MT-ATP6

Chr MT

ATP synthase F0 subunit 6

Also known as: ATPase6, MTATP6

NCBI Gene: 4508 ENSG00000198899 UniProt: P00846

This gene encodes ATP synthase F0 subunit 6, a component of Complex V that synthesizes ATP in the mitochondrial respiratory chain. Mutations cause NARP syndrome at 70-90% heteroplasmy levels, maternally inherited Leigh syndrome at >90% heteroplasmy, and Charcot-Marie-Tooth-like neuropathy, with phenotype severity strongly dependent on the degree of heteroplasmy. Inheritance is maternal through the mitochondrial genome.

GeneReviews ResearchSummary from Curated mito context

Enables proton channel activity. Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in proton motive force-driven mitochondrial ATP synthesis and proton transmembrane transport. Located in mitochondrion. Part of proton-transporting ATP synthase complex. Implicated in Leber hereditary optic neuropathy; NARP syndrome; Parkinson's disease; multiple sclerosis; and systemic lupus erythematosus. [provided by Alliance of Genome Resources, Jul 2025]

GeneReviews ResearchGenerating clinical summary…

Multiplemechanism

Clinical Summary— MT-ATP6

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Gene-Disease Validity (ClinGen)

mitochondrial disease · MTDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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ClinVar Variants

13 unique Pathogenic / Likely Pathogenic· 120 VUS of 321 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MT-ATP6

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD

Constraint data not available from gnomAD.

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMT-ATP6-related neuropathy, ataxia, retinitis pigmentosa syndromeOTHERmitochondrial

This gene — mechanism propensity

0.87top 5%

GOF

0.81top 10%

LOF

0.1499th %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

321 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic8

VUS120

Likely Benign87

Benign92

Conflicting1

Pathogenic

Likely Pathogenic

120

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

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

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	—	—	—	—	5
Likely Pathogenic	—	—	—	—	8
VUS	—	—	—	—	120
Likely Benign	—	—	—	—	87
Benign	—	—	—	—	92
Conflicting	—				1
Total	—				313

Counts from ClinVar esearch · Updated hourly

View in ClinVar →

19 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap MT-ATP6 — 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-ATP6 · protein map & ClinVar variants

