ATL1

Chr 14AD

atlastin GTPase 1

Also known as: AD-FSP, ATL-1, FSP1, HSN1D, SPG3, SPG3A, atlastin1

NCBI Gene: 51062 ENSG00000198513 UniProt: Q8WXF7 OMIM: 606439

The protein is a GTPase that localizes to endoplasmic reticulum and Golgi membranes and functions in axonal maintenance. Mutations cause autosomal dominant spastic paraplegia type 3A and hereditary sensory neuropathy type ID. The mechanism involves loss of function, as indicated by the high intolerance to loss-of-function variants (pLI 0.98, LOEUF 0.31).

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a GTPase and a Golgi body transmembrane protein. The encoded protein can form a homotetramer and has been shown to interact with spastin and with mitogen-activated protein kinase kinase kinase kinase 4. This protein may be involved in axonal maintenance as evidenced by the fact that defects in this gene are a cause of spastic paraplegia type 3. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.312 OMIM phenotypes

Clinical Summary— ATL1

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Gene-Disease Validity (ClinGen)

neuropathy, hereditary sensory, type 1D · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

95 unique Pathogenic / Likely Pathogenic· 302 VUS of 695 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ATL1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.31LOEUF

pLI 0.981

Z-score 4.62

OE 0.15 (0.08–0.31)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.63Z-score

OE missense 0.57 (0.50–0.65)

168 obs / 295.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.15 (0.08–0.31)

0≤0.351.4

Missense OE?0.57 (0.50–0.65)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 5 / 34.2Missense obs/exp: 168 / 295.2Syn Z: 0.08

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveATL1-related hereditary spastic paraplegiaOTHERAD

This gene — mechanism propensity

0.5771th %ile

GOF

0.6345th %ile

LOF

0.4627th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 21% of P/LP variants are LoF · LOEUF 0.31

GOFprediction above median · 75% of P/LP are missense

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNHere, we show that dominant-negative mutants of ATL1 in PC-12 cells inhibit nerve growth factor (NGF)-induced neurite outgrowth.1

LOFBeetz et al. (2007) reported a family in which spastic paraplegia segregated with a deletion of exon 1 of the SPAST gene (604277) in the proband, her brother, and her 2 sons. Although the proband and her brother also had a deletion of the ATL1 gene, the ATL1 deletion did not segregate with the disor2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

695 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic40

Likely Pathogenic55

VUS302

Likely Benign185

Benign46

Conflicting49

Pathogenic

Likely Pathogenic

302

VUS

185

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	13	25	2	0	40
Likely Pathogenic	7	46	1	1	55
VUS	11	254	36	1	302
Likely Benign	0	3	94	88	185
Benign	0	0	39	7	46
Conflicting	—				49
Total	31	328	172	97	677

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap ATL1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →