Is AP4B1 p.Pro280Ser (c.838C>T) pathogenic?

AP4B1 p.Pro280Ser (c.838C>T) is classified Uncertain significance in AP4B1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-30). AlphaMissense: ambiguous (0.3932); Ultra-rare (popmax 0.0571%, sas); Associated with Inborn genetic diseases.

What condition is associated with AP4B1 p.Pro280Ser (c.838C>T)?

AP4B1 p.Pro280Ser (c.838C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AP4B1 p.Pro280Ser (c.838C>T) in the general population?

AP4B1 p.Pro280Ser (c.838C>T) is ultra-rare (popmax 0.0571%, sas) (gnomAD).

What do computational predictors say about AP4B1 p.Pro280Ser (c.838C>T)?

AlphaMissense predicts ambiguous (score 0.3932) — an in-silico prediction, not a clinical call.

AP4B1 p.Pro280Ser

c.838C>T · rs373681764 · VCV434226

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3932 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0571%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3932	ambiguous
REVEL	0.292	indeterminate
SaProt	LLR -8.90	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -0.92, phastCons 0.86
Regional constraint	o/e 1.01	unconstrained · MANE · 9,649 bp · p 0.84 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0571% South Asian · 52/91,090 alleles

Filtering AF 0.0447% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0403%

Overall 0.00427% 69/1,614,050 alleles · ultra-rare exomes 67/1,461,888 · genomes 2/152,162 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0571%	1,752
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)	0.00119%	84,289

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: AP4B1
Protein: p.Pro280Ser
Coding: c.838C>T
MANE Select: NM_001253852
dbSNP: rs373681764
Type: single nucleotide variant
Location: chr1:113900180 (GRCh38)
Gene constraint: LOEUF 0.777 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.56 · 5 PDB

Full AP4B1 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

AP4B1 p.Pro280Arg Uncertain significance ★ ⚠ same residue
AP4B1 c.114-2A>G Pathogenic ★★ same condition
AP4B1 c.470-6T>G Uncertain significance ★★ same condition
AP4B1 p.Ala361Val Uncertain significance ★★ ⚠ same condition
AP4B1 p.Ala83Pro Uncertain significance ★★ ⚠ same condition
AP4B1 p.Arg130Gln Uncertain significance ★★ ⚠ same condition
AP4B1 p.Arg169His Uncertain significance ★★ ⚠ same condition
AP4B1 p.Arg224Cys 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/ap4b1-p-pro280ser (accessed [today's date]).

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