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

MITOMAP Disease Variants — MT-ATP6

MITOMAP ↗

Variant	AA	Disease	Status	GenBank
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%
m.8573G>A	G16D	Patient with suspected mitochondrial disease	Reported by paper as Benign	10.260%
m.8578C>T	P18S	Spinocerebellar ataxia	Reported	4.750%
m.8579C>T	P18L	ATP6/8 deficiency	Reported	0.000%
m.8597T>C	I24T	Leigh Syndrome	Reported	2.600%
m.8605C>T	P27S	Isolated mitochondrial cardiomyopathy	Reported	0.770%
m.8606C>T	P27L	Possible association with sepsis	Reported	0.000%
m.8608C>T	P28S	Patient with suspected mitochondrial disease	Reported	0.150%
m.8611C>CC	frameshift	Ataxia, microcephaly, developmental delay, intellectual disability / ATP6/8 deficiency	Reported	0.000%
m.8611C>A	L29M	Neurodevelopmental delay +cerebellar atrophy +strabismus	Reported	0.770%
m.8612T>C	L29P	Arm and leg weakness, incontinence, developmental delay, autism, epilepsy / ATP6/8 deficiency	Reported	0.000%
m.8618T>TT	frameshift	NARP/cognitive decline+abnormal brain MRI+impaired kidney function	Cfrm [LP]	0.000%
m.8639T>C	I38T	Possible LHON modulator	Reported	3.980%
m.8668T>C	W48R	LHON	Reported	5.970%
m.8672T>C	L49P	lntrauterine growth retardation+truncal hypotonia+microcephaly+developmental delay+left ventricular noncompaction+WPW	Reported	0.000%
m.8691A>G	K55K	Infantile mito disease w subclinical hypothyroidism	Reported	1.070%
m.8716A>TA	frameshift	ATP6/8 deficiency	Reported as 8716dupT	0.000%
m.8719G>A	G65Term	Suspected mito disease	Reported [VUS]	0.000%
m.8723G>T	R66L	Patient with suspected mitochondrial disease / ATP6/8 deficiency	Reported	0.000%
m.8741T>G	L72R	MILS protective factor	Reported	0.000%
m.8746T>C	S74P	ATP6/8 deficiency	Reported	0.000%
m.8777T>C	L84P	Adult-onset cerebellar ataxia�	Reported	0.000%
m.8779C>T	L85F	Possible LHON modulator	Reported	0.150%
m.8782G>A	G86Term	Cerebellar ataxia+diabetes+kidney disease / ataxia+myoclonic epilepsy / ATP6/8 deficiency	Reported	0.000%
m.8783G>A	G86E	Unspecified suspected mitochondrial disorder	Reported [VUS]	0.310%
m.8794C>T	H90Y	Exercise Endurance / Coronary Atherosclerosis risk	Reported	278.310%
m.8795A>G	H90R	MILS protective factor	Reported	0.000%
m.8797T>C	S91P	Leigh syndrome spectrum	Reported	0.000%
m.8806C>G	P94A	Suspected mito disease	Reported	0.000%
m.8812A>G	T96A	Spinocerebellar ataxia / PCOS patient	Reported	11.950%
m.8821T>G	S99A	Possible LHON helper variant	Reported	0.000%
m.8836A>G	M104V	LHON	Reported	28.180%
m.8839G>C	A105P	NARP syndrome	Reported [VUS]	0.000%
m.8843T>C	I106T	Patient with suspected mitochondrial disease / PCOS patient	Reported by paper as Likely Benign	35.540%
m.8851T>C	W109R	BSN / Leigh syndrome	Cfrm [VUS*]	0.610%
m.8858G>A	G111D	ATP6/8 deficiency	Reported	0.000%
m.8879G>T	R118L	Adult-onset cerebellar ataxia�- possible helper mutant for m.8777C	Reported	0.000%
m.8881T>C	S119P	Patient with suspected mitochondrial disease	Reported	0.460%
m.8890A>G	K122E	Juvenile-onset metabolic syndrome	Reported	0.000%
m.8902G>A	A126T	Suspected mito disease	Reported	1.380%
m.8909T>C	F128S	Recurrent severe kidney disease and multiple systemic dysfunctions	Reported	0.000%
m.8921G>A	G132D	Patient with suspected mitochondrial disease	Reported	1.380%
m.8932C>T	P136S	Prostate tumor / Neuromuscular disorder / dilated cardiomyopathy	Reported [B]	41.820%
m.8936T>A	L137H	Atypical Leigh syndrome	Reported [VUS]	0.150%
m.8938A>G	I138V	Patient with suspected mitochondrial disease	Reported	7.810%
m.8950G>A	V142I	LDYT / Spinocerebellar Ataxia	Reported	13.170%
