Is ATP2C2 p.Phe899Cys (c.2696T>G) pathogenic?

ATP2C2 p.Phe899Cys (c.2696T>G) is classified Uncertain significance in ATP2C2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: likely pathogenic (0.9377); Very rare (popmax 0.00267%, afr).

How common is ATP2C2 p.Phe899Cys (c.2696T>G) in the general population?

ATP2C2 p.Phe899Cys (c.2696T>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ATP2C2 p.Phe899Cys (c.2696T>G)?

AlphaMissense predicts likely pathogenic (score 0.9377) — an in-silico prediction, not a clinical call.

ATP2C2 p.Phe899Cys

c.2696T>G · VCV4644279

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9377 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9377	likely pathogenic · top 7% in ATP2C2
REVEL	0.991	strongly pathogenic-leaning
SaProt	LLR -14.66	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 1.59	unconstrained · MANE · 95 kb · p 2.4e-95 · regional, not allelic
Overall
CADD	27.6	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 0.00267% African / African-American · 2/74,914 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000496% 8/1,613,728 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,457
Remaining individualsnot grpmax-eligible	0.0016%	62,470
European (non-Finnish)	0.000424%	235,974

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.Phe899Cys
Coding: c.2696T>G
MANE Select: NM_014861
Type: single nucleotide variant
Location: chr16:84462103 (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-phe899cys (accessed [today's date]).

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