ATP13A2

Chr 1AR

ATPase cation transporting 13A2

Also known as: CLN12, HSA9947, KRPPD, PARK9, SPG78

NCBI Gene: 23400 ENSG00000159363 UniProt: Q9NQ11 OMIM: 610513

This gene encodes a P5-type ATPase that transports inorganic cations and localizes to the lysosome membrane. Biallelic mutations cause Kufor-Rakeb syndrome (a juvenile-onset parkinsonism with pyramidal signs and dementia) and autosomal recessive spastic paraplegia 78. Mutations can cause disease through multiple mechanisms depending on the variant type, with the gene showing moderate constraint against loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the P5 subfamily of ATPases which transports inorganic cations as well as other substrates. Mutations in this gene are associated with Kufor-Rakeb syndrome (KRS), also referred to as Parkinson disease 9. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Kufor-Rakeb syndromeMIM #606693

Spastic paraplegia 78, autosomal recessiveMIM #617225

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · Kufor-Rakeb syndrome · AR · ClinGen 2022
Strong · autosomal recessive spastic paraplegia type 78 · AR · Genomics England PanelApp
Supportive · parkinsonism due to ATP13A2 deficiency · AR · Orphanet

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.58

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — ATP13A2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.58LOEUF

pLI 0.000

Z-score 4.12

OE 0.42 (0.30–0.58)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.40Z-score

OE missense 0.85 (0.80–0.91)

624 obs / 730.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.42 (0.30–0.58)

0≤0.351.4

Missense OE?0.85 (0.80–0.91)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 24 / 57.8Missense obs/exp: 624 / 730.5Syn Z: -0.54

Background carrier burden — how many people carry a rare variant somewhere in ATP13A2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 30

1,627 rare PASS variants

Rare truncating (LoF)

1 in 600

217 rare PASS variants

Rare synonymous (reference)

1 in 46

717 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ATP13A2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 41	1 in 640
South Asian	~43k	1 in 29	1 in 980
Remaining (unassigned)	~30k	1 in 27	1 in 380
European (Finnish)	~27k	1 in 76	1 in 890
Admixed American	~22k	1 in 28	1 in 700
African / African American	~21k	1 in 29	1 in 930
East Asian	~20k	1 in 34	1 in 760
Ashkenazi Jewish	~13k	1 in 90	1 in 1,400
Middle Eastern	~2,884	1 in 35	≈ 1 in 690

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 28 of 29 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 29.? see exons ↓