Is ATP8A2 p.Ala1069Ser (c.3205G>T) pathogenic?

ATP8A2 p.Ala1069Ser (c.3205G>T) is classified Uncertain significance in ATP8A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-02). AlphaMissense: likely benign (0.0846); Ultra-rare (popmax 0.0117%, amr).

How common is ATP8A2 p.Ala1069Ser (c.3205G>T) in the general population?

ATP8A2 p.Ala1069Ser (c.3205G>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about ATP8A2 p.Ala1069Ser (c.3205G>T)?

AlphaMissense predicts likely benign (score 0.0846) — an in-silico prediction, not a clinical call.

ATP8A2 p.Ala1069Ser

c.3205G>T · rs2296242 · VCV1405628

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0846 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0846	likely benign
REVEL	0.255	benign-leaning
SaProt	LLR -6.51	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 4.4	GERP -1.1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 180 kb · p 0.34 · regional, not allelic
Overall
CADD	18.58	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 0.0117% Admixed American · 7/60,002 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000434% 7/1,613,718 alleles · ultra-rare

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.Ala1069Ser
Coding: c.3205G>T
MANE Select: NM_016529
dbSNP: rs2296242
Type: single nucleotide variant
Location: chr13:25961596 (GRCh38)
Gene constraint: LOEUF 0.728 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 81.12
Residue 1069: a UniProt-annotated variant site (in camrq4; uncertain significance); a UniProt-annotated variant site (in)

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

Similar variants

ATP8A2 p.Ala1069Thr Benign ★ same residue
ATP8A2 c.1782+2T>C Pathogenic ★★ same type
ATP8A2 c.2212-1G>C Pathogenic ★★ same type
ATP8A2 c.3272+1G>A Pathogenic/Likely pathogenic ★★ same type
ATP8A2 c.77-2A>G Pathogenic/Likely pathogenic ★★ same type
ATP8A2 p.Arg586Ter Pathogenic/Likely pathogenic ★★ same type
ATP8A2 p.Asp765Tyr Likely pathogenic ★★ same type
ATP8A2 p.Ala1091Val Uncertain significance ★★ ⚠ same type

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-ala1069ser (accessed [today's date]).

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