GeneBe

SPAST

spastin, the group of AAA ATPases

Basic information

Region (hg38): 2:32063556-32157637

Previous symbols: [ "SPG4" ]

Links

ENSG00000021574 ∙ NCBI:6683 ∙ OMIM:604277 ∙ HGNC:11233 ∙ Uniprot:Q9UBP0 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

  • hereditary spastic paraplegia 4 (Strong), mode of inheritance: AD
  • hereditary spastic paraplegia 4 (Moderate), mode of inheritance: AD
  • hereditary spastic paraplegia 4 (Strong), mode of inheritance: AD
  • hereditary spastic paraplegia 4 (Supportive), mode of inheritance: AD
  • hereditary spastic paraplegia 4 (Definitive), mode of inheritance: AD
  • Charlevoix-Saguenay spastic ataxia (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Spastic paraplegia 4, autosomal dominantADGeneralGenetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testingNeurologic9302257; 9736780; 10699187; 11134375; 11843700; 11309678; 12471215; 15159500; 15210521; 15248095; 14872021; 16682546; 16055926; 16832076; 17345589; 17098887; 17895902; 18401025; 19652142; 18701882; 19939411; 20301339; 20562464; 20932283; 21659953; 21834905; 22192498; 22960362

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SPAST gene.

  • Hereditary spastic paraplegia 4 (279 variants)
  • not provided (117 variants)
  • Hereditary spastic paraplegia (20 variants)
  • Spastic paraplegia (2 variants)
  • Cerebral palsy (1 variants)
  • Tics (1 variants)
  • Tip-toe gait (1 variants)
  • Inborn genetic diseases (1 variants)
  • Fatigue;Abnormal myelination;Seizure (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SPAST gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type Pathogenic Likely pathogenic VUS Likely benign Benign Sum
synonymous
2
clinvar
6
clinvar
94
clinvar
 102
missense
64
clinvar
78
clinvar
259
clinvar
17
clinvar
1
clinvar
 419
nonsense
59
clinvar
9
clinvar
 68
start loss
1
clinvar
2
clinvar
 3
frameshift
140
clinvar
31
clinvar
1
clinvar
 172
inframe indel
4
clinvar
7
clinvar
14
clinvar
 25
splice donor/acceptor (+/-2bp)
63
clinvar
14
clinvar
1
clinvar
 78
splice region
6
6
24
9
2
 47
non coding
3
clinvar
49
clinvar
79
clinvar
53
clinvar
 184
Total 336 139 330 191 55

