Is AP1B1 p.Pro614Ser (c.1840C>T) pathogenic?

AP1B1 p.Pro614Ser (c.1840C>T) is classified Uncertain significance in AP1B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely benign (0.057); Ultra-rare (popmax 0.0122%, amr); Associated with Inborn genetic diseases.

What condition is associated with AP1B1 p.Pro614Ser (c.1840C>T)?

AP1B1 p.Pro614Ser (c.1840C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AP1B1 p.Pro614Ser (c.1840C>T) in the general population?

AP1B1 p.Pro614Ser (c.1840C>T) is ultra-rare (popmax 0.0122%, amr) (gnomAD).

What do computational predictors say about AP1B1 p.Pro614Ser (c.1840C>T)?

AlphaMissense predicts likely benign (score 0.057) — an in-silico prediction, not a clinical call.

AP1B1 p.Pro614Ser

c.1840C>T · VCV4114101

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.057 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.057	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -6.29	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 1.5	GERP -0.69, phastCons 0.91
Regional constraint	o/e 0.86	unconstrained · MANE · 13 kb · p 0.0016 · regional, not allelic
Overall
CADD	16.85	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 0.0122% Admixed American · 7/57,246 alleles

Filtering AF 0.00727% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00679%

Overall 0.00731% 117/1,600,210 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0122%	8,178
European (non-Finnish)	0.00868%	11,519
Remaining individualsnot grpmax-eligible	0.00806%	12,414
African / African-American	0.00401%	24,959

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.Pro614Ser
Coding: c.1840C>T
MANE Select: NM_001127
Type: single nucleotide variant
Location: chr22:29340814 (GRCh38)
Gene constraint: LOEUF 0.476 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 20 PDB
Residue 614: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AP1B1 p.Asp234Asn Uncertain significance ★★ ⚠ same condition
AP1B1 p.Gly568Ser Uncertain significance ★★ ⚠ same condition
AP1B1 c.2310-3C>G Uncertain significance ★ same condition
AP1B1 p.Ala254Thr Uncertain significance ★ ⚠ same condition
AP1B1 p.Ala352Thr Uncertain significance ★ ⚠ same condition
AP1B1 p.Ala410Thr Uncertain significance ★ ⚠ same condition
AP1B1 p.Ala598Val Uncertain significance ★ ⚠ same condition
AP1B1 p.Ala689Pro Uncertain significance ★ ⚠ same condition

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-pro614ser (accessed [today's date]).

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