Is ATP2C2 p.Ala331Pro (c.991G>C) pathogenic?

ATP2C2 p.Ala331Pro (c.991G>C) is classified Uncertain significance in ATP2C2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-15). AlphaMissense: likely pathogenic (0.9778); Very rare (popmax 8.47e-05%, nfe).

How common is ATP2C2 p.Ala331Pro (c.991G>C) in the general population?

ATP2C2 p.Ala331Pro (c.991G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ATP2C2 p.Ala331Pro (c.991G>C)?

AlphaMissense predicts likely pathogenic (score 0.9778) — an in-silico prediction, not a clinical call.

ATP2C2 p.Ala331Pro

c.991G>C · rs2507339912 · VCV2261222

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9778 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9778	likely pathogenic · top 2% in ATP2C2
REVEL	0.865	moderately pathogenic-leaning
SaProt	LLR -17.00	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 1.59	unconstrained · MANE · 95 kb · p 2.4e-95 · regional, not allelic
Overall
CADD	28.8	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,012 alleles

Overall 6.2e-05% 1/1,612,186 alleles · very rare exomes 1/1,459,880 · genomes 0/152,306 · joint denominator

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.Ala331Pro
Coding: c.991G>C
MANE Select: NM_014861
dbSNP: rs2507339912
Type: single nucleotide variant
Location: chr16:84439170 (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-ala331pro (accessed [today's date]).

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