Is ATP8A2 p.Cys747Arg (c.2239T>C) pathogenic?

ATP8A2 p.Cys747Arg (c.2239T>C) is classified Uncertain significance in ATP8A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-12-02). AlphaMissense: ambiguous (0.5489); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with ATP8A2 p.Cys747Arg (c.2239T>C)?

ATP8A2 p.Cys747Arg (c.2239T>C) is associated with Inborn genetic diseases (ClinVar).

How common is ATP8A2 p.Cys747Arg (c.2239T>C) in the general population?

ATP8A2 p.Cys747Arg (c.2239T>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about ATP8A2 p.Cys747Arg (c.2239T>C)?

AlphaMissense predicts ambiguous (score 0.5489) — an in-silico prediction, not a clinical call.

ATP8A2 p.Cys747Arg

c.2239T>C · rs1292589928 · VCV2225218

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5489 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5489	ambiguous
REVEL	0.496	indeterminate
SaProt	LLR -7.66	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 288 kb · p 5e-12 · regional, not allelic
Overall
CADD	24.6	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 0.00134% African / African-American · 1/74,862 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000435% 7/1,610,196 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,862
European (non-Finnish)	0.000509%	196,358

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: ATP8A2
Protein: p.Cys747Arg
Coding: c.2239T>C
MANE Select: NM_016529
dbSNP: rs1292589928
Type: single nucleotide variant
Location: chr13:25699200 (GRCh38)
Gene constraint: LOEUF 0.728 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 81.12
Residue 747: a UniProt-annotated variant site (in camrq4; uncertain significance)

Full ATP8A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ATP8A2 p.Ala335Thr Uncertain significance ★★ ⚠ same condition
ATP8A2 p.Ala692Ser Uncertain significance ★★ ⚠ same condition
ATP8A2 p.Ala761Val Uncertain significance ★★ ⚠ same condition
ATP8A2 p.Ala853Thr Uncertain significance ★★ ⚠ same condition
ATP8A2 p.Arg1120Trp Uncertain significance ★★ ⚠ same condition
ATP8A2 p.Arg1147Trp Uncertain significance ★★ ⚠ same condition
ATP8A2 p.Asn61Lys Uncertain significance ★★ ⚠ same condition
ATP8A2 p.Asp474Tyr Uncertain significance ★★ ⚠ 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/atp8a2-p-cys747arg (accessed [today's date]).

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