Is ATP8A2 p.Ile136Ser (c.407T>G) pathogenic?

ATP8A2 p.Ile136Ser (c.407T>G) is classified Uncertain significance in ATP8A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-05). AlphaMissense: ambiguous (0.4427); Very rare (popmax 0.00484%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ATP8A2 p.Ile136Ser (c.407T>G)?

ATP8A2 p.Ile136Ser (c.407T>G) is associated with Inborn genetic diseases (ClinVar).

How common is ATP8A2 p.Ile136Ser (c.407T>G) in the general population?

ATP8A2 p.Ile136Ser (c.407T>G) is very rare (popmax 0.00484%, nfe) (gnomAD).

What do computational predictors say about ATP8A2 p.Ile136Ser (c.407T>G)?

AlphaMissense predicts ambiguous (score 0.4427) — an in-silico prediction, not a clinical call.

ATP8A2 p.Ile136Ser

c.407T>G · rs756242481 · VCV2201206

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4427 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00484%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4427	ambiguous
REVEL	0.935	strongly pathogenic-leaning
SaProt	LLR -7.19	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 179 kb · p 0.05 · regional, not allelic
Overall
CADD	25.0	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 0.00484% European (non-Finnish) · 56/1,157,972 alleles

Filtering AF 0.00382% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00343%

Overall 0.00373% 59/1,581,516 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00484%	20,678
African / African-American	0.00269%	37,218
Remaining individualsnot grpmax-eligible	0.00163%	61,194

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.Ile136Ser
Coding: c.407T>G
MANE Select: NM_016529
dbSNP: rs756242481
Type: single nucleotide variant
Location: chr13:25530647 (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-ile136ser (accessed [today's date]).

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