Is ATP8A2 p.Ile21Val (c.61A>G) pathogenic?

ATP8A2 p.Ile21Val (c.61A>G) is classified Uncertain significance in ATP8A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-18). AlphaMissense: likely benign (0.0788); Very rare (popmax 0.00839%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ATP8A2 p.Ile21Val (c.61A>G)?

ATP8A2 p.Ile21Val (c.61A>G) is associated with Inborn genetic diseases (ClinVar).

How common is ATP8A2 p.Ile21Val (c.61A>G) in the general population?

ATP8A2 p.Ile21Val (c.61A>G) is very rare (popmax 0.00839%, nfe) (gnomAD).

What do computational predictors say about ATP8A2 p.Ile21Val (c.61A>G)?

AlphaMissense predicts likely benign (score 0.0788) — an in-silico prediction, not a clinical call.

ATP8A2 p.Ile21Val

c.61A>G · VCV3974044

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0788 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00839%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0788	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -5.60	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 2.8	GERP -0.21, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 179 kb · p 0.05 · regional, not allelic
Overall
CADD	15.55	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 0.00839% European (non-Finnish) · 93/1,108,236 alleles

Filtering AF 0.00698% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00648%

Overall 0.00652% 96/1,472,580 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00839%	11,917
Remaining individualsnot grpmax-eligible	0.00538%	18,583

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.Ile21Val
Coding: c.61A>G
MANE Select: NM_016529
Type: single nucleotide variant
Location: chr13:25372273 (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.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-ile21val (accessed [today's date]).

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