m.8951T>C	V142A	Patient with ataxia	Reported	1.530%
m.8959G>A	E145K	Developmental delay, intellectual disability, low citrilline / ATP6/8 deficiency	Reported	0.610%
m.8969G>C	S148T	Suspected mito disease	Reported	0.000%
m.8969G>A	S148N	Mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) / IgG nephropathy / ATP6/8 deficiency	Cfrm [LP]	0.150%
m.8975T>C	L150P	Suspected mito disease	Reported	3.520%
m.8989G>C	A155P	NARP syndrome	Reported	0.000%
m.8993TG>CA	L156P	Developmental delay & myopathy	Cfrm [LP]	0.000%
m.8993T>G	L156R	NARP / Leigh Disease / MILS / ATP6/8 deficiency / other	Cfrm [P]	0.920%
m.8993T>C	L156P	NARP / Leigh Disease / MILS / ATP6/8 deficiency / other	Cfrm [P]	0.310%
m.8999T>C	V158A	Patient with suspected mitochondrial disease	Reported	1.380%
m.9005T>C	L160P	ATP6/8 deficiency	Reported	0.310%
m.9008C>G	T161S	Suspected mito disease	Reported	0.310%
m.9010G>A	A162T	Unspecified neurological disorder	Reported	4.290%
m.9016A>G	I164V	LHON	Reported	1.990%
m.9017T>C	I164T	Unspecified neurological disorder	Reported	2.140%
m.9019A>G	T165A	Suspected mito disease	Reported	0.000%
m.9025G>A	G167S	Motor neuropathy, Leigh-like, colon cancer	Reported [VUS]	7.050%
m.9026G>A	G167D	Spinocerebellar ataxia / patient with suspected mitochondrial disease	Reported [VUS]	0.460%
m.9029A>G	H168R	LHON-like	Reported	0.150%
m.9032T>C	L169P	NARP / Complex phenotype with microcephaly, ataxia, hearing loss, lactic acidosis / ATP6/8 deficiency	Reported [VUS]	0.000%
m.9035T>C	L170P	Ataxia syndromes / ATP6/8 deficiency	Cfrm [LP]	0.000%
m.9041A>G	H172R	Patient with suspected mitochondrial disease	Reported	7.960%
m.9049G>A	G175Term	Unspecified suspected mitochondrial disorder / ATP6/8 deficiency	Reported [VUS]	0.000%
m.9055G>A	A177T	PD protective factor	Reported	404.220%
m.9058A>G	T178A	Patients with (1) LVNC cardiomyopathy; (2) autism, intellectual disability, epilepsy; (3) PCOS	Reported as (1) possible association or as (2) benign	6.280%
m.9071C>T	S182L	Potentially functional variant cosegregating with LHON3635A	Reported	2.450%
m.9088T>C	S188P	Patient with suspected mitochondrial disease	Reported by paper as Likely Benign	3.830%
m.9098T>C	I191T	Predisposition to anti-retroviral mito disease	Reported	10.570%
m.9101T>C	I192T	LHON	Reported	10.260%
m.9115A>G	I197V	Patient with suspected mitochondrial disease	Reported	5.050%
m.9127AT>-	IL-PTerm	NARP	Reported	0.000%
m.9133G>A	E203K	Patient with suspected mitochondrial disease	Reported	0.610%
m.9134A>G	E203G	Hypotonia, lactic acidosis, HCM, IUGR	Reported [VUS]	0.000%
m.9139G>A	A205T	LHON	Reported - possibly synergistic	7.960%
m.9152T>C	I209T	Patient with suspected mitochondrial disease	Reported [VUS]	2.600%
m.9154C>T	Q210Term	Peripheral neuropathy ataxia IgA nephropathy	Reported	0.000%
m.9155A>T	Q210L	Developmental delay, intellectual disability, low citrilline	Reported	0.000%
m.9155A>G	Q210R	MIDD, renal insufficiency	Cfrm [LP]	0.000%
m.9157G>A	A211T	Mitochondrial neuromuscular disease	Reported	0.920%
m.9166T>C	F214L	EXIT+more / bilateral optic neuropathy	Reported	0.000%
m.9176T>G	L217R	Leigh Disease / Spastic Paraplegia / Spinocerebellar Ataxia / ATP6/8 deficiency	Cfrm [LP]	0.150%
m.9176T>C	L217P	FBSN / Leigh Disease / Spinocerebellar Ataxia / ATP6/8 deficiency	Cfrm [P]	0.460%
m.9185T>C	L220P	Leigh Disease / Ataxia syndromes / NARP-like disease / Episodic weakness and Charcot-Marie-Tooth / ATP6/8 deficiency	Cfrm [P]	0.460%
m.9191T>C	L222P	Leigh Disease	Cfrm [LP]	0.000%
m.9204AT>-	frameshift	ATP6/8 deficiency	Reported	0.000%
m.9205TA>-	Term-M	Encephalopathy / Seizures / Lacticacidemia	Cfrm [LP]	0.000%