Highest pathogenic variant AF is 0.00000662

Variants in SPAST

This is a list of pathogenic ClinVar variants found in the SPAST region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position Type Phenotype Significance ClinVar
2-32063612-G-T Hereditary spastic paraplegia 4 Uncertain significance (Jan 12, 2018)335822
2-32063656-C-T Spastic paraplegia, autosomal dominant Uncertain significance (Jun 14, 2016)335823
2-32063664-G-A Hereditary spastic paraplegia 4 Uncertain significance (Jan 13, 2018)335824
2-32063718-CGGCGGGCACACGGGGGTCTGTGGCCCCCGCCGTAGCAGTGGCTGCCGCCGTCGCTTGGTTCCCGTCGGTCTGCGGGAGGCGGGTTATGGCGGCGGCGGCAGTGAGAGCTGTGAATGAATTCTCCGGGTGGACGAGGGAAGAAGAAAGGCTCCGGCGGCGCCAGCAACCCGGTGCCTCCCAGGCCTCCGCCCCCTTGCCTGGCCCCCGCCCCTCCCGCCGCCGGGCCGGCCCCTCCGCCCGAGTCGCCGCATAAGCGGAACCTGTACTATTTCTCCTACCCGCTGTTTGTAGGCTTCGCGCTGCTGCGTTTGGTCGCCTTCCACCTGGGGCTCCTCTTCGTGTGGCTCTGCCAGCGCTTCTCCCGCGCCCTCATGGCAGCCAAGAGGAGCTCCGGGGCCGCGCCAGCACCTGCCTCGGCCTCGGCCCCGGCGCCGGTGCCGGGCGGCGAGGCCGAGCGCGTCCGAGTCTTCCACAAACAGGCCTTCGAGTACATCTCCATTGCCCTGCGCATCGATGAGGATGAGAAAGGTAACTAGGGGGCTGGGGGAGGGGGCGGCGGCGCCGGGAAGAAGGCGGTGGGGTCGCCGGGGGAGGGCAACACCTGCGTCCCTTTTCTGCGGGAGGGGACGGTGCACCCCCGGAATTGATATGCCCCGGGAGACTGCTTTCCCGTAGGTCGGAGCCTCATCTTCTAGTATTCTTAAAACCTCTCCCCTTTCAGGGCACTGTAGCTGTCGACTTTGTTTCAGACACCAGCCTTCCCCCACACTTCTGCATGACCCAGGTCACTATGAGACACCCAGACGTGTTGATGACAGTGACATTTGTCCTAGAGTGACCACACTGATCCTTTCTAGCACTGTGAAGAGTGTGCAGCTTCCTCTGAACCAAGGTTTCCAAAAGGTTTTGATATTGAAGAAGCAGTGCCGCCTTACTGGCTTTTAATGAAAGCAGAGTATTGTAGTGTCAGAAAAAAAGAACAAATGGTGACAATTTTGAAAGAAATAGCTGCATATGACTGCAGTTGAATTTGCATCATTTTAATCAAGATAATCATTTTATCAGTACAACGATTCCTGAATACTTTTTCAATGAAGTTATATTTAGCATAAAACTTTTCCCCCTGTTGCTTTGATTTTAATTAAAACAGTATTCCAAAGTAGCCTTTAATTTCCAAGTTGAAATGTTTGATGAATGGATTGCGTAAACTTAAACATACCACTTTACAGTAAAACCTAAAACAACTATGTATGTTTCTGAATGAAAGCAAGGATACTACATCTTTCGGGTTTCTTTTAAGCTAACTTTTTTTTTTTTTTGAGACGGAATCTCGCCCTGTCGCCCAAGCTGGAGTGCAATGGTGCAGTCTCGGCTCACTGCAACCTCCGACTCCCTGGTTCCAGCGATTCTCCTGCCTCAGCCTCCCGAGTAGCTGGGATTACAGGCACGCACCACCACGCCTGGCTAATTTTTGTATTTTTAGTAGAGTAGGGATTTCACCATGTTGGCCAGGATGGTCTCCATCTCCTGACCTCGTGATCGGGTCGCCTCGGCCTCCCAAAGTGCTGGTAATACAGGCATGAGCCACCGCGCCTGGCCTTAAGCTAACATTTTTTATTATATGTGCCAGGCATTGTGCTATTAGCTTTGCATGTGTTATCTTTTTTCTTTTTAAAAAAAATAGCAACCATCCCAGACCATGAAAAGTGTTATTTAATCCTCACAATAACTTTGTGAGATGAAGGTATTATTGGTATCAGCATTTTAGAGATGAAGAAAATGAGGCCCAAAAGATAAAGGAGGTTATTCCAAACCTGTGCTAATAATGAAATTTCTTTTATGGAAAATAAGTGAAATTAGGAGAAGTCTAACTTTTACAATTCTCCCCTTTTATCCTTACTTCCAGTATGCTGAGATCTTGCTTCTCCCTCTGCCAAAAACACCCACTTTTCTACCACACCTCAATTAGATACTCACTTGCATTGTCCATTAGTGAAAACAGAAACAATCTGCACTTCATTCATAGTGTCTGTCTCTACTGCCAACTCCAAAAACTGTTCTAGAATTTCAATCTTGTTGAAACCTGTTTCCTTTGTGGGGCCTGGGAGTGGGAAGTGGGATATAAGGAAAGAGGCAGTTATTCATTGTTTTGGACAGTAAGGAAAGAGTGACGGTTAAGAGAGGTCAAGGAGGGTGTTAACATTTAAGAATACTATGTGTTTGTAGAAGGAAATTTTTTGTTAACTGCTCCATTCTTTTTTTTTTTTTTTTTTGAGATGGAGTCTCCCTGTGTCACCCAGACTGGA-C Hereditary spastic paraplegia 4 Pathogenic (Aug 07, 2014)5674
2-32063727-CACG-C Spastic paraplegia, autosomal dominant Uncertain significance (Jun 14, 2016)335825
2-32063742-C-A Hereditary spastic paraplegia 4 Uncertain significance (Jan 13, 2018)896136
2-32063791-C-T Hereditary spastic paraplegia 4 • not specified • SPAST-related disorder Likely benign (Jan 12, 2018)335826
2-32063825-G-A Hereditary spastic paraplegia 4 • Hereditary spastic paraplegia Uncertain significance (Jul 01, 2019)335827
2-32063828-G-A Uncertain significance (Feb 28, 2022)1703982
2-32063832-A-G Hereditary spastic paraplegia 4 Uncertain significance (Jan 10, 2024)2650803
2-32063834-G-C Hereditary spastic paraplegia 4 Uncertain significance (Jul 07, 2023)1917540
2-32063836-ATT-A Hereditary spastic paraplegia 4 Pathogenic (Nov 27, 2021)468574
2-32063841-C-G Hereditary spastic paraplegia Uncertain significance (May 01, 2020)1344038
2-32063841-C-T Hereditary spastic paraplegia 4 Uncertain significance (Aug 19, 2023)1693809
2-32063842-C-G Hereditary spastic paraplegia 4 Uncertain significance (Feb 14, 2024)2055101
2-32063843-G-T Hereditary spastic paraplegia 4 Likely benign (Jul 06, 2022)2181952
2-32063847-G-T Hereditary spastic paraplegia 4 Pathogenic (May 05, 2023)2862316
2-32063848-G-A Hereditary spastic paraplegia 4 Uncertain significance (Jul 02, 2022)2132633
2-32063850-C-A Hereditary spastic paraplegia 4 Conflicting classifications of pathogenicity (Nov 21, 2022)392495
2-32063851-G-C Hereditary spastic paraplegia 4 Uncertain significance (Dec 02, 2021)1384983
2-32063851-G-T Hereditary spastic paraplegia 4 Uncertain significance (Aug 11, 2021)1430837
2-32063854-G-A Hereditary spastic paraplegia 4 Uncertain significance (Nov 18, 2023)3004860
2-32063855-G-A Hereditary spastic paraplegia 4 Likely benign (Apr 13, 2023)2960456
2-32063857-A-G Hereditary spastic paraplegia 4 Uncertain significance (Aug 16, 2022)2420948
2-32063857-A-AG Pathogenic (Oct 23, 2020)987172

