Is ATP8A2 p.Arg720Ter (c.2158C>T) pathogenic?

ATP8A2 p.Arg720Ter (c.2158C>T) is classified Likely pathogenic in ATP8A2 (ClinVar, Single submitter, 2 submitters; last evaluated 2020-06-09). Very rare (popmax 0.00017%, nfe); Associated with cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4.

What condition is associated with ATP8A2 p.Arg720Ter (c.2158C>T)?

ATP8A2 p.Arg720Ter (c.2158C>T) is associated with cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4 (ClinVar).

How common is ATP8A2 p.Arg720Ter (c.2158C>T) in the general population?

ATP8A2 p.Arg720Ter (c.2158C>T) 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.Arg720Ter

c.2158C>T · rs1566306570 · VCV1029608

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

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	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 24 of 37
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.62	GERP -1.8, phastCons 0.96
Overall
CADD	38.0	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) · 2/1,177,820 alleles

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

Overall 0.000206% 3/1,458,956 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,012
European (non-Finnish)grpmax	0.00017%	588,911

Finnish 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.Arg720Ter
Coding: c.2158C>T
MANE Select: NM_016529
dbSNP: rs1566306570
Type: single nucleotide variant
Location: chr13:25589646 (GRCh38)
Gene constraint: LOEUF 0.728 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 81.12
Residue 720: 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.Arg720Gln Uncertain significance ★★ ⚠ same residue
ATP8A2 p.Arg720Leu Uncertain significance ★ ⚠ 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

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-arg720ter (accessed [today's date]).

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