Is ATP1A2 p.Pro331= (c.993T>G) pathogenic?

ATP1A2 p.Pro331= (c.993T>G) is classified Likely benign in ATP1A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-19). Ultra-rare (popmax 0.0318%, amr); Associated with familial hemiplegic migraine.

What condition is associated with ATP1A2 p.Pro331= (c.993T>G)?

ATP1A2 p.Pro331= (c.993T>G) is associated with familial hemiplegic migraine (ClinVar).

How common is ATP1A2 p.Pro331= (c.993T>G) in the general population?

ATP1A2 p.Pro331= (c.993T>G) is ultra-rare (popmax 0.0318%, amr) (gnomAD).

How is Familial or sporadic hemiplegic migraine inherited?

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

ATP1A2 p.Pro331=

c.993T>G · rs773614984 · VCV529759

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0318%, amr)

Conditions

familial hemiplegic migraine

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.125	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -13	GERP -4.7
Overall
CADD	0.169	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0318% Admixed American · 19/59,782 alleles

Filtering AF 0.0208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00118% 19/1,609,284 alleles · ultra-rare exomes 17/1,457,096 · genomes 2/152,188 · joint denominator

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: ATP1A2
Protein: p.Pro331=
Coding: c.993T>G
MANE Select: NM_000702
dbSNP: rs773614984
Type: single nucleotide variant
Location: chr1:160127796 (GRCh38)
Gene constraint: LOEUF 0.598 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.25

Full ATP1A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial hemiplegic migraine — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial or sporadic hemiplegic migraine (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ATP1A2 p.Pro331Ala Pathogenic ★ same residue
ATP1A2 p.Ala297Thr Pathogenic/Likely pathogenic ★★ same condition
ATP1A2 p.Ala606Thr Pathogenic ★★ same condition
ATP1A2 p.Arg1002Gln Pathogenic/Likely pathogenic ★★ same condition
ATP1A2 p.Arg383His Pathogenic/Likely pathogenic ★★ same condition
ATP1A2 p.Arg412Ter Pathogenic/Likely pathogenic ★★ same condition
ATP1A2 p.Arg421Ter Pathogenic/Likely pathogenic ★★ same condition
ATP1A2 p.Arg493Ter 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/atp1a2-p-pro331 (accessed [today's date]).

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