Is ATP2A3 p.Ala652Pro (c.1954G>C) pathogenic?

ATP2A3 p.Ala652Pro (c.1954G>C) is classified Uncertain significance in ATP2A3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-08). AlphaMissense: likely pathogenic (0.8936); Very rare (popmax 0.000254%, nfe).

How common is ATP2A3 p.Ala652Pro (c.1954G>C) in the general population?

ATP2A3 p.Ala652Pro (c.1954G>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about ATP2A3 p.Ala652Pro (c.1954G>C)?

AlphaMissense predicts likely pathogenic (score 0.8936) — an in-silico prediction, not a clinical call.

ATP2A3 p.Ala652Pro

c.1954G>C · VCV4175889

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8936 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8936	likely pathogenic
REVEL	0.936	strongly pathogenic-leaning
SaProt	LLR -12.90	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 25 kb · p 1.8e-12 · regional, not allelic
Overall
CADD	29.6	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

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,990 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,936 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: ATP2A3
Protein: p.Ala652Pro
Coding: c.1954G>C
MANE Select: NM_005173
Type: single nucleotide variant
Location: chr17:3941117 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.75

Full ATP2A3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ATP2A3 c.2525-6C>G Likely benign ★★ same type
ATP2A3 p.Ala299= Likely benign ★★ same type
ATP2A3 p.Arg491= Benign ★★ same type
ATP2A3 p.Arg560= Benign/Likely benign ★★ same type
ATP2A3 p.Arg674Cys Likely benign ★★ ⚠ same type
ATP2A3 p.Ile716= Benign/Likely benign ★★ same type
ATP2A3 p.Ser877= Benign ★★ same type
ATP2A3 c.2611-1G>C 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/atp2a3-p-ala652pro (accessed [today's date]).

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