Is AP1B1 p.Ser427Ile (c.1280G>T) pathogenic?

AP1B1 p.Ser427Ile (c.1280G>T) is classified Uncertain significance in AP1B1 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.888); Very rare (popmax 0.00549%, sas).

How common is AP1B1 p.Ser427Ile (c.1280G>T) in the general population?

AP1B1 p.Ser427Ile (c.1280G>T) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about AP1B1 p.Ser427Ile (c.1280G>T)?

AlphaMissense predicts likely pathogenic (score 0.888) — an in-silico prediction, not a clinical call.

AP1B1 p.Ser427Ile

c.1280G>T · rs1183324698 · VCV1049300

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.888 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.888	likely pathogenic
REVEL	0.504	indeterminate
SaProt	LLR -15.08	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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 18 kb · p 1.2e-17 · regional, not allelic
Overall
CADD	25.0	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

Grpmax group 0.00549% South Asian · 5/91,076 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000342% 5/1,461,448 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: AP1B1
Protein: p.Ser427Ile
Coding: c.1280G>T
MANE Select: NM_001127
dbSNP: rs1183324698
Type: single nucleotide variant
Location: chr22:29349375 (GRCh38)
Gene constraint: LOEUF 0.476 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 20 PDB

Full AP1B1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP1B1 p.Asp234Asn Uncertain significance ★★ ⚠ same type
AP1B1 p.Gly568Ser Uncertain significance ★★ ⚠ same type
AP1B1 c.1060-157T>G Benign ★★ same type
AP1B1 c.1156-114A>G Benign ★★ same type
AP1B1 c.143+27C>A Benign ★★ same type
AP1B1 c.1438-174G>A Benign ★★ same type
AP1B1 c.1537-39C>G Benign ★★ same type
AP1B1 c.1537-74A>G Benign ★★ 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/ap1b1-p-ser427ile (accessed [today's date]).

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