Is ATP2A2 p.Met366Val (c.1096A>G) pathogenic?

ATP2A2 p.Met366Val (c.1096A>G) is classified Conflicting classifications of pathogenicity in ATP2A2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-09-01). AlphaMissense: likely benign (0.221); Ultra-rare (popmax 0.0683%, amr); Associated with Inborn genetic diseases.

What condition is associated with ATP2A2 p.Met366Val (c.1096A>G)?

ATP2A2 p.Met366Val (c.1096A>G) is associated with Inborn genetic diseases (ClinVar).

How common is ATP2A2 p.Met366Val (c.1096A>G) in the general population?

ATP2A2 p.Met366Val (c.1096A>G) is ultra-rare (popmax 0.0683%, amr) (gnomAD).

What do computational predictors say about ATP2A2 p.Met366Val (c.1096A>G)?

AlphaMissense predicts likely benign (score 0.221) — an in-silico prediction, not a clinical call.

ATP2A2 p.Met366Val

c.1096A>G · rs199776454 · VCV1049373

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.221 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0683%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.221	likely benign
REVEL	0.366	indeterminate
SaProt	LLR -9.99	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 5,228 bp · p 0.043 · regional, not allelic
Overall
CADD	23.0	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 0.0683% Admixed American · 41/60,022 alleles

Filtering AF 0.0517% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0459%

Overall 0.014% 226/1,610,066 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0683%	1,464
European (non-Finnish)	0.015%	6,646
Remaining individualsnot grpmax-eligible	0.0128%	7,797

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.Met366Val
Coding: c.1096A>G
MANE Select: NM_170665
dbSNP: rs199776454
Type: single nucleotide variant
Location: chr12:110332597 (GRCh38)
Gene constraint: LOEUF 0.205 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.46 · 15 PDB
Residue 366: a β-strand

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-met366val (accessed [today's date]).

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