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
SPASTprotein_codingprotein_codingENST00000315285 1794027
pLI Probability
LOF Intolerant 		pRec Probability
LOF Recessive 		Individuals with
no LOFs 		Individuals with
Homozygous LOFs 		Individuals with
Heterozygous LOFs 		Defined p
0.9990.000611125740061257460.0000239
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense1.242793440.8110.00001753967
Missense in Polyphen51121.740.418921478
Synonymous-2.361571241.270.000006021234
Loss of Function4.97334.60.08680.00000180410

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.0001230.000123
Ashkenazi Jewish0.000.00
East Asian0.00005530.0000544
Finnish0.000.00
European (Non-Finnish)0.00002640.0000264
Middle Eastern0.00005530.0000544
South Asian0.000.00
Other0.000.00

dbNSFP

Source: dbNSFP

Function
FUNCTION: ATP-dependent microtubule severing protein that specifically recognizes and cuts microtubules that are polyglutamylated (PubMed:11809724, PubMed:15716377, PubMed:16219033, PubMed:17389232, PubMed:20530212, PubMed:22637577, PubMed:26875866). Preferentially recognizes and acts on microtubules decorated with short polyglutamate tails: severing activity increases as the number of glutamates per tubulin rises from one to eight, but decreases beyond this glutamylation threshold (PubMed:26875866). Severing activity is not dependent on tubulin acetylation or detyrosination (PubMed:26875866). Microtubule severing promotes reorganization of cellular microtubule arrays and the release of microtubules from the centrosome following nucleation. It is critical for the biogenesis and maintenance of complex microtubule arrays in axons, spindles and cilia. SPAST is involved in abscission step of cytokinesis and nuclear envelope reassembly during anaphase in cooperation with the ESCRT-III complex (PubMed:19000169, PubMed:21310966, PubMed:26040712). Recruited at the midbody, probably by IST1, and participates in membrane fission during abscission together with the ESCRT-III complex (PubMed:21310966). Recruited to the nuclear membrane by IST1 and mediates microtubule severing, promoting nuclear envelope sealing and mitotic spindle disassembly during late anaphase (PubMed:26040712). Required for membrane traffic from the endoplasmic reticulum (ER) to the Golgi and endosome recycling (PubMed:23897888). Recruited by IST1 to endosomes and regulates early endosomal tubulation and recycling by mediating microtubule severing (PubMed:23897888). Probably plays a role in axon growth and the formation of axonal branches (PubMed:15716377). {ECO:0000255|HAMAP-Rule:MF_03021, ECO:0000269|PubMed:11809724, ECO:0000269|PubMed:15716377, ECO:0000269|PubMed:16219033, ECO:0000269|PubMed:17389232, ECO:0000269|PubMed:19000169, ECO:0000269|PubMed:20530212, ECO:0000269|PubMed:21310966, ECO:0000269|PubMed:22637577, ECO:0000269|PubMed:23897888, ECO:0000269|PubMed:26040712, ECO:0000269|PubMed:26875866}.;
Disease
DISEASE: Spastic paraplegia 4, autosomal dominant (SPG4) [MIM:182601]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. {ECO:0000269|PubMed:10610178, ECO:0000269|PubMed:10699187, ECO:0000269|PubMed:11015453, ECO:0000269|PubMed:11039577, ECO:0000269|PubMed:11087788, ECO:0000269|PubMed:11309678, ECO:0000269|PubMed:11809724, ECO:0000269|PubMed:11843700, ECO:0000269|PubMed:11985387, ECO:0000269|PubMed:12124993, ECO:0000269|PubMed:12161613, ECO:0000269|PubMed:12163196, ECO:0000269|PubMed:12202986, ECO:0000269|PubMed:12460147, ECO:0000269|PubMed:12552568, ECO:0000269|PubMed:12939659, ECO:0000269|PubMed:14732620, ECO:0000269|PubMed:15159500, ECO:0000269|PubMed:15210521, ECO:0000269|PubMed:15248095, ECO:0000269|PubMed:15326248, ECO:0000269|PubMed:15482961, ECO:0000269|PubMed:15667412, ECO:0000269|PubMed:15716377, ECO:0000269|PubMed:15891913, ECO:0000269|PubMed:16339213, ECO:0000269|PubMed:16682546, ECO:0000269|PubMed:16684598, ECO:0000269|PubMed:17389232, ECO:0000269|PubMed:17594340, ECO:0000269|PubMed:19000169, ECO:0000269|PubMed:20214791, ECO:0000269|PubMed:20550563, ECO:0000269|PubMed:20562464, ECO:0000269|PubMed:20718791, ECO:0000269|PubMed:20932283, ECO:0000269|PubMed:21546041, ECO:0000269|PubMed:22960362, ECO:0000269|PubMed:23279441, ECO:0000269|PubMed:24824479, ECO:0000269|PubMed:25045380, ECO:0000269|PubMed:25421405, ECO:0000269|PubMed:28572275}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.198

Intolerance Scores

loftool
0.0336
rvis_EVS
-0.07
rvis_percentile_EVS
48.54

Haploinsufficiency Scores

pHI
0.673
hipred
Y
hipred_score
0.768
ghis
0.589

Essentials

essential_gene_CRISPR
N
essential_gene_CRISPR2
N
essential_gene_gene_trap
N
gene_indispensability_pred
E
gene_indispensability_score
0.508

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

Mouse Genome Informatics

Gene name
Spast
Phenotype
normal phenotype; reproductive system phenotype; hematopoietic system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); hearing/vestibular/ear phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan);

Zebrafish Information Network

Gene name
spast
Affected structure
primary motor neuron
Phenotype tag
abnormal
Phenotype quality
morphology

Gene ontology

Biological process
mitotic cytokinesis;microtubule bundle formation;endoplasmic reticulum to Golgi vesicle-mediated transport;axonogenesis;anterograde axonal transport;metabolic process;exit from mitosis;axonal transport of mitochondrion;positive regulation of microtubule depolymerization;cytoplasmic microtubule organization;nuclear envelope reassembly;positive regulation of cytokinesis;cytokinetic process;protein hexamerization;microtubule severing;mitotic spindle disassembly;protein homooligomerization;cytoskeleton-dependent cytokinesis;membrane fission
Cellular component
ESCRT III complex;nucleus;nucleoplasm;cytoplasm;endosome;endoplasmic reticulum;endoplasmic reticulum membrane;lipid droplet;centrosome;spindle;cytosol;microtubule;microtubule cytoskeleton;integral component of membrane;midbody;cytoplasmic vesicle;nuclear membrane;perinuclear region of cytoplasm;extracellular exosome;axon cytoplasm
Molecular function
protein binding;ATP binding;microtubule binding;microtubule-severing ATPase activity;isomerase activity;ATPase activity;alpha-tubulin binding;protein-containing complex binding;beta-tubulin binding