Is AP2A2 p.Thr89Met (c.266C>T) pathogenic?

AP2A2 p.Thr89Met (c.266C>T) is classified Uncertain significance in AP2A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-11). AlphaMissense: likely pathogenic (0.8083); Very rare (popmax 0.00659%, sas).

How common is AP2A2 p.Thr89Met (c.266C>T) in the general population?

AP2A2 p.Thr89Met (c.266C>T) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about AP2A2 p.Thr89Met (c.266C>T)?

AlphaMissense predicts likely pathogenic (score 0.8083) — an in-silico prediction, not a clinical call.

AP2A2 p.Thr89Met

c.266C>T · VCV3876743

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8083 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8083	likely pathogenic
REVEL	0.331	indeterminate
SaProt	LLR -12.15	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 2, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 22 kb · p 5.3e-10 · regional, not allelic
Overall
CADD	26.7	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 0.00659% South Asian · 6/91,004 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00143% 23/1,613,418 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,167
African / African-American	0.00267%	37,464
East Asian	0.00223%	44,872
European (non-Finnish)	0.00119%	84,259

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: AP2A2
Protein: p.Thr89Met
Coding: c.266C>T
MANE Select: NM_012305
Type: single nucleotide variant
Location: chr11:970298 (GRCh38)
Gene constraint: LOEUF 0.437 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.30

Full AP2A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP2A2 p.Ala136Ser Uncertain significance ★ ⚠ same type
AP2A2 p.Ala136Thr Uncertain significance ★ ⚠ same type
AP2A2 p.Ala168Thr Uncertain significance ★ ⚠ same type
AP2A2 p.Ala274Pro Uncertain significance ★ ⚠ same type
AP2A2 p.Ala304Val Uncertain significance ★ ⚠ same type
AP2A2 p.Ala375Thr Uncertain significance ★ ⚠ same type
AP2A2 p.Ala3Val Uncertain significance ★ ⚠ same type
AP2A2 p.Ala435Val 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/ap2a2-p-thr89met (accessed [today's date]).

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