Is ATP2C2 p.Val147Ala (c.440T>C) pathogenic?

ATP2C2 p.Val147Ala (c.440T>C) is classified Uncertain significance in ATP2C2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-08). AlphaMissense: ambiguous (0.4432); Very rare (popmax 0.00517%, nfe).

How common is ATP2C2 p.Val147Ala (c.440T>C) in the general population?

ATP2C2 p.Val147Ala (c.440T>C) is very rare (popmax 0.00517%, nfe) (gnomAD).

What do computational predictors say about ATP2C2 p.Val147Ala (c.440T>C)?

AlphaMissense predicts ambiguous (score 0.4432) — an in-silico prediction, not a clinical call.

ATP2C2 p.Val147Ala

c.440T>C · rs374685827 · VCV2405353

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4432 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00517%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4432	ambiguous
REVEL	0.634	indeterminate
SaProt	LLR -10.80	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.5, phastCons 1
Regional constraint	o/e 1.59	unconstrained · MANE · 95 kb · p 2.4e-95 · regional, not allelic
Overall
CADD	22.4	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 0.00517% European (non-Finnish) · 61/1,180,016 alleles

Filtering AF 0.0041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.00403% 65/1,614,018 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00517%	19,345
Remaining individualsnot grpmax-eligible	0.0048%	20,826
Admixed American	0.00167%	60,002

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.Val147Ala
Coding: c.440T>C
MANE Select: NM_014861
dbSNP: rs374685827
Type: single nucleotide variant
Location: chr16:84410590 (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-val147ala (accessed [today's date]).

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