SPG11

Chr 15AR

SPG11 vesicle trafficking associated, spatacsin

Also known as: ALS5, CMT2X, KIAA1840

NCBI Gene: 80208ENSG00000104133UniProt: Q96JI7

The protein encoded by this gene is a potential transmembrane protein that is phosphorylated upon DNA damage. Defects in this gene are a cause of spastic paraplegia type 11 (SPG11). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

Primary Disease Associations & Inheritance

Spastic paraplegia 11, autosomal recessiveMIM #604360
AR
Amyotrophic lateral sclerosis 5, juvenileMIM #602099
AR
Charcot-Marie-Tooth disease, axonal, type 2XMIM #616668
AR
Spastic paraplegia 11, autosomal recessiveMIM #604360
AR
467
ClinVar variants
95
Pathogenic / LP
0.00
pLI score
3
Active trials
Clinical Summary— SPG11
🧬
Gene-Disease Validity (ClinGen)
hereditary spastic paraplegia 11 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
95 Pathogenic / Likely Pathogenic· 181 VUS of 467 total submissions
💊
Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.81LOEUF
pLI 0.000
Z-score 3.30
OE 0.67 (0.56–0.81)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-1.39Z-score
OE missense 1.11 (1.06–1.16)
1360 obs / 1223.0 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.67 (0.56–0.81)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.11 (1.06–1.16)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.13
0≤1.21.6
LoF obs/exp: 81 / 120.0Missense obs/exp: 1360 / 1223.0Syn Z: -2.17

ClinVar Variant Classifications

467 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic42
Likely Pathogenic53
VUS181
Likely Benign189
Benign1
Conflicting1
42
Pathogenic
53
Likely Pathogenic
181
VUS
189
Likely Benign
1
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
31
0
11
0
42
Likely Pathogenic
38
0
15
0
53
VUS
4
166
10
1
181
Likely Benign
0
3
73
113
189
Benign
0
0
1
0
1
Conflicting
—1
Total73169110114467

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SPG11 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SPG11-related spastic paraplegia

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

2 OMIM entries

OMIM

Spastic paraplegia 11, autosomal recessive

MIM #604360

Molecular basis of disorder known

Autosomal recessive

Amyotrophic lateral sclerosis 5, juvenile

MIM #602099

Molecular basis of disorder known

Autosomal recessive

Charcot-Marie-Tooth disease, axonal, type 2X

MIM #616668

Molecular basis of disorder known

Autosomal recessive

Spastic paraplegia 11, autosomal recessive

MIM #604360

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — SPG11
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical and genetic spectra of 1550 index patients with hereditary spastic paraplegia.
Méreaux JL et al.·Brain
2022Cohort
The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy.
Deneubourg C et al.·Autophagy
2022
SPG11: clinical and genetic features of seven Czech patients and literature review.
Doleckova K et al.·Neurol Res
2022Review
Movement disorders in hereditary spastic paraplegias.
Pedroso JL et al.·Arq Neuropsiquiatr
2023Review
Janus-faced spatacsin (SPG11): involvement in neurodevelopment and multisystem neurodegeneration.
Pozner T et al.·Brain
2020Review
Clinical and Genetic Spectrum in a Large Cohort of Hereditary Spastic Paraplegia.
Cao Y et al.·Mov Disord
2024Cohort
Naringenin and SMER28 target lysosomal reformation and rescue SPG11 and SPG15 hereditary spastic paraplegia phenotypes.
Vantaggiato C et al.·Pharmacol Res
2025
Burden of pathogenetic and likely pathogenetic variants in SPG7, SPG11 and AP4 genes in Amyotrophic Lateral Sclerosis. A case-control study.
Doronzio PN et al.·J Neurol
2025
Neuropsychology and MRI correlates of neurodegeneration in SPG11 hereditary spastic paraplegia.
Utz KS et al.·Orphanet J Rare Dis
2022
The genetic landscape of Parkinson's disease.
Lunati A et al.·Rev Neurol (Paris)
2018Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Hereditary Spastic ParaplegiaSPG47SPG50

Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia

RECRUITING
NCT04712812Boston Children's HospitalStarted 2020-04-27
Amyotrophic Lateral Sclerosis

Development of Targeted RNA-Seq for Amyotrophic Lateral Sclerosis Diagnosis

RECRUITING
NCT06083584Centre Hospitalier Universitaire de NīmesStarted 2023-11-22
RNA sequencing
Rare DisordersUndiagnosed DisordersDisorders of Unknown Prevalence

Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

RECRUITING
NCT01793168Sanford HealthStarted 2010-07

External Resources

Links to major genomics databases and tools