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Intellectual disability

Gene: ATP6AP2

Green List (high evidence)
ATP6AP2 (ATPase H+ transporting accessory protein 2)
EnsemblGeneIds (GRCh38): ENSG00000182220
EnsemblGeneIds (GRCh37): ENSG00000182220
OMIM: 300556, Gene2Phenotype
ATP6AP2 is in 10 panels

7 reviews

Ida Ertmanska (Genomics England Curator)

Green List (high evidence)

Comment on mode of inheritance: As there is an affected female reported in literature with a heterozygous ATP6AP2 variant and intellectual disability, the MOI should be changed to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males).
Created: 10 Jul 2026, 2:54 p.m. | Last Modified: 10 Jul 2026, 2:54 p.m.
Panel Version: 10.54
PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients.

PMID: 38274877 Liang et al., 2024
Report of a male patient with developmental and epileptic encephalopathy (DEE) carrying an ATP6AP2 c.858G>A (p.Ala286=) variant. SpliceAI score = Splice-Altering / moderate (0.25). An in vitro splicing assay for the ATP6AP2 gene mRNA revealed that the variant caused a deletion in exon 8 and a corresponding protein truncation of p.Phe247_Ala286del. Patient presentation: tonic seizures at 3.5 months of age, MRI indicated impaired brain white matter development and reduced left hippocampal volume.

PMID: 30985297 Hirose et al., 2019
Study identified a de novo intronic ATP6AP2 variant c.301-11_301-10delTT in a boy with XLID and fulminant early postnatal neurodegeneration. He was diagnosed at the age of 2 weeks with seizures and mild facial dysmorphism, he developed intractable seizures and generalized limb spasticity. MRI showed rapidly decreasing cortical gray and white matter volumes, a thin, poorly developing corpus callosum, and myelination deficits. Variant is expected to increase exon 4 skipping - confirmed by RT-PCR (20% full-length ATP6AP2 (fl-ATP6AP2) and 80% ATP6AP2Δe4 transcripts).

Other reports not curated in detail:
PMID: 26467484 Gupta et al., 2015: 'A splice site mutation in ATP6AP2 causes X-linked intellectual disability, epilepsy, and parkinsonism'
PMID: 15746149 Ramser et al., 2005: 'A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor'
PMID: 11782983 Hedera et al., 2002: 'Novel mental retardation-epilepsy syndrome linked to Xp21.1-p11.4'

ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).
Created: 10 Jul 2026, 2:52 p.m. | Last Modified: 10 Jul 2026, 2:52 p.m.
Panel Version: 10.54

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423; syndromic X-linked intellectual disability Hedera type, MONDO:0010319

Publications

Created: 10 Jul 2026, 2:52 p.m.
Last Modified: 10 Jul 2026, 2:52 p.m.
Panel version: 10.54

Louise Daugherty (Genomics England Curator)

Comment on list classification: Changed from Amber to Green. From external review comment and further publications to support gene-disease association. There are more than three unrelated cases and pathogenic variants for X-linked intellectual disability, Hedera type (PMID:26467484;11782983 15746149; 29127204).
Created: 13 Aug 2018, 3:27 p.m.
Comment on publications: added publication PMID:29127204 (2017) suggested by external reviewer with functional evidence on more variants support the rating of this gene to be promoted to Green. Two hemizygous mutations in ATP6AP2 were identified by whole exome sequencing in three male individuals from two unrelated families. A Portuguese boy was shown to carry a hemizygous missense mutation c.293T>C (p.L98S) in exon 3.The mutation was absent in the parents and the two brothers. In contrast, the neighboring polymorphism c.268C>G was transmitted by the heterozygous mother to all sons. Together, this suggested that p.L98S, which is evolutionary conserved between vertebrates and invertebrates, is a de novo mutation. Another hemizygous missense mutation, c.212G>A (p.R71H), was found in the same exon in two individuals of a German family. Both mutations were absent from more than 60,000 control individuals in the ExAC server. Functional studies using cell culture, Drosophila, and mouse models suggest that the missense mutations reduce the interaction with V0 assembly factors and, consequently, V-ATPase activity.
Created: 13 Aug 2018, 3:20 p.m.
Comment on phenotypes: added disease from Gene2Phenotype and Orphanet : X-linked intellectual disability, Hedera type is a rare X-linked intellectual disability syndrome characterized by an onset in infancy of delayed motor and speech milestones, generalized tonic-clonic seizures and drop attacks, and mild to moderate intellectual disability. Additional, less common manifestations include scoliosis, ataxia (resulting in progressive gait disturbance), and bilateral pes planovalgus. Physical appearance is normal with no dysmorphic features reported.
Created: 13 Aug 2018, 3:19 p.m.
Created: 13 Aug 2018, 2:58 p.m.

Panel version: 2.370

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Please note additional recent publication with functional evidence on more variants.
Created: 14 Jun 2018, 9:35 a.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Publications

Variants in this GENE are reported as part of current diagnostic practice

Created: 14 Jun 2018, 9:35 a.m.

