# NM_014946.4(SPAST):c.879G>A (p.Pro293=)

https://sugi.bio/variant/spast-p-pro293

## Summary

**SPAST p.Pro293= (c.879G>A)** is classified **Benign/Likely benign** in SPAST (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-05-01). Low-frequency (popmax 1.47%, nfe); Associated with hereditary spastic paraplegia 4.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs145264166 · 14 submitters · 2 linked conditions · low-frequency (popmax 1.47%, nfe)

## For patients & families {#patients}

This is a change in the SPAST gene that is classified as benign/likely benign — not considered disease-causing, submitted by 14 submitters, and is linked to hereditary spastic paraplegia 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, Adult, Childhood, Infancy |
| Prevalence | 1-9 / 1 000 000 (Portugal) |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | SPAST is a diagnostic-grade gene on 13 Genomics England panels |

**Commonly reported features of Autosomal dominant spastic paraplegia type 4** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Urinary urgency — Frequent (79-30%)
- Spasticity — Frequent (79-30%)
- Brisk reflexes — Frequent (79-30%)
- Lower limb spasticity — Frequent (79-30%)
- Babinski sign — Frequent (79-30%)
- Functional motor deficit — Frequent (79-30%)
- Impaired vibration sensation at ankles — Frequent (79-30%)
- Lower limb muscle weakness — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004925/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SPAST](https://sugi.bio/atlas/gene/SPAST/) |
| Protein change (HGVS p.) | p.Pro293= |
| Coding change (HGVS c.) | c.879G>A |
| MANE Select transcript | [NM_014946](https://www.ncbi.nlm.nih.gov/nuccore/NM_014946) |
| dbSNP | [rs145264166](https://www.ncbi.nlm.nih.gov/snp/rs145264166/) |
| Variant type | single nucleotide variant |
| Location | chr2:32115710-32115710 (GRCh38) |
| ClinVar | [VCV219840](https://www.ncbi.nlm.nih.gov/clinvar/variation/219840/) |

**All HGVS expressions:** `LRG_714:g.57100G>A`, `LRG_714t1:c.879G>A`, `NC_000002.11:g.32340779G>A`, `NC_000002.12:g.32115710G>A`, `NG_008730.1:g.57100G>A`, `NM_001363823.2:c.876G>A`, `NM_001363875.2:c.780G>A`, `NM_001377959.1:c.783G>A`, `NM_014946.4:c.879G>A`, `NM_199436.2:c.783G>A`

## 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 0.67, GERP -1.9, phastCons 0.945 — weakly conserved position
- CADD: **PHRED 12.06**. 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: **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 SPAST (785 scored positions, the nearest 1 base 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 **1.47%** (nfe) · FAF95 1.45% · FAF99 1.44% · 17,234/1,174,802 in the highest group · 20,070/1,607,230 alleles overall — low-frequency (popmax 1.47%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 1.93% | 52 |
| European (non-Finnish) (grpmax) | 1.47% | 68 |
| Remaining individuals (not grpmax-eligible) | 1.22% | 82 |
| Finnish (not grpmax-eligible) | 0.996% | 100 |
| Admixed American | 0.77% | 130 |
| Amish (not grpmax-eligible) | 0.439% | 228 |
| Middle Eastern | 0.248% | 403 |
| South Asian | 0.246% | 406 |
| African / African-American | 0.211% | 474 |
| East Asian | 0.0179% | 5,579 |

Ashkenazi Jewish 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}

**SPAST** population constraint: LOEUF 0.69, pLI 0.11467, missense-Z 0.23048; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **293** lies in the 'sufficient for microtubule severing' region; the 'required for interaction with microtubules and microtubule severing' region; the 'disordered' region; a UniProt-annotated variant site (in spg4); the 'required for interaction with rtn1' region.

AlphaFold model confidence (whole protein): pLDDT 77.03, 48% of residues very-high.

**7 experimental structure(s)** (PDB): [3EAB](https://www.rcsb.org/structure/3EAB), [3VFD](https://www.rcsb.org/structure/3VFD), [5Z6Q](https://www.rcsb.org/structure/5Z6Q), [5Z6R](https://www.rcsb.org/structure/5Z6R), [6PEK](https://www.rcsb.org/structure/6PEK), [6PEN](https://www.rcsb.org/structure/6PEN).

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

*Describes the biological roles of SPAST (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:** SPAST's established molecular role includes microtubule binding. p.Pro293= falls in the sufficient for microtubule severing region.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Sealing of the nuclear envelope (NE) by ESCRT-III](https://reactome.org/content/detail/R-HSA-9668328) | curated |

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

**Molecular function:** microtubule binding, microtubule severing ATPase activity, alpha-tubulin binding, beta-tubulin binding.

**Biological process:** mitotic cytokinesis, microtubule bundle formation, endoplasmic reticulum to Golgi vesicle-mediated transport, exit from mitosis, nuclear membrane reassembly, positive regulation of cytokinesis.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-05-01.

**Submitter consensus:** conflicting (9 Benign, 4 Likely benign, 1 benign).

**Submission history:** 14 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2016-07-28 |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Benign | criteria provided, single submitter | clinical testing | 2020-12-08 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Athena Diagnostics | benign | criteria provided, single submitter | clinical testing | 2024-06-25 |
| Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Likely benign | criteria provided, single submitter | clinical testing | 2017-01-26 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2016-03-29 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-03-06 |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Likely benign | no assertion criteria provided | clinical testing |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2016-06-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-03 |
| CeGaT Center for Human Genetics Tuebingen | Benign | criteria provided, single submitter | clinical testing | 2026-05-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-23 |

## Associated conditions {#conditions}

[hereditary spastic paraplegia 4](https://sugi.bio/atlas/disease/hereditary-spastic-paraplegia-4/), [hereditary spastic paraplegia](https://sugi.bio/atlas/disease/hereditary-spastic-paraplegia/).

**Reported phenotype names (ClinVar):** Hereditary spastic paraplegia 4, not provided, not specified, Hereditary spastic paraplegia, none provided, Spastic paraplegia 4, autosomal dominant, Spastic Paraplegia 4, Familial spastic paraplegia autosomal dominant 2, AllHighlyPenetrant, Familial spastic paraparesis.

## Similar variants {#similar}

Related SPAST variant pages (same residue, condition, or type): [SPAST p.Pro293Leu](/variant/spast-p-pro293leu), [SPAST c.1004+1G>C](/variant/spast-c-1004-plus-1g-c), [SPAST c.1004+1G>T](/variant/spast-c-1004-plus-1g-t), [SPAST c.1004+2T>G](/variant/spast-c-1004-plus-2t-g), [SPAST c.1098+1G>A](/variant/spast-c-1098-plus-1g-a), [SPAST c.1099-1G>A](/variant/spast-c-1099-minus-1g-a), [SPAST c.1099-2A>C](/variant/spast-c-1099-minus-2a-c), [SPAST c.1173+1G>A](/variant/spast-c-1173-plus-1g-a).

### 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 219840). 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.*