Is ATP2A3 p.Pro500Ser (c.1498C>T) pathogenic?

ATP2A3 p.Pro500Ser (c.1498C>T) is classified Uncertain significance in ATP2A3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-10). AlphaMissense: likely benign (0.1319); Ultra-rare (popmax 0.0387%, afr).

How common is ATP2A3 p.Pro500Ser (c.1498C>T) in the general population?

ATP2A3 p.Pro500Ser (c.1498C>T) is ultra-rare (popmax 0.0387%, afr) (gnomAD).

What do computational predictors say about ATP2A3 p.Pro500Ser (c.1498C>T)?

AlphaMissense predicts likely benign (score 0.1319) — an in-silico prediction, not a clinical call.

ATP2A3 p.Pro500Ser

c.1498C>T · VCV3456540

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1319 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0387%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1319	likely benign
REVEL	0.32	indeterminate
SaProt	LLR -10.89	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.9, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 25 kb · p 1.8e-12 · regional, not allelic
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0387% African / African-American · 29/74,906 alleles

Filtering AF 0.0277% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0239%

Overall 0.00186% 30/1,613,260 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0387%	2,583
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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.Pro500Ser
Coding: c.1498C>T
MANE Select: NM_005173
Type: single nucleotide variant
Location: chr17:3942653 (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-pro500ser (accessed [today's date]).

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