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).

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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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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 OE0.15 (0.08–0.31)

0≤0.351.4

Missense OE0.57 (0.50–0.65)

0≤0.61.4

Synonymous OE0.99

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

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 · LOEUF 0.31

GOFprediction above median

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.PMID:28240257

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 disorPMID:17657515

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