38) |
| ClinVar | [VCV2295](https://www.ncbi.nlm.nih.gov/clinvar/variation/2295/) |

**All HGVS expressions:** `LRG_268:g.63079C>T`, `LRG_268t1:c.5929C>T`, `NC_000009.11:g.135172294G>A`, `NC_000009.12:g.132296907G>A`, `NG_007946.1:g.63079C>T`, `NM_001351527.2:c.5929C>T`, `NM_001351528.2:c.5929C>T`, `NM_015046.7:c.5929C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.8042)
- REVEL 0.749 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.794 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 2.518, GERP -0.075, phastCons 0.999 — highly conserved (agrees)
- CADD: **PHRED 22.0**. 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.*
- Regional missense constraint: **o/e 0.70** across the covering region of the MANE Select transcript (132,264,914–132,296,926), spanning 32,012 bp. Chi-square p 3e-13. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for SETX (1,640 scored positions, the nearest 19 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.00119%** (nfe) · FAF95 0.000688% · FAF99 0.000539% · 14/1,180,032 in the highest group · 17/1,614,004 alleles overall — very rare (popmax 0.00119%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,829 |
| European (non-Finnish) (grpmax) | 0.00119% | 84,288 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

Residue **1977** lies in the upf1-type sf1b helicase atp-binding domain.

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. p.Leu1977Phe falls in the upf1-type sf1b helicase atp-binding domain.


### 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2023-11-15.

**Submitter consensus:** conflicting (3 Likely pathogenic, 1 Pathogenic, 1 Uncertain significance).

**Submission history:** 5 submissions (2006–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2006-12-12 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-09-10 |
| Athena Diagnostics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-12-19 |
| Genome-Nilou Lab | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-02-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-11-15 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Amyotrophic lateral sclerosis type 4, Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, not provided, AMYOTROPHIC LATERAL SCLEROSIS 4, JUVENILE, NEURONOPATHY, DISTAL HEREDITARY MOTOR, WITH PYRAMIDAL FEATURES, Ataxia-ocular apraxia-2, ATAXIA-OCULOMOTOR APRAXIA 2, Ataxia with Oculomotor Apraxia, Ataxia with Oculomotor Apraxia Type 2, none provided.

## Similar variants {#similar}

Related SETX variant pages (same residue, condition, or type): [SETX p.Arg111Ter](/variant/setx-p-arg111ter), [SETX p.Arg1363Ter](/variant/setx-p-arg1363ter), [SETX p.Arg1606Ter](/variant/setx-p-arg1606ter), [SETX p.Arg1778Ter](/variant/setx-p-arg1778ter), [SETX p.Arg2098Ter](/variant/setx-p-arg2098ter), [SETX p.Arg332Trp](/variant/setx-p-arg332trp), [SETX p.Arg778Ter](/variant/setx-p-arg778ter), [SETX p.Gln1695Ter](/variant/setx-p-gln1695ter).

### 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 2295). 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.*