Is ATP2A2 p.Pro993Ser (c.2977C>T) pathogenic?

ATP2A2 p.Pro993Ser (c.2977C>T) is classified Uncertain significance in ATP2A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-09). AlphaMissense: likely benign (0.0999); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with ATP2A2 p.Pro993Ser (c.2977C>T)?

ATP2A2 p.Pro993Ser (c.2977C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ATP2A2 p.Pro993Ser (c.2977C>T) in the general population?

ATP2A2 p.Pro993Ser (c.2977C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about ATP2A2 p.Pro993Ser (c.2977C>T)?

AlphaMissense predicts likely benign (score 0.0999) — an in-silico prediction, not a clinical call.

ATP2A2 p.Pro993Ser

c.2977C>T · VCV3971312

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0999 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0999	likely benign
REVEL	0.199	benign-leaning
SaProt	LLR -5.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 2,986 bp · p 3.1e-14 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00134% African / African-American · 1/74,904 alleles

Overall 6.2e-05% 1/1,614,018 alleles · very rare exomes 0/1,461,892 · genomes 1/152,126 · joint denominator

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: ATP2A2
Protein: p.Pro993Ser
Coding: c.2977C>T
MANE Select: NM_170665
Type: single nucleotide variant
Location: chr12:110346318 (GRCh38)
Gene constraint: LOEUF 0.205 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.46 · 15 PDB
Residue 993: the 'interaction with tmem64 and pdia3' region; a UniProt-annotated variant site (in dd)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ATP2A2 p.Leu942Phe Uncertain significance ★★ ⚠ same condition
ATP2A2 p.Ala899= Likely benign ★★ same condition
ATP2A2 p.Asn661= Likely benign ★★ same condition
ATP2A2 p.Ile103Val Likely benign ★★ same condition
ATP2A2 c.1761+6C>T Uncertain significance ★ same condition
ATP2A2 p.Ala216Ser Uncertain significance ★ ⚠ same condition
ATP2A2 p.Arg139Gln Uncertain significance ★ ⚠ same condition
ATP2A2 p.Arg619Gln Uncertain significance ★ ⚠ 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-pro993ser (accessed [today's date]).

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