Is ATP2B2 p.Arg739Pro (c.2216G>C) pathogenic?

ATP2B2 p.Arg739Pro (c.2216G>C) is classified Uncertain significance in ATP2B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-29). AlphaMissense: likely pathogenic (0.9998); Very rare (popmax 0.00041%).

How common is ATP2B2 p.Arg739Pro (c.2216G>C) in the general population?

ATP2B2 p.Arg739Pro (c.2216G>C) is very rare (popmax 0.00041%) (gnomAD).

What do computational predictors say about ATP2B2 p.Arg739Pro (c.2216G>C)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

ATP2B2 p.Arg739Pro

c.2216G>C · rs778544762 · VCV2745967

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00041%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic · top 5% in ATP2B2
REVEL	0.955	strongly pathogenic-leaning
SaProt	LLR -15.51	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 7.6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 28 kb · p 6e-17 · regional, not allelic
Overall
CADD	34.0	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

Grpmax group 0.00041%

Overall 0.00041% 6/1,461,656 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00783%	12,769
Remaining individualsnot grpmax-eligible	0.0016%	62,488

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ATP2B2
Protein: p.Arg739Pro
Coding: c.2216G>C
MANE Select: NM_001001331
dbSNP: rs778544762
Type: single nucleotide variant
Location: chr3:10350498 (GRCh38)
Gene constraint: LOEUF 0.19 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.83
Residue 739: a UniProt-annotated variant site (in dfna82)

Full ATP2B2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ATP2B2 c.2136+1G>A Pathogenic/Likely pathogenic ★★ same type
ATP2B2 p.Arg1132Ter Pathogenic/Likely pathogenic ★★ same type
ATP2B2 p.Glu457Lys Likely pathogenic ★★ same type
ATP2B2 p.Gly821Arg Pathogenic ★★ same type
ATP2B2 p.Thr503Met Pathogenic/Likely pathogenic ★★ same type
ATP2B2 c.2316+5G>A Uncertain significance ★★ same type
ATP2B2 c.3420+1998G>T Uncertain significance ★★ same type
ATP2B2 p.Ala135Val 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/atp2b2-p-arg739pro (accessed [today's date]).

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