ATAD3A

Chr 1ADAR

ATPase family AAA domain containing 3A

Also known as: HAYOS, PHRINL

NCBI Gene: 55210ENSG00000197785UniProt: Q9NVI7

This gene encodes a ubiquitously expressed mitochondrial membrane protein that contributes to mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. This gene is a member of the ATPase family AAA-domain containing 3 gene family which, in humans, includes two other paralogs. Naturally occurring mutations in this gene are associated with distinct neurological syndromes including Harel-Yoon syndrome. High-level expression of this gene is associated with poor survival in breast cancer patients. A homozygous knockout of the orthologous gene in mice results in embryonic lethality at day 7.5 due to growth retardation and defective development of the trophoblast lineage. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]

Primary Disease Associations & Inheritance

Harel-Yoon syndromeMIM #617183
ADAR
Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethalMIM #618810
AR
577
ClinVar variants
156
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ATAD3A
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
156 Pathogenic / Likely Pathogenic· 307 VUS of 577 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.
0.83LOEUF
pLI 0.000
Z-score 2.35
OE 0.56 (0.39–0.83)
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.
0.01Z-score
OE missense 1.00 (0.92–1.08)
401 obs / 401.7 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.0.56 (0.39–0.83)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.00 (0.92–1.08)
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.1.10
0≤1.21.6
LoF obs/exp: 19 / 33.7Missense obs/exp: 401 / 401.7Syn Z: -0.99

ClinVar Variant Classifications

577 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic129
Likely Pathogenic27
VUS307
Likely Benign64
Benign28
Conflicting22
129
Pathogenic
27
Likely Pathogenic
307
VUS
64
Likely Benign
28
Benign
22
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
2
124
0
129
Likely Pathogenic
10
4
13
0
27
VUS
4
250
53
0
307
Likely Benign
0
14
12
38
64
Benign
0
4
15
9
28
Conflicting
—22
Total1727421747577

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

View in ClinVar →

Protein Context — Lollipop Plot

ATAD3A · protein map & ClinVar variants

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

Gene2Phenotype Curations

ATAD3A-related disorder with global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy

definitive
ADDominant NegativeAltered Gene Product Structure
Dev. Disorders
G2P ↗

ATAD3A-related disorder with global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Harel-Yoon syndrome

MIM #617183

Molecular basis of disorder known

Autosomal dominantAutosomal recessive

Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal

MIM #618810

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.
Harel T et al.·Am J Hum Genet
2016
Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A.
Lepelley A et al.·J Exp Med
2021Case report
The mysteries of LETM1 pleiotropy.
Mohammed SEM et al.·Pharmacol Res
2024Review
Ketogenic Diet Attenuates Refractory Epilepsy of Harel-Yoon Syndrome With ATAD3A Variants: A Case Report and Review of Literature.
Chen Y et al.·Pediatr Neurol
2023Review
The value of ATAD3A as a potential biomarker for bladder cancer.
Liu Z et al.·Cancer Med
2023
Clinical characteristics and induced pluripotent stem cells (iPSCs) disease model of Harel-Yoon syndrome caused by compound heterozygous ATAD3A variants.
Jiang Z et al.·Hum Cell
2025Functional
Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism.
Gunning AC et al.·Am J Hum Genet
2020
Elevated FBXL6 activates ATAD3A through K63-linked polyubiquitination and promotes the malignant progression of TNBC via metabolic reprogramming.
Wu Y et al.·Int J Biol Macromol
2025
Transcriptome analysis of atad3-null zebrafish embryos elucidates possible disease mechanisms.
Ezer S et al.·Orphanet J Rare Dis
2025Functional
ATAD3A-related pontocerebellar hypoplasia: new patients and insights into phenotypic variability.
Skopkova M et al.·Orphanet J Rare Dis
2023Cohort
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