Is AP2B1 p.Phe369Cys (c.1106T>G) pathogenic?

AP2B1 p.Phe369Cys (c.1106T>G) is classified Uncertain significance in AP2B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-01). AlphaMissense: likely pathogenic (0.9993); Absent from gnomAD v4.1.

How common is AP2B1 p.Phe369Cys (c.1106T>G) in the general population?

AP2B1 p.Phe369Cys (c.1106T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AP2B1 p.Phe369Cys (c.1106T>G)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

AP2B1 p.Phe369Cys

c.1106T>G · VCV3922495

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic · top 8% in AP2B1
REVEL	0.825	moderately pathogenic-leaning
SaProt	LLR -16.04	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 7.9	phastCons 1
Regional constraint	o/e 0.36	constrained · MANE · 23 kb · p 2e-28 · regional, not allelic
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AP2B1
Protein: p.Phe369Cys
Coding: c.1106T>G
MANE Select: NM_001030006
Type: single nucleotide variant
Location: chr17:35627677 (GRCh38)
Gene constraint: LOEUF 0.275 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.48 · 22 PDB
Residue 369: an α-helix

Full AP2B1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP2B1 p.Leu199= Benign ★★ same type
AP2B1 p.Ala612Thr Uncertain significance ★ ⚠ same type
AP2B1 p.Ala723Val Uncertain significance ★ ⚠ same type
AP2B1 p.Ala77Gly Uncertain significance ★ ⚠ same type
AP2B1 p.Arg746His Uncertain significance ★ ⚠ same type
AP2B1 p.Asn152Ser Uncertain significance ★ ⚠ same type
AP2B1 p.Asn179Asp Uncertain significance ★ ⚠ same type
AP2B1 p.Asn195Ser 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/ap2b1-p-phe369cys (accessed [today's date]).

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