ATP5F1A

Chr 18ARAD

ATP synthase F1 subunit alpha

Also known as: ATP5A, ATP5A1, ATP5AL2, ATPM, COXPD22, HEL-S-123m, MC5DN4, MC5DN4A

NCBI Gene: 498 ENSG00000152234 UniProt: P25705

This gene encodes the alpha subunit of the F1 catalytic core of mitochondrial ATP synthase, which synthesizes ATP using the proton electrochemical gradient across the inner mitochondrial membrane during oxidative phosphorylation. Mutations cause mitochondrial complex V (ATP synthase) deficiency with nuclear types 4A and 4B, presenting as combined oxidative phosphorylation deficiency and encephalopathy. The condition follows both autosomal recessive and autosomal dominant inheritance patterns.

Summary from RefSeq, OMIM, UniProt

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Primary Disease Associations & Inheritance

?Combined oxidative phosphorylation deficiency 22MIM #616045

?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4B, encephalopathic typeMIM #615228

Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4AMIM #620358

Active trials

Pubs (1 yr)

P/LP submissions

—

P/LP missense

0.18

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

Clinical Summary— ATP5F1A

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). 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

0.18LOEUF

pLI 0.999

Z-score 4.55

OE 0.04 (0.01–0.18)

Highly constrained

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

Missense Constraint

2.44Z-score

OE missense 0.62 (0.55–0.70)

205 obs / 329.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.04 (0.01–0.18)

0≤0.351.4

Missense OE0.62 (0.55–0.70)

0≤0.61.4

Synonymous OE1.05

0≤1.21.6

LoF obs/exp: 1 / 26.0Missense obs/exp: 205 / 329.5Syn Z: -0.44

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongATP5F1A-related failure to thrive, hyperlactatemia and hyperammonemiaOTHERAD

strongATP5F1A-related mitochondrial encephalopathyOTHERAR

0.7036th %ile

GOF

0.4777th %ile

LOF

0.48top 25%

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-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

LOFLOEUF 0.18

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

DNMovement disorders have been described in a subset of cases carrying autosomal dominant variants in structural subunits genes ATP5F1A and ATP5MC3. Functional studies in mutant fibroblasts revealed no decrease of ATP5F1B protein amount but severe reduction of complex V activity and impaired mitochondPMID:36860166

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