Is ATP8A2 p.Pro110Arg (c.329C>G) pathogenic?

ATP8A2 p.Pro110Arg (c.329C>G) is classified Uncertain significance in ATP8A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-09). AlphaMissense: likely pathogenic (0.8263); Ultra-rare (popmax 0.016%, amr).

How common is ATP8A2 p.Pro110Arg (c.329C>G) in the general population?

ATP8A2 p.Pro110Arg (c.329C>G) is ultra-rare (popmax 0.016%, amr) (gnomAD).

What do computational predictors say about ATP8A2 p.Pro110Arg (c.329C>G)?

AlphaMissense predicts likely pathogenic (score 0.8263) — an in-silico prediction, not a clinical call.

ATP8A2 p.Pro110Arg

c.329C>G · rs199883588 · VCV2197331

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8263 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8263	likely pathogenic
REVEL	0.937	strongly pathogenic-leaning
SaProt	LLR -13.67	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 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 179 kb · p 0.05 · regional, not allelic
Overall
CADD	33.0	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 0.016% Admixed American · 9/56,106 alleles

Filtering AF 0.00832% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00624%

Overall 0.000572% 9/1,572,084 alleles · ultra-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.Pro110Arg
Coding: c.329C>G
MANE Select: NM_016529
dbSNP: rs199883588
Type: single nucleotide variant
Location: chr13:25530569 (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

Similar variants

ATP8A2 c.1782+2T>C Pathogenic ★★ same type
ATP8A2 c.2212-1G>C Pathogenic ★★ same type
ATP8A2 c.3272+1G>A Pathogenic/Likely pathogenic ★★ same type
ATP8A2 c.77-2A>G Pathogenic/Likely pathogenic ★★ same type
ATP8A2 p.Arg586Ter Pathogenic/Likely pathogenic ★★ same type
ATP8A2 p.Asp765Tyr Likely pathogenic ★★ same type
ATP8A2 p.Ala1091Val Uncertain significance ★★ ⚠ same type
ATP8A2 p.Ala335Thr Uncertain significance ★★ ⚠ 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/atp8a2-p-pro110arg (accessed [today's date]).

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