Is AP2A1 p.Val469Ile (c.1405G>A) pathogenic?

AP2A1 p.Val469Ile (c.1405G>A) is classified Uncertain significance in AP2A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely benign (0.187); Very rare (popmax 0.00203%, nfe).

How common is AP2A1 p.Val469Ile (c.1405G>A) in the general population?

AP2A1 p.Val469Ile (c.1405G>A) is very rare (popmax 0.00203%, nfe) (gnomAD).

What do computational predictors say about AP2A1 p.Val469Ile (c.1405G>A)?

AlphaMissense predicts likely benign (score 0.187) — an in-silico prediction, not a clinical call.

AP2A1 p.Val469Ile

c.1405G>A · VCV4114812

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.187 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00203%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.187	likely benign
REVEL	0.201	benign-leaning
SaProt	LLR -4.09	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 9.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 2,894 bp · p 7.1e-28 · regional, not allelic
Overall
CADD	25.8	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 0.00203% European (non-Finnish) · 24/1,179,794 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00149% 24/1,613,736 alleles · very 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: AP2A1
Protein: p.Val469Ile
Coding: c.1405G>A
MANE Select: NM_130787
Type: single nucleotide variant
Location: chr19:49800100 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.78

Full AP2A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP2A1 c.2115-388C>T Benign ★★ same type
AP2A1 p.Ala365= Benign ★★ same type
AP2A1 c.2114+403C>T Uncertain significance ★ ⚠ same type
AP2A1 c.2115-363G>A Uncertain significance ★ ⚠ same type
AP2A1 c.2115-371C>A Uncertain significance ★ ⚠ same type
AP2A1 c.2115-372G>A Uncertain significance ★ ⚠ same type
AP2A1 c.2115-383T>C Uncertain significance ★ ⚠ same type
AP2A1 c.2115-383T>G 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/ap2a1-p-val469ile (accessed [today's date]).

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