Is ATP8A2 p.Arg588fs (c.1761dup) pathogenic?

ATP8A2 p.Arg588fs (c.1761dup) is classified Pathogenic/Likely pathogenic in ATP8A2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-12-16). Very rare (popmax 0.00017%, nfe); Associated with cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4.

What condition is associated with ATP8A2 p.Arg588fs (c.1761dup)?

ATP8A2 p.Arg588fs (c.1761dup) is associated with cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4 (ClinVar).

How common is ATP8A2 p.Arg588fs (c.1761dup) in the general population?

ATP8A2 p.Arg588fs (c.1761dup) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Dysequilibrium syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ATP8A2 p.Arg588fs

c.1761dup · rs1156904586 · VCV522073

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 20 of 37
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,922 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,836 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)grpmax	0.00017%	589,960

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ATP8A2
Protein: p.Arg588fs
Coding: c.1761dup
MANE Select: NM_016529
dbSNP: rs1156904586
Type: Duplication
Location: chr13:25577115 (GRCh38)
Gene constraint: LOEUF 0.728 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 81.12
Residue 588: a UniProt-annotated variant site (in camrq4; uncertain significance)

Full ATP8A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Dysequilibrium syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

ATP8A2 p.Arg588Trp Likely pathogenic ★ ⚠ same residue
ATP8A2 p.Asp851fs Likely pathogenic ★ same condition
ATP8A2 p.Glu1106fs Pathogenic ★ same condition
ATP8A2 p.Lys442fs Likely pathogenic ★ same condition
ATP8A2 c.1782+2T>C Pathogenic ★★ same condition
ATP8A2 c.2212-1G>C Pathogenic ★★ same condition
ATP8A2 c.3272+1G>A Pathogenic/Likely pathogenic ★★ same condition
ATP8A2 c.77-2A>G Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/atp8a2-p-arg588fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown