Is ATP8A2 p.Pro492Ala (c.1474C>G) pathogenic?

ATP8A2 p.Pro492Ala (c.1474C>G) is classified Uncertain significance in ATP8A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-31). AlphaMissense: likely benign (0.1146); Very rare (popmax 0.00267%, afr); Associated with cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4.

What condition is associated with ATP8A2 p.Pro492Ala (c.1474C>G)?

ATP8A2 p.Pro492Ala (c.1474C>G) is associated with cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4 (ClinVar).

How common is ATP8A2 p.Pro492Ala (c.1474C>G) in the general population?

ATP8A2 p.Pro492Ala (c.1474C>G) is very rare (popmax 0.00267%, afr) (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.Pro492Ala (c.1474C>G)?

AlphaMissense predicts likely benign (score 0.1146) — an in-silico prediction, not a clinical call.

ATP8A2 p.Pro492Ala

c.1474C>G · rs1015253382 · VCV2439398

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1146 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4

Computational evidence

Protein change
AlphaMissense	0.1146	likely benign
REVEL	0.217	benign-leaning
SaProt	LLR -8.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 288 kb · p 5e-12 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,880 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,612,068 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,440
South Asian	0.0011%	90,838

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.Pro492Ala
Coding: c.1474C>G
MANE Select: NM_016529
dbSNP: rs1015253382
Type: single nucleotide variant
Location: chr13:25570767 (GRCh38)
Gene constraint: LOEUF 0.728 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 81.12

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 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
ATP8A2 p.Arg659Gln 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-pro492ala (accessed [today's date]).

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