ATAD3A

Chr 1ADAR

ATPase family AAA domain containing 3A

Also known as: HAYOS, PHRINL

NCBI Gene: 55210 ENSG00000197785 UniProt: Q9NVI7 OMIM: 612316

ATAD3A encodes a mitochondrial membrane protein essential for mitochondrial network organization, metabolism, protein synthesis, and cholesterol metabolism. Mutations cause Harel-Yoon syndrome and a neonatal lethal form of pontocerebellar hypoplasia with hypotonia and respiratory insufficiency, following both autosomal dominant and autosomal recessive inheritance patterns. The gene is extremely intolerant to loss-of-function variants, consistent with the severe neonatal phenotypes observed.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAD/ARLOEUF 0.832 OMIM phenotypes

Clinical Summary— ATAD3A

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

0.83LOEUF

pLI 0.000

Z-score 2.35

OE 0.56 (0.39–0.83)

Tolerant

Typical tolerance to LoF variation

Missense Constraint

0.01Z-score

OE missense 1.00 (0.92–1.08)

401 obs / 401.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.56 (0.39–0.83)

0≤0.351.4

Missense OE1.00 (0.92–1.08)

0≤0.61.4

Synonymous OE1.10

0≤1.21.6

LoF obs/exp: 19 / 33.7Missense obs/exp: 401 / 401.7Syn Z: -0.99

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveATAD3A-related disorder with global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathyDNAD

strongATAD3A-related disorder with global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathyLOFAR

0.85top 10%

GOF

0.77top 25%

LOF

0.2091th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median · 1 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

DNThe dominant-negative patient mutation affects the Walker A motif, which is responsible for ATP binding in the AAA module of ATAD3A, and we show that the recombinant mutant ATAD3A protein has a markedly reduced ATPase activity.PMID:28158749

GOFThese findings suggested that the mutation acts as a toxic gain-of-function allele and results in decreased mitochondria in neurons and muscle.PMID:27640307

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.