Panel version: 2.104

Sarah Leigh (Genomics England Curator)

I don't know

Associated with phenotype in OMIM and as a possible G2P. At least 2 variants reported, (c.321C>T, p.D107D) affects normal splicing (PMID 15746149) and c.168+6T-A predicted to affect splicing (PMID 26467484)
Created: 15 Dec 2017, 9:38 a.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Publications

Created: 15 Dec 2017, 9:38 a.m.

Panel version: Imported from Intellectual disability update Dec 2017 panel version 0.13

Caroline Wright (Sanger)

Red List (low evidence)

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
MENTAL RETARDATION X-LINKED WITH EPILEPSY (MRXE)

Publications

  • 0

Created: 5 Nov 2017, 2:42 a.m.

Panel version: 0

BRIDGE consortium (NIHRBR-RD)

Green List (high evidence)

This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_ddg2p_2_4_2017;in_omim_20150205_movement . Main mutation mechanism : Uncertain
Created: 27 Jul 2017, 5:08 p.m.
Evidences key, gene present in following gene lists and main mutation mechanism : ddg2p_20141118; gilissen_2014_candidate; omim_20150205_movement; Nijmegen_ID_diagnostic; Nijmegen_ID_candidates; GEL_ID_red_20160217; neuro_20160418_strict; Uncertain. This is a pertinent gene from the BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene comes from the SPEED_NEURO_v3.0_20170404 gene list. The following experts from the BRIDGE consortium NIHRBR-RD contributed to this panel: - Professor F. Lucy Raymond, Cambridge Institute for Medical Research, University of Cambridge - Manju Kurian, Paediatric neurologist, Great Ormond Street Hosptial - Keren Carss, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Alba Sanchis-Juan, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Marie Erwood NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Louise Daugherty, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust
Created: 19 Jul 2017, 12:02 p.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Publications

Created: 2 Aug 2017, 2:43 p.m.

Panel version: 1.354

Lu Raymond (university of cambridge )

Red List (low evidence)

Created: 23 Feb 2016, 11:12 a.m.

Panel version: 0.306

Details

Mode of Inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Victorian Clinical Genetics Services
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • Emory Genetics Laboratory
Phenotypes
  • Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423
  • syndromic X-linked intellectual disability Hedera type, MONDO:0010319
Tags
Q3_26_MOI
OMIM
300556
Clinvar variants
Variants in ATP6AP2
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

10 Jul 2026, Gel status: 3

Added Tag

Ida Ertmanska (Genomics England Curator)

Tag Q3_26_MOI tag was added to gene: ATP6AP2.

8 Jul 2026, Gel status: 3

Set Phenotypes

Ida Ertmanska (Genomics England Curator)

Phenotypes for gene: ATP6AP2 were changed from Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423 syndromic X-linked intellectual disability Hedera type, MONDO:0010319 to Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423; syndromic X-linked intellectual disability Hedera type, MONDO:0010319

8 Jul 2026, Gel status: 3

Set Phenotypes

Ida Ertmanska (Genomics England Curator)

Phenotypes for gene: ATP6AP2 were changed from Mental retardation, X-linked, syndromic, Hedera type, 300423; MENTAL RETARDATION X-LINKED WITH EPILEPSY; X-linked intellectual disability, Hedera type to Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423 syndromic X-linked intellectual disability Hedera type, MONDO:0010319

28 Sep 2018, Gel status: 4

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to ATP6AP2.

13 Aug 2018, Gel status: 3

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: atp6ap2 has been classified as Green List (High Evidence).

13 Aug 2018, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: ATP6AP2 were set to 26467484; 15746149; 29127204; 25529582; 11782983

13 Aug 2018, Gel status: 2

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: ATP6AP2 were set to Mental retardation, X-linked, syndromic, Hedera type, 300423; MENTAL RETARDATION X-LINKED WITH EPILEPSY; X-linked intellectual disability, Hedera type

13 Aug 2018, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: ATP6AP2 were set to 26467484; 15746149; 29127204; 25529582

12 Mar 2018, Gel status: 2

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

5 Jan 2018, Gel status: 2

Added New Source, Set publications

Ellen McDonagh (Genomics England Curator)

Expert Review Amber was added to ATP6AP2. Panel: Intellectual disability Publications for gene ATP6AP2 was set to ['26467484', ' 15746149', ' ']

13 Nov 2015, Gel status: 1

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

Set Mode of Inheritance, Added New Source

Ellen McDonagh (Genomics England Curator)

ATP6AP2 was added to Intellectual disabilitypanel. Source: Expert Review Red Model of inheritance for gene ATP6AP2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females

24 Jun 2015, Gel status: 2

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene ATP6AP2 was changed to X-LINKED: hemizygous mutation in males, may be caused by monoallelic mutations in females

24 Jun 2015, Gel status: 2

Added New Source

Ellen McDonagh (Genomics England Curator)

ATP6AP2 was added to Intellectual disabilitypanel. Sources: Emory Genetics Laboratory,Radboud University Medical Center, Nijmegen

24 Jun 2015, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

ATP6AP2 was added to Intellectual disabilitypanel. Sources: Emory Genetics Laboratory,Radboud University Medical Center, Nijmegen