Is ATP2C2 p.Pro419Arg (c.1256C>G) pathogenic?

ATP2C2 p.Pro419Arg (c.1256C>G) is classified Uncertain significance in ATP2C2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.1733); Ultra-rare (popmax 0.0948%, sas).

How common is ATP2C2 p.Pro419Arg (c.1256C>G) in the general population?

ATP2C2 p.Pro419Arg (c.1256C>G) is ultra-rare (popmax 0.0948%, sas) (gnomAD).

What do computational predictors say about ATP2C2 p.Pro419Arg (c.1256C>G)?

AlphaMissense predicts likely benign (score 0.1733) — an in-silico prediction, not a clinical call.

ATP2C2 p.Pro419Arg

c.1256C>G · VCV4176604

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1733 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0948%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1733	likely benign
REVEL	0.379	indeterminate
SaProt	LLR -11.68	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.59	unconstrained · MANE · 95 kb · p 2.4e-95 · regional, not allelic
Overall
CADD	23.3	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 0.0948% South Asian · 86/90,742 alleles

Filtering AF 0.0785% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0725%

Overall 0.00607% 98/1,613,670 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0948%	1,055
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0112%	8,928
East Asian	0.00223%	44,888
European (non-Finnish)	0.000254%	393,323

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: ATP2C2
Protein: p.Pro419Arg
Coding: c.1256C>G
MANE Select: NM_014861
Type: single nucleotide variant
Location: chr16:84440903 (GRCh38)
Gene constraint: LOEUF 1.712 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 81.13

Full ATP2C2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ATP2C2 p.Ala813Val Uncertain significance ★★ ⚠ same type
ATP2C2 p.Tyr877Ser Uncertain significance ★★ ⚠ same type
ATP2C2 c.2148-9C>G Benign ★★ same type
ATP2C2 c.2334-8C>T Benign ★★ same type
ATP2C2 c.2481+7G>T Benign ★★ same type
ATP2C2 c.2482-19C>G Benign ★★ same type
ATP2C2 c.2482-2A>C Benign ★★ same type
ATP2C2 p.Ala138Thr Benign ★★ 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/atp2c2-p-pro419arg (accessed [today's date]).

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