Is AP2B1 p.Pro286Leu (c.857C>T) pathogenic?

AP2B1 p.Pro286Leu (c.857C>T) is classified Uncertain significance in AP2B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-03). AlphaMissense: likely pathogenic (0.9726); Very rare (popmax 0.00134%, afr).

How common is AP2B1 p.Pro286Leu (c.857C>T) in the general population?

AP2B1 p.Pro286Leu (c.857C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about AP2B1 p.Pro286Leu (c.857C>T)?

AlphaMissense predicts likely pathogenic (score 0.9726) — an in-silico prediction, not a clinical call.

AP2B1 p.Pro286Leu

c.857C>T · rs1307364903 · VCV2314895

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9726 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9726	likely pathogenic
REVEL	0.486	indeterminate
SaProt	LLR -16.22	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 6	phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 19 kb · p 2e-13 · regional, not allelic
Overall
CADD	24.6	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 0.00134% African / African-American · 1/74,860 alleles

Overall 0.000124% 2/1,613,830 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,860
European (non-Finnish)	8.47e-05%	1,179,980

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: AP2B1
Protein: p.Pro286Leu
Coding: c.857C>T
MANE Select: NM_001030006
dbSNP: rs1307364903
Type: single nucleotide variant
Location: chr17:35626761 (GRCh38)
Gene constraint: LOEUF 0.275 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.48 · 22 PDB
Residue 286: 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-pro286leu (accessed [today's date]).

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