Is ATP8A2 p.Ala554Gly (c.1661C>G) pathogenic?

ATP8A2 p.Ala554Gly (c.1661C>G) is classified Uncertain significance in ATP8A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-02). AlphaMissense: likely benign (0.2124); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ATP8A2 p.Ala554Gly (c.1661C>G)?

ATP8A2 p.Ala554Gly (c.1661C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ATP8A2 p.Ala554Gly (c.1661C>G) in the general population?

ATP8A2 p.Ala554Gly (c.1661C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ATP8A2 p.Ala554Gly (c.1661C>G)?

AlphaMissense predicts likely benign (score 0.2124) — an in-silico prediction, not a clinical call.

ATP8A2 p.Ala554Gly

c.1661C>G · rs1342694245 · VCV2240021

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2124 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2124	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -11.93	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.9, phastCons 0.99
Regional constraint	o/e 0.75	unconstrained · MANE · 288 kb · p 5e-12 · regional, not allelic
Overall
CADD	25.6	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 8.48e-05% European (non-Finnish) · 1/1,179,236 alleles

Overall 6.84e-05% 1/1,460,992 alleles · very rare

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.Ala554Gly
Coding: c.1661C>G
MANE Select: NM_016529
dbSNP: rs1342694245
Type: single nucleotide variant
Location: chr13:25571691 (GRCh38)
Gene constraint: LOEUF 0.728 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 81.12

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.Ala554= Uncertain significance ★ same residue
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

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-ala554gly (accessed [today's date]).

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