Is ATP2A3 p.Pro391Arg (c.1172C>G) pathogenic?

ATP2A3 p.Pro391Arg (c.1172C>G) is classified Uncertain significance in ATP2A3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-24). AlphaMissense: likely pathogenic (0.9178); Absent from gnomAD v4.1.

How common is ATP2A3 p.Pro391Arg (c.1172C>G) in the general population?

ATP2A3 p.Pro391Arg (c.1172C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ATP2A3 p.Pro391Arg (c.1172C>G)?

AlphaMissense predicts likely pathogenic (score 0.9178) — an in-silico prediction, not a clinical call.

ATP2A3 p.Pro391Arg

c.1172C>G · VCV3805743

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9178 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9178	likely pathogenic
REVEL	0.788	moderately pathogenic-leaning
SaProt	LLR -17.07	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 25 kb · p 1.8e-12 · regional, not allelic
Overall
CADD	32.0	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: ATP2A3
Protein: p.Pro391Arg
Coding: c.1172C>G
MANE Select: NM_005173
Type: single nucleotide variant
Location: chr17:3945072 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.75
Residue 391: the 'interaction with phospholamban 1' region

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-pro391arg (accessed [today's date]).

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