Is ATP8A2 p.Arg228His (c.683G>A) pathogenic?

ATP8A2 p.Arg228His (c.683G>A) is classified Uncertain significance in ATP8A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-20). AlphaMissense: likely benign (0.1384); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with ATP8A2 p.Arg228His (c.683G>A)?

ATP8A2 p.Arg228His (c.683G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ATP8A2 p.Arg228His (c.683G>A) in the general population?

ATP8A2 p.Arg228His (c.683G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ATP8A2 p.Arg228His (c.683G>A)?

AlphaMissense predicts likely benign (score 0.1384) — an in-silico prediction, not a clinical call.

ATP8A2 p.Arg228His

c.683G>A · VCV3329781

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1384 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1384	likely benign
REVEL	0.261	benign-leaning
SaProt	LLR -6.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP -0.24, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 179 kb · p 0.05 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 · 2/74,892 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00229% 37/1,613,942 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,829
African / African-Americangrpmax	0.00267%	37,446
European (non-Finnish)	0.00237%	42,142
East Asian	0.00223%	44,892
South Asian	0.0022%	45,543
Admixed American	0.00167%	59,988

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg228His
Coding: c.683G>A
MANE Select: NM_016529
Type: single nucleotide variant
Location: chr13:25541950 (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

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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-arg228his (accessed [today's date]).

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