Is ATP8A2 p.Arg588Trp (c.1762C>T) pathogenic?

ATP8A2 p.Arg588Trp (c.1762C>T) is classified Likely pathogenic in ATP8A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). AlphaMissense: ambiguous (0.5379); Very rare (popmax 0.00223%, eas); Associated with cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4.

What condition is associated with ATP8A2 p.Arg588Trp (c.1762C>T)?

ATP8A2 p.Arg588Trp (c.1762C>T) is associated with cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4 (ClinVar).

How common is ATP8A2 p.Arg588Trp (c.1762C>T) in the general population?

ATP8A2 p.Arg588Trp (c.1762C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Dysequilibrium syndrome inherited?

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

What do computational predictors say about ATP8A2 p.Arg588Trp (c.1762C>T)?

AlphaMissense predicts ambiguous (score 0.5379) — an in-silico prediction, not a clinical call.

ATP8A2 p.Arg588Trp

c.1762C>T · VCV4856236

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5379 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4

Computational evidence

Protein change
AlphaMissense	0.5379	ambiguous
REVEL	0.54	indeterminate
SaProt	LLR -14.61	damaging
Splicing
SpliceAI	Δ0.20	donor loss · deltas
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 288 kb · p 5e-12 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,864 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000547% 8/1,461,690 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,250
East Asiangrpmax	0.00223%	44,864
European (non-Finnish)	0.000424%	235,973

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.Arg588Trp
Coding: c.1762C>T
MANE Select: NM_016529
Type: single nucleotide variant
Location: chr13:25577118 (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.Arg588fs Pathogenic/Likely pathogenic ★★ same residue
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
ATP8A2 p.Arg586Ter Pathogenic/Likely pathogenic ★★ same condition
ATP8A2 p.Asp765Tyr Likely pathogenic ★★ same condition
ATP8A2 p.Arg1147Trp Uncertain significance ★★ ⚠ 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-arg588trp (accessed [today's date]).

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