Is ATP2A2 p.Arg677Pro (c.2030G>C) pathogenic?

ATP2A2 p.Arg677Pro (c.2030G>C) is classified Uncertain significance in ATP2A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-21). AlphaMissense: likely pathogenic (0.9994); Absent from gnomAD v4.1; Associated with Darier disease.

What condition is associated with ATP2A2 p.Arg677Pro (c.2030G>C)?

ATP2A2 p.Arg677Pro (c.2030G>C) is associated with Darier disease, acrokeratosis verruciformis (ClinVar).

How common is ATP2A2 p.Arg677Pro (c.2030G>C) in the general population?

ATP2A2 p.Arg677Pro (c.2030G>C) is absent from gnomAD v4.1 (gnomAD).

How is Darier disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ATP2A2 p.Arg677Pro (c.2030G>C)?

AlphaMissense predicts likely pathogenic (score 0.9994) — an in-silico prediction, not a clinical call.

ATP2A2 p.Arg677Pro

c.2030G>C · rs1879294675 · VCV1342440

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9994 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Darier disease

Computational evidence

Protein change
AlphaMissense	0.9994	likely pathogenic · top 4% in ATP2A2
REVEL	0.941	strongly pathogenic-leaning
SaProt	LLR -15.93	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 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.28	constrained · MANE · 2,423 bp · p 1.4e-21 · 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ATP2A2
Protein: p.Arg677Pro
Coding: c.2030G>C
MANE Select: NM_170665
dbSNP: rs1879294675
Type: single nucleotide variant
Location: chr12:110340927 (GRCh38)
Gene constraint: LOEUF 0.205 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.46 · 15 PDB
Residue 677: a β-strand; a binding site; a UniProt-annotated variant site (in dd)

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

Disease context

Darier disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acrokeratosis verruciformis

For Darier disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (United Kingdom)

Similar variants

ATP2A2 p.Arg677Ter Pathogenic ★ same residue
ATP2A2 p.Asn767Ser Pathogenic/Likely pathogenic ★★ same condition
ATP2A2 p.Asp702Asn Pathogenic ★★ same condition
ATP2A2 p.Pro602Leu Pathogenic ★★ same condition
ATP2A2 p.Leu942Phe Uncertain significance ★★ ⚠ same condition
ATP2A2 p.Lys169Arg Uncertain significance ★★ ⚠ same condition
ATP2A2 p.Val933Met Uncertain significance ★★ ⚠ same condition
ATP2A2 c.1096-16C>T Benign/Likely benign ★★ 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-arg677pro (accessed [today's date]).

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