Is ATP1A3 p.Phe90= (c.270C>T) pathogenic?

ATP1A3 p.Phe90= (c.270C>T) is classified Conflicting classifications of pathogenicity in ATP1A3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-01-20). Very rare (popmax 0.000169%, nfe); Associated with alternating hemiplegia of childhood 2.

What condition is associated with ATP1A3 p.Phe90= (c.270C>T)?

ATP1A3 p.Phe90= (c.270C>T) is associated with alternating hemiplegia of childhood 2, dystonia 12 (ClinVar).

How common is ATP1A3 p.Phe90= (c.270C>T) in the general population?

ATP1A3 p.Phe90= (c.270C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is Alternating hemiplegia of childhood inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

ATP1A3 p.Phe90=

c.270C>T · rs782539594 · VCV329429

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

alternating hemiplegia of childhood 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 2, phastCons 1
Overall
CADD	13.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,040 alleles

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

Overall 0.000137% 2/1,461,878 alleles · very 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: ATP1A3
Protein: p.Phe90=
Coding: c.270C>T
MANE Select: NM_152296
dbSNP: rs782539594
Type: single nucleotide variant
Location: chr19:41988023 (GRCh38)
Gene constraint: LOEUF 0.173 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.94 · 17 PDB
Residue 90: an α-helix

Full ATP1A3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

alternating hemiplegia of childhood 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dystonia 12

For Alternating hemiplegia of childhood (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Denmark)

Similar variants

ATP1A3 c.358-1G>A Likely pathogenic ★★ same condition
ATP1A3 p.Ala320Pro Pathogenic/Likely pathogenic ★★ same condition
ATP1A3 p.Arg597His Likely pathogenic ★★ same condition
ATP1A3 p.Arg756Cys Pathogenic/Likely pathogenic ★★ same condition
ATP1A3 p.Arg756His Pathogenic/Likely pathogenic ★★ same condition
ATP1A3 p.Asn773Ser Pathogenic ★★ same condition
ATP1A3 p.Asp609Tyr Pathogenic/Likely pathogenic ★★ same condition
ATP1A3 p.Asp742Tyr 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/atp1a3-p-phe90 (accessed [today's date]).

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