Hereditary spastic paraplegia: genes and variants

Genes linked to Hereditary spastic paraplegia

• SPAST: Spastin

  It severs microtubules and remodels the axonal cytoskeleton, enabling organelle transport and maintenance of very long corticospinal axons. Dominant loss-of-function variants are the most common cause of hereditary spastic paraplegia, classically SPG4.

  138 disease-causing and 255 uncertain variants in SPAST are linked to Hereditary spastic paraplegia.

• ATL1: Atlastin-1

  It promotes homotypic fusion of endoplasmic-reticulum membranes and is required for normal organization of the tubular ER network, especially in long axons. Dominant pathogenic variants are a common cause of hereditary spastic paraplegia type 3A.

  50 disease-causing and 191 uncertain variants in ATL1 are linked to Hereditary spastic paraplegia.

• KIF1A: Kinesin-like protein KIF1A

  It transports synaptic vesicle precursors and other cargo along axonal microtubules toward nerve terminals. Pathogenic variants cause a broad KIF1A-associated neurological disorder spectrum including hereditary sensory neuropathy, spastic paraplegia, optic atrophy, ataxia, and developmental impairment.

  41 disease-causing and 299 uncertain variants in KIF1A are linked to Hereditary spastic paraplegia.

• SPG7: Mitochondrial inner membrane m-AAA protease component paraplegin

  It participates in mitochondrial inner-membrane protein quality control and respiratory homeostasis as part of the m-AAA protease machinery. Biallelic pathogenic variants cause SPG7-related disease, commonly presenting with spastic ataxia, optic neuropathy, or progressive gait impairment.

  26 disease-causing and 311 uncertain variants in SPG7 are linked to Hereditary spastic paraplegia.

• KIF5A: Kinesin heavy chain isoform 5A

  It drives anterograde transport of organelles and proteins along axonal microtubules and is especially important in long motor neurons. Pathogenic variants can cause hereditary spastic paraplegia, axonal Charcot-Marie-Tooth disease, or amyotrophic lateral sclerosis depending on the affected region and mechanism.

  24 disease-causing and 43 uncertain variants in KIF5A are linked to Hereditary spastic paraplegia.

• PLP1: Myelin proteolipid protein

  It supports central-nervous-system myelin structure and is required for oligodendrocyte and axonal integrity. Gene duplication most commonly causes Pelizaeus-Merzbacher disease, while other variants can cause spastic paraplegia type 2 or milder leukodystrophy.

  14 disease-causing and 57 uncertain variants in PLP1 are linked to Hereditary spastic paraplegia.

• REEP1: Receptor expression-enhancing protein 1

  It shapes tubular endoplasmic-reticulum membranes and supports interactions between the ER and neuronal cytoskeleton, particularly in long corticospinal axons. Pathogenic variants are a common cause of hereditary spastic paraplegia type 31 and can occasionally produce distal motor neuropathy.

  12 disease-causing and 96 uncertain variants in REEP1 are linked to Hereditary spastic paraplegia.

• FGG: Fibrinogen gamma chain

  It contributes the gamma chains of fibrinogen and provides binding sites important for fibrin polymerization, platelet interactions, and clot stabilization. Pathogenic variants can cause quantitative or qualitative fibrinogen disorders and, in some alleles, hereditary renal amyloidosis.

  1 disease-causing and 0 uncertain variants in FGG are linked to Hereditary spastic paraplegia.

• GNAS: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short

  It produces the stimulatory G-alpha subunit that activates adenylyl cyclase downstream of many hormone receptors, with complex tissue-specific imprinting at the locus. Inactivating variants cause pseudohypoparathyroidism-spectrum disorders, while activating somatic variants cause McCune-Albright syndrome and some endocrine tumors.

  1 disease-causing and 0 uncertain variants in GNAS are linked to Hereditary spastic paraplegia.

• PHF6: PHD finger protein 6

  It participates in chromatin regulation, transcription, and ribosome biogenesis during development and hematopoiesis. Germline loss-of-function variants cause Borjeson-Forssman-Lehmann syndrome, while somatic mutations occur recurrently in T-cell leukemia and myeloid malignancies.

  1 disease-causing and 0 uncertain variants in PHF6 are linked to Hereditary spastic paraplegia.

• POLG: DNA polymerase subunit gamma-1

  It replicates and repairs mitochondrial DNA and is therefore essential for maintaining mitochondrial genome copy number and integrity. Pathogenic variants cause a broad spectrum including Alpers syndrome, progressive external ophthalmoplegia, epilepsy, ataxia, neuropathy, and liver disease.

  0 disease-causing and 10 uncertain variants in POLG are linked to Hereditary spastic paraplegia.

• SETX: Helicase senataxin

  It resolves RNA-DNA hybrids and supports transcription termination, RNA processing, and genome stability, particularly in long-lived neurons. Different pathogenic mechanisms cause ataxia with oculomotor apraxia type 2 or juvenile amyotrophic lateral sclerosis type 4.

  0 disease-causing and 16 uncertain variants in SETX are linked to Hereditary spastic paraplegia.

Weakly linked (only a few uncertain records): L1CAM, NSD1, GFAP, JAK3, SETBP1, SPTBN2 and TBK1.

Where Hereditary spastic paraplegia variants cluster

• KIF1A Kinesin motor (positions 5–354): 40 of 41 disease-causing changes, 4.7× more than its size predicts.
• KIF5A Microtubule-binding (positions 174–315): 20 of 24 disease-causing changes, 6.1× more than its size predicts.
• ATL1 3HB (three-helix bundle) domain (positions 347–438): 21 of 50 disease-causing changes, 2.5× more than its size predicts.
• REEP1 Transmembrane (positions 1–21): 7 of 12 disease-causing changes, 5.6× more than its size predicts.
• KIF5A Necessary for interaction with ZFYVE27 (positions 271–361): 6 of 24 disease-causing changes, 2.8× more than its size predicts.

Known disease-causing variants in Hereditary spastic paraplegia

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Uncertain variants in Hereditary spastic paraplegia that look disease-causing

Which prediction tools work for Hereditary spastic paraplegia

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• REVEL: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaGenome (regulatory): 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 94 out of 100
• AlphaMissense: 94 out of 100
• PolyPhen-2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 90 out of 100
• MetaLR: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 85 out of 100
• phyloP: 80 out of 100
• AlphaGenome (splicing): 76 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Pelizaeus-Merzbacher disease is also caused by PLP1 variants; they fall mostly in different places as the Hereditary spastic paraplegia variants (51 disease-causing).

Diseases related to Hereditary spastic paraplegia

• Amyotrophic lateral sclerosis, also linked to KIF5A and SETX
• Neuropathy, hereditary sensory, type 2C, also linked to ATL1 and KIF1A
• Spastic ataxia, also linked to SETX and SPG7
• Mitochondrial disease, also linked to POLG and SPG7
• Possible mitochondrial disorder - nuclear genes, also linked to POLG and SPG7
• Mitochondrial DNA maintenance disorder, also linked to POLG and SPG7
• Autosomal recessive spastic paraplegia type 78, also linked to KIF1A and SPG7
• Hypertrophic cardiomyopathy, also linked to FGG
• Charcot-Marie-Tooth disease, also linked to KIF5A
• Noonan syndrome, also linked to FGG
• Progressive sclerosing poliodystrophy, also linked to POLG
• Pelizaeus-Merzbacher disease, also linked to PLP1

Frequently asked questions

Which genes are linked to Hereditary spastic paraplegia?

In CATVariant, Hereditary spastic paraplegia is linked to 12 analyzed proteins: SPAST (Spastin), ATL1 (Atlastin-1), KIF1A (Kinesin-like protein KIF1A), SPG7 (Mitochondrial inner membrane m-AAA protease component paraplegin), KIF5A (Kinesin heavy chain isoform 5A), PLP1 (Myelin proteolipid protein) and 6 more.

How many genetic variants are linked to Hereditary spastic paraplegia?

1,750 variants: 308 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,289 are of uncertain significance or have conflicting reports.

Which uncertain variants in Hereditary spastic paraplegia look disease-causing?

7 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example REEP1 P19T, REEP1 A20T, SPAST P509L, SPAST R503Q and SPAST R499S. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Hereditary spastic paraplegia?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.94, based on 85 disease-causing and 1039 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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