MT-ATP8

Chr MT

ATP synthase F0 subunit 8

Also known as: ATPase8, MTATP8

NCBI Gene: 4509 ENSG00000228253 UniProt: P03928 OMIM: 516070

ATP synthase F0 subunit 8 is a component of Complex V in the mitochondrial respiratory chain, essential for ATP synthesis through oxidative phosphorylation. Mutations cause cardiomyopathy and neuropathy, often occurring as part of single large mitochondrial deletions that also affect MT-ATP6. Inheritance is maternal through mitochondrial DNA, and clinical severity depends on the degree of heteroplasmy.

GeneReviews OMIM ResearchSummary from Curated mito context

Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in proton motive force-driven mitochondrial ATP synthesis. Located in mitochondrion. Part of proton-transporting ATP synthase complex. Implicated in multiple sclerosis and urinary bladder cancer. [provided by Alliance of Genome Resources, Jul 2025]

GeneReviews OMIM ResearchGenerating clinical summary…

Multiplemechanism

Clinical Summary— MT-ATP8

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Gene-Disease Validity (ClinGen)

mitochondrial disease · MTLimited

Limited evidence — not for standalone diagnostic reporting

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 34 VUS of 101 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MT-ATP8

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD

Constraint data not available from gnomAD.

This gene — mechanism propensity

0.94top 5%

GOF

0.6639th %ile

LOF

0.08100th %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

GOFprediction above median

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.

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

ClinVar Variant Classifications

101 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic2

VUS34

Likely Benign24

Benign37

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories· variant type breakdown unavailable

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	—	—	—	—	3
Likely Pathogenic	—	—	—	—	2
VUS	—	—	—	—	34
Likely Benign	—	—	—	—	24
Benign	—	—	—	—	37
Total	—				100

Counts from ClinVar esearch · Updated hourly

View in ClinVar →

14 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap MT-ATP8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

MT-ATP8 · protein map & ClinVar variants

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

MITOMAP Disease Variants — MT-ATP8

MITOMAP ↗

Variant	AA	Disease	Status	GenBank
m.8381A>G	T6A	MIDD / LVNC cardiomyopathy-assoc./ ATP6/8 deficiency	Reported	2.600%
m.8382C>T	T6I	Suspected mito disease / optic neuropathy	Reported	1.380%
m.8391G>A	W9Term	ATP6/8 deficiency	Reported	0.000%
m.8393C>T	P10S	Reversible brain pseudoatrophy	Reported	48.250%
m.8403T>C	I13T	Episodic weakness and progressive neuropathy / ATP6/8 deficiency	Reported	0.610%
m.8411A>G	M16V	Severe mitochondrial disorder	Reported	0.310%
m.8412T>C	M16T	Possible LHON helper mutation	Reported	3.370%
m.8414C>T	L17F	Increased risk of T2DM and high altitude polycythemia (HAPC) in hg D4; longevity; reduced risk of esophageal cancer [D1-D2-D3-D4 marker]	Reported	367.150%
m.8418T>C	L18P	Severe bilateral optic neuropathy	Reported [VUS]	0.150%
m.8424T>C	L20P	LS / failure to thrive / hypotonia / seizures; Suspected mito disease	Reported	0.000%
m.8481C>T	P39L	Tetralogy of Fallot patient	Reported	2.300%
m.8490T>C	M42T	Peripheral neuropathy of T2DM	Reported	3.830%
m.8519G>A	E52K	Possible susceptibility to bullous pemphigoid	Reported	25.270%
m.8527A>G	ATP8:K54K ATP6:M1M	Neuromuscular disorder, possible helper mutation / dlated cardiomyopathy	Reported	41.820%
m.8528T>C	ATP8:W55R ATP6:M1T	Infantile cardiomyopathy / hyperammonemia / ATP6/8 deficiency	Cfrm [LP]	0.000%
m.8529G>A	ATP8:W55Term ATP6:M1M	Apical HCM	Reported [VUS]	0.000%
m.8535A>G	ATP8:K57Term ATP6:E3E	ATP6/8 deficiency	Reported	0.000%
m.8551T>C	ATP8:H62H ATP6:F9L	Possible LHON helper mutation	Reported	2.760%
m.8558C>T	ATP8:P65S ATP6:A11V	Possibly LVNC cardiomyopathy-associated	Reported	2.300%
m.8561C>T	ATP8:P66S ATP6:P12L	Ataxia w psychomotor delay	Reported	0.000%
m.8561C>G	ATP8:P66A ATP6:P12R	Ataxia w neuropathy, DM, SNHL, and hypogonadism	Reported	0.000%
m.8570T>C	ATP8:Term69Q ATP6:L15P	Congenital sideroblastic anemia (CSA) / ATP6/8 deficiency / MILS	Reported [VUS]	0.000%
m.8572G>A	ATP8:Term69Term ATP6:G16S	Spinocerebellar ataxia	Reported	41.820%