Is ATP8A2 p.Leu261Phe (c.781C>T) pathogenic?

ATP8A2 p.Leu261Phe (c.781C>T) is classified Uncertain significance in ATP8A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-31). AlphaMissense: likely benign (0.0893); Very rare (popmax 0.00224%, eas).

How common is ATP8A2 p.Leu261Phe (c.781C>T) in the general population?

ATP8A2 p.Leu261Phe (c.781C>T) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about ATP8A2 p.Leu261Phe (c.781C>T)?

AlphaMissense predicts likely benign (score 0.0893) — an in-silico prediction, not a clinical call.

ATP8A2 p.Leu261Phe

c.781C>T · rs1261608142 · VCV2061538

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0893 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0893	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -8.88	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 -0.006	GERP -2.1, phastCons 0.74
Regional constraint	o/e 0.90	unconstrained · MANE · 179 kb · p 0.05 · regional, not allelic
Overall
CADD	16.88	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 0.00224% East Asian · 1/44,638 alleles

Overall 0.00014% 2/1,428,110 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,638
Admixed American	0.00173%	57,928

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.Leu261Phe
Coding: c.781C>T
MANE Select: NM_016529
dbSNP: rs1261608142
Type: single nucleotide variant
Location: chr13:25543292 (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-leu261phe (accessed [today's date]).

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