ATL3

Chr 11AD

atlastin GTPase 3

NCBI Gene: 25923ENSG00000184743UniProt: Q6DD88

Atlastin-3 (ATL3) is a membrane-anchored GTPase that mediates the GTP-dependent fusion of endoplasmic reticulum (ER) membranes, maintaining the continuous ER network. It facilitates the formation of three-way junctions where ER tubules intersect (PubMed:18270207, PubMed:19665976, PubMed:24459106, PubMed:27619977, PubMed:37102997). Two atlastin-3 on neighboring ER tubules bind GTP and form loose homodimers through the GB1/RHD3-type G domains and 3HB regions. Upon GTP hydrolysis, the 3HB regions tighten, pulling the membranes together to drive their fusion. After fusion, the homodimer disassembles upon release of inorganic phosphate (Pi). Subsequently, GDP dissociates, resetting the monomers to a conformation ready for a new fusion cycle (By similarity)

Primary Disease Associations & Inheritance

Neuropathy, hereditary sensory, type IFMIM #615632
AD
560
ClinVar variants
11
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ATL3
🧬
Gene-Disease Validity (ClinGen)
neuropathy, hereditary sensory, type 1F · ADModerate

Moderate evidence — consider for supplementary testing

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
11 Pathogenic / Likely Pathogenic· 298 VUS of 560 total submissions

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.
0.90LOEUF
pLI 0.000
Z-score 1.98
OE 0.62 (0.43–0.90)
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.
1.15Z-score
OE missense 0.81 (0.73–0.90)
232 obs / 286.7 exp
Tolerant

Mild missense constraint

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.0.62 (0.43–0.90)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.81 (0.73–0.90)
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.1.08
0≤1.21.6
LoF obs/exp: 19 / 30.9Missense obs/exp: 232 / 286.7Syn Z: -0.68

ClinVar Variant Classifications

560 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7
Likely Pathogenic4
VUS298
Likely Benign197
Benign32
Conflicting22
7
Pathogenic
4
Likely Pathogenic
298
VUS
197
Likely Benign
32
Benign
22
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
5
0
7
Likely Pathogenic
0
0
4
0
4
VUS
21
230
42
5
298
Likely Benign
0
8
91
98
197
Benign
0
1
27
4
32
Conflicting
—22
Total21241169107560

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

View in ClinVar →

Protein Context — Lollipop Plot

ATL3 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
ATLASTIN GTPase 3; ATL3
MIM #609369 · *

Neuropathy, hereditary sensory, type IF

MIM #615632

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — ATL3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies.
Lischka A et al.·Brain
2023
Genetic overlap between ALS and other neurodegenerative or neuromuscular disorders.
Olsen CG et al.·Amyotroph Lateral Scler Frontotemporal Degener
2024
Rare mutations in ATL3, SPTLC2 and SCN9A explaining hereditary sensory neuropathy and congenital insensitivity to pain in a Brazilian cohort.
Cintra VP et al.·J Neurol Sci
2021Cohort
A novel nonsense variant in the ATL3 gene is associated with disturbed pain sensitivity, numbness of distal limbs and muscle weakness.
Mohammadi S et al.·Ann Hum Genet
2023
Sensory neuropathy with bone destruction due to a mutation in the membrane-shaping atlastin GTPase 3.
Kornak U et al.·Brain
2014
ER remodeling by the large GTPase atlastin promotes vacuolar growth of Legionella pneumophila.
Steiner B et al.·EMBO Rep
2017Functional
Mammalian knock out cells reveal prominent roles for atlastin GTPases in ER network morphology.
Zhao G et al.·Exp Cell Res
2016
Deletion of STAT5a/b in vascular smooth muscle abrogates the male bias in hypoxic pulmonary hypertension in mice: implications in the human disease.
Yang YM et al.·Mol Med
2015
Nongenomic STAT5-dependent effects on Golgi apparatus and endoplasmic reticulum structure and function.
Lee JE et al.·Am J Physiol Cell Physiol
2012
Definitive evidence using enucleated cytoplasts for a nongenomic basis for the cystic change in endoplasmic reticulum structure caused by STAT5a/b siRNAs.
Lee JE et al.·Am J Physiol Cell Physiol
2013
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools