SPG11

Chr 15AR

SPG11 vesicle trafficking associated, spatacsin

Also known as: ALS5, CMT2X, KIAA1840

NCBI Gene: 80208 ENSG00000104133 UniProt: Q96JI7 OMIM: 604360

The protein encoded by SPG11 is a transmembrane protein that becomes phosphorylated in response to DNA damage and localizes to the cytoplasm and cytosol. Mutations cause autosomal recessive spastic paraplegia type 11, juvenile amyotrophic lateral sclerosis type 5, and axonal Charcot-Marie-Tooth disease type 2X. The pathogenic mechanism involves disruption of the protein's response to DNA damage, leading to progressive neurodegeneration affecting motor neurons and peripheral nerves.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Spastic paraplegia 11, autosomal recessiveMIM #604360

Amyotrophic lateral sclerosis 5, juvenileMIM #602099

Charcot-Marie-Tooth disease, axonal, type 2XMIM #616668

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · hereditary spastic paraplegia 11 · AR · ClinGen 2023
Strong · Charcot-Marie-Tooth disease axonal type 2X · AR · Genomics England PanelApp
Strong · amyotrophic lateral sclerosis type 5 · AR · Genomics England PanelApp
Supportive · juvenile amyotrophic lateral sclerosis · AR · Orphanet

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.81

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — SPG11

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.81LOEUF

pLI 0.000

Z-score 3.30

OE 0.67 (0.56–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-1.39Z-score

OE missense 1.11 (1.06–1.16)

1360 obs / 1223.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.67 (0.56–0.81)

0≤0.351.4

Missense OE?1.11 (1.06–1.16)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 81 / 120.0Missense obs/exp: 1360 / 1223.0Syn Z: -2.17

Background carrier burden — how many people carry a rare variant somewhere in SPG11?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 18

3,377 rare PASS variants

Rare truncating (LoF)

1 in 210

577 rare PASS variants

Rare synonymous (reference)

1 in 55

1,225 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SPG11. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 26	1 in 220
South Asian	~43k	1 in 16	1 in 160
Remaining (unassigned)	~30k	1 in 17	1 in 200
European (Finnish)	~27k	1 in 87	1 in 430
Admixed American	~22k	1 in 18	1 in 210
African / African American	~21k	1 in 19	1 in 140
East Asian	~20k	1 in 19	1 in 240
Ashkenazi Jewish	~13k	1 in 150	1 in 360
Middle Eastern	~2,884	1 in 21	1 in 160

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 37 of 40 coding exons well covered in gnomAD exomes; exons 13, 17, 27 marginal. Genomes: all 40.? see exons ↓