Is ATP2A2 p.Ala724= (c.2172G>A) pathogenic?

ATP2A2 p.Ala724= (c.2172G>A) is classified Benign in ATP2A2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-25). Common (popmax 7.26%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with Darier disease.

What condition is associated with ATP2A2 p.Ala724= (c.2172G>A)?

ATP2A2 p.Ala724= (c.2172G>A) is associated with Darier disease, acrokeratosis verruciformis (ClinVar).

How is Darier disease inherited?

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

ATP2A2 p.Ala724=

Q: How common is ATP2A2 p.Ala724= (c.2172G>A) in the general population?

ATP2A2 p.Ala724= (c.2172G>A) is common (popmax 7.26%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2172G>A · rs56243033 · VCV307178

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 7.26%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

Darier disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.021	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -16	GERP -5.1
Overall
CADD	0.565	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.26% European (non-Finnish) · 85,705/1,180,024 alleles

Filtering AF 7.22% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.21%

Overall 6.34% 102,391/1,614,176 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	7.48%	13
European (non-Finnish)grpmax	7.26%	14
Amishnot grpmax-eligible	6.15%	16
Remaining individualsnot grpmax-eligible	5.45%	18
South Asian	5.43%	18
Middle Eastern	4.8%	21
Ashkenazi Jewishnot grpmax-eligible	3.09%	32
Admixed American	2.46%	41
African / African-American	1.05%	95
East Asian	0.0401%	2,493

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala724=
Coding: c.2172G>A
MANE Select: NM_170665
dbSNP: rs56243033
Type: single nucleotide variant
Location: chr12:110342302 (GRCh38)
Gene constraint: LOEUF 0.205 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.46 · 15 PDB
Residue 724: an α-helix; 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.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
ATP2A2 c.1287+3A>G 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-ala724 (accessed [today's date]).

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