Is AP2B1 p.Pro697Ser (c.2089C>T) pathogenic?

AP2B1 p.Pro697Ser (c.2089C>T) is classified Uncertain significance in AP2B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-10). AlphaMissense: likely benign (0.0805); Very rare (popmax 0.00144%, nfe).

How common is AP2B1 p.Pro697Ser (c.2089C>T) in the general population?

AP2B1 p.Pro697Ser (c.2089C>T) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about AP2B1 p.Pro697Ser (c.2089C>T)?

AlphaMissense predicts likely benign (score 0.0805) — an in-silico prediction, not a clinical call.

AP2B1 p.Pro697Ser

c.2089C>T · rs1476214337 · VCV2295230

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0805 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0805	likely benign
REVEL	0.105	moderately benign-leaning
SaProt	LLR -8.26	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 7.5	GERP 2.4, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 2,482 bp · p 0.0063 · regional, not allelic
Overall
CADD	24.4	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P683S vs ClinVar P697S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00144% European (non-Finnish) · 17/1,179,834 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000718%

Overall 0.00105% 17/1,613,900 alleles · very rare exomes 17/1,461,650 · genomes 0/152,250 · joint denominator

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.Pro697Ser
Coding: c.2089C>T
MANE Select: NM_001030006
dbSNP: rs1476214337
Type: single nucleotide variant
Location: chr17:35671811 (GRCh38)
Gene constraint: LOEUF 0.275 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.48 · 22 PDB

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

Similar variants

AP2B1 p.Pro697Ala Uncertain significance ★ ⚠ same residue
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

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-pro697ser (accessed [today's date]).

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