Is ATP2A2 p.Ala726Val (c.2177C>T) pathogenic?

ATP2A2 p.Ala726Val (c.2177C>T) is classified Uncertain significance in ATP2A2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-05-07). AlphaMissense: likely pathogenic (0.99); Absent from gnomAD v4.1; Associated with ATP2A2-related disorder.

What condition is associated with ATP2A2 p.Ala726Val (c.2177C>T)?

ATP2A2 p.Ala726Val (c.2177C>T) is associated with ATP2A2-related disorder (ClinVar).

How common is ATP2A2 p.Ala726Val (c.2177C>T) in the general population?

ATP2A2 p.Ala726Val (c.2177C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ATP2A2 p.Ala726Val (c.2177C>T)?

AlphaMissense predicts likely pathogenic (score 0.99) — an in-silico prediction, not a clinical call.

ATP2A2 p.Ala726Val

c.2177C>T · VCV3353752

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.99 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ATP2A2-related disorder

Computational evidence

Protein change
AlphaMissense	0.99	likely pathogenic
REVEL	0.892	moderately pathogenic-leaning
SaProt	LLR -15.55	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.28	constrained · MANE · 2,423 bp · p 1.4e-21 · regional, not allelic
Overall
CADD	28.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ATP2A2
Protein: p.Ala726Val
Coding: c.2177C>T
MANE Select: NM_170665
Type: single nucleotide variant
Location: chr12:110342307 (GRCh38)
Gene constraint: LOEUF 0.205 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.46 · 15 PDB
Residue 726: an α-helix; a UniProt-annotated variant site (in dd)

Full ATP2A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ATP2A2-related disorder

Similar variants

ATP2A2 p.Ala803Thr Pathogenic/Likely pathogenic ★★ same condition
ATP2A2 p.Asn767Ser Pathogenic/Likely pathogenic ★★ same condition
ATP2A2 p.Ile348Thr Pathogenic/Likely pathogenic ★★ same condition
ATP2A2 p.Met1Leu Pathogenic ★★ same condition
ATP2A2 c.118+2T>C Likely pathogenic ★ same condition
ATP2A2 p.Arg559Ter Pathogenic ★ same condition
ATP2A2 p.Arg677Ter Pathogenic ★ same condition
ATP2A2 p.Cys268Phe 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/atp2a2-p-ala726val (accessed [today's date]).

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