Is ATP2B2 p.Val577Met (c.1729G>A) pathogenic?

ATP2B2 p.Val577Met (c.1729G>A) is classified Uncertain significance in ATP2B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: ambiguous (0.4449); Ultra-rare (popmax 0.0245%, eas).

How common is ATP2B2 p.Val577Met (c.1729G>A) in the general population?

ATP2B2 p.Val577Met (c.1729G>A) is ultra-rare (popmax 0.0245%, eas) (gnomAD).

What do computational predictors say about ATP2B2 p.Val577Met (c.1729G>A)?

AlphaMissense predicts ambiguous (score 0.4449) — an in-silico prediction, not a clinical call.

ATP2B2 p.Val577Met

c.1729G>A · VCV4175997

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4449 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, eas)

Computational evidence

Protein change
AlphaMissense	0.4449	ambiguous
REVEL	0.611	indeterminate
SaProt	LLR -11.80	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP -0.26, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 28 kb · p 6e-17 · regional, not allelic
Overall
CADD	25.0	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 0.0245% East Asian · 11/44,834 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00564% 91/1,612,528 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0245%	4,076
Middle Eastern	0.0165%	6,054
European (non-Finnish)	0.00577%	17,333
South Asian	0.00549%	18,215
African / African-American	0.004%	25,009
Admixed American	0.00333%	30,006
Remaining individualsnot grpmax-eligible	0.0016%	62,428

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.Val577Met
Coding: c.1729G>A
MANE Select: NM_001001331
Type: single nucleotide variant
Location: chr3:10360054 (GRCh38)
Gene constraint: LOEUF 0.19 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.83

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-val577met (accessed [today's date]).

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