Is ATP2C1 p.Phe702= (c.2106C>T) pathogenic?

ATP2C1 p.Phe702= (c.2106C>T) is classified Conflicting classifications of pathogenicity in ATP2C1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-06-02). Very rare (popmax 0.00017%, nfe); Associated with Hailey-Hailey disease.

What condition is associated with ATP2C1 p.Phe702= (c.2106C>T)?

ATP2C1 p.Phe702= (c.2106C>T) is associated with Hailey-Hailey disease (ClinVar).

How common is ATP2C1 p.Phe702= (c.2106C>T) in the general population?

ATP2C1 p.Phe702= (c.2106C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Hailey-Hailey disease inherited?

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

ATP2C1 p.Phe702=

c.2106C>T · rs2062610077 · VCV902444

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

Hailey-Hailey disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.367	indeterminate
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.66	GERP -0.23, phastCons 1
Overall
CADD	12.24	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,177,840 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,459,330 alleles · very rare

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: ATP2C1
Protein: p.Phe702=
Coding: c.2106C>T
MANE Select: NM_001378687
dbSNP: rs2062610077
Type: single nucleotide variant
Location: chr3:130996091 (GRCh38)
Gene constraint: LOEUF 0.402 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.33 · 11 PDB
Residue 702: an α-helix; a UniProt-annotated variant site (in hhd)

Full ATP2C1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Hailey-Hailey disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

ATP2C1 p.Phe702Leu Uncertain significance ★ same residue
ATP2C1 c.1308+1G>T Pathogenic ★★ same condition
ATP2C1 p.Arg799Ter Pathogenic ★★ same condition
ATP2C1 p.Tyr452Ter Pathogenic/Likely pathogenic ★★ same condition
ATP2C1 c.-180-57C>T Uncertain significance ★★ same condition
ATP2C1 p.His394Arg Uncertain significance ★★ ⚠ same condition
ATP2C1 p.Val198Gly Uncertain significance ★★ ⚠ same condition
ATP2C1 c.117+7G>A 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/atp2c1-p-phe702 (accessed [today's date]).

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