ATP11A

protein-coding

ATPase phospholipid transporting 11A, the group of ATPase phospholipid transporting

Gene summary

The protein encoded by this gene is an integral membrane ATPase. The encoded protein is probably phosphorylated in its intermediate state and likely drives the transport of ions such as calcium across membranes. [provided by RefSeq, Apr 2022]

MANE transcript

NM_015205.3

Inheritance

ClinVar variants

P:6U:229B:73

Top phenotype

Deafness, autosomal dominant 84; Auditory neuropathy, autosomal dominant 2

gnomAD constraint

pLI —, LoF o/e 0.33

Max pathogenic AF

—

Genomic locus

chr13:112,690,038-112,887,168

External References & Databases

Ensembl (ENSG00000068650)

Transcript & Mutation Effects

hg38 • Region Span ~197.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hearing loss, autosomal dominant 84STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030724

Submitter: PanelApp Australia

leukodystrophy, hypomyelinating, 24STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859242

Submitter: PanelApp Australia

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

auditory neuropathy, autosomal dominant 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0957279

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant nonsyndromic hearing lossMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: ClinGen

ATP11A was first reported in relation to autosomal dominant nonsyndromic hearing loss in 2022 (Pater et al., PMID: 35278131). ATP11A-related hearing loss is slowly progressive, nonsyndromic, and sensorineural. Variants in ATP11A have been reported in individuals with the following disease entities: auditory neuropathy, autosomal dominant 2 (MIM: 620384), leukodystrophy, hypomyelinating, 24 (MIM:619851), and deafness, autosomal dominant 84 (MIM:619810). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, phenotypic variability, or inheritance pattern between auditory neuropathy, autosomal dominant 2 and deafness, autosomal dominant 84. Therefore, the disease entities have been lumped into one term, autosomal dominant nonsyndromic hearing loss. We have split out leukodystrophy, hypomyelinating, 24 and this will be addressed by a separate GCEP. One intronic, one frameshift, and one large deletion variants that have been reported in four probands in two publications (PMIDs: 35278131, 36300302) are included in this curation. The mechanism of pathogenicity is unknown at this time, but the three known variants all caused splicing defects affecting the last or second to last exon, most likely leading to a truncated protein. This gene-disease relationship is also supported by expression studies, a conditional knock-out mouse model, and a loss of function zebrafish model; However, the model organisms may not recapitulate the mechanism of disease in humans, as the proposed mechanism in humans in haploinsufficiency (PMIDs: 36300302, 40223426). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Hearing Loss GCEP on the meeting date May 21st, 2025 (SOP Version 11).

leukodystrophy, hypomyelinating, 24LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0859242

Submitter: Ambry Genetics

hearing loss, autosomal dominant 84MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0030724

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Deafness, autosomal dominant 84; Auditory neuropathy, autosomal dominant 2AD

Manifestation: Audiologic/Otolaryngologic; Neurologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Comments: The onset of hearing loss in Deafness, autosomal dominant 84 has been described as variable; Leukodystrophy, hypomyelinating, 24 has been described as involving hypothyroidism, cataracts, and frequent infections in one described individual

Refs: 35278131; 34403372; 36300302

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATP11A variants in ClinVar

10 Conditions Cataloged

Inborn genetic diseasesTotal: 185

ATP11A-related disorderTotal: 82

not providedTotal: 68

not specifiedTotal: 20

Hearing loss, autosomal dominant 84Total: 12

Leukodystrophy, hypomyelinating, 24Total: 10

Auditory neuropathy, autosomal dominant 2Total: 4

Autosomal dominant nonsyndromic hearing loss 33Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015205.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			7 clinvar	35 clinvar	9 clinvar	51
missense	2 clinvar	1 clinvar	209 clinvar	28 clinvar	1 clinvar	241
nonsense			3 clinvar			3
start loss						0
frameshift	1 clinvar	1 clinvar	2 clinvar			4
splice donor/acceptor (+/-2bp)	1 clinvar		8 clinvar			9
Total	4	2	229	63	10	308

Highest pathogenic variant AF is 8.382778e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015205.3	RefSeq	NP_056020.2	29	MANE Select
ENST00000375645.8	Ensembl	ENSP00000364796.3	29	MANE Select
NM_001405661.1	RefSeq	NP_001392590.1	29	Standard
NM_001405662.1	RefSeq	NP_001392591.1	29	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lung fibrosis
Neutrophil degranulation
Ion channel transport
Innate Immune System
Immune System

Biological Process

neutrophil degranulation
phospholipid translocation

Molecular Function

magnesium ion binding
phospholipid-translocating ATPase activity
protein binding
ATP binding

Cellular Component

lysosomal membrane
early endosome
endoplasmic reticulum
trans-Golgi network
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000487903
Coding exons: 29
Length: 196840
Individuals with no LoFs: 125645
Homozygous LoFs: 0
Heterozygous LoFs: 103
Defined: 125748
p: 0.000410

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.37	592	693	0.854	0.0000437	7450
Missense (PolyPhen)		136	218.02	0.62381		2358
Synonymous	-1.13	324	299	1.08	0.0000232	2131
Loss of Function	5.19	23	69.8	0.330	0.00000359	768

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00056	0.00055	rare
Latino/Admixed American	0.00034	0.00029	rare
Ashkenazi Jewish	0.00044	0.00040	rare
East Asian	0.00040	0.00038	rare
Finnish	0.00029	0.00028	rare
European (Non-Finnish)	0.00044	0.00041	rare
South Asian	0.00060	0.00052	rare
Other	0.00072	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids from the outer to the inner leaflet of various membranes and ensures the maintenance of asymmetric distribution of phospholipids. Phospholipid translocation seems also to be implicated in vesicle formation and in uptake of lipid signaling molecules (Probable). May be involved in the uptake of farnesyltransferase inhibitor drugs, such as lonafarnib. {ECO:0000269|PubMed:15860663, ECO:0000305}.;

Recessive Scores

pRec: 0.106

Intolerance Scores

LoFtool: 0.136
RVIS EVS: -1.61
RVIS percentile EVS: 3.01

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: N
Indispensability score: 0.171

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium