Is AP3B2 p.Ser33Phe (c.98C>T) pathogenic?

AP3B2 p.Ser33Phe (c.98C>T) is classified Uncertain significance in AP3B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-24). AlphaMissense: likely pathogenic (0.6054); Ultra-rare (popmax 0.0188%, amr).

How common is AP3B2 p.Ser33Phe (c.98C>T) in the general population?

AP3B2 p.Ser33Phe (c.98C>T) is ultra-rare (popmax 0.0188%, amr) (gnomAD).

What do computational predictors say about AP3B2 p.Ser33Phe (c.98C>T)?

AlphaMissense predicts likely pathogenic (score 0.6054) — an in-silico prediction, not a clinical call.

AP3B2 p.Ser33Phe

c.98C>T · rs753249898 · VCV1369791

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6054 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0188%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6054	likely pathogenic
REVEL	0.201	benign-leaning
SaProt	LLR -9.56	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.1, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 29 kb · p 3.5e-16 · regional, not allelic
Overall
CADD	29.4	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 0.0188% Admixed American · 9/47,794 alleles

Filtering AF 0.00982% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00728%

Overall 0.00106% 16/1,512,394 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0188%	5,310
European (non-Finnish)	0.000618%	161,709

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: AP3B2
Protein: p.Ser33Phe
Coding: c.98C>T
MANE Select: NM_001278512
dbSNP: rs753249898
Type: single nucleotide variant
Location: chr15:82709609 (GRCh38)
Gene constraint: LOEUF 0.52 · pLI 0.22 (gnomAD)
Structure: AlphaFold pLDDT 75.73

Full AP3B2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP3B2 p.Ser33= Likely benign ★ same residue
AP3B2 c.114-1G>A Likely pathogenic ★★ same type
AP3B2 p.Arg977Ter Pathogenic ★★ same type
AP3B2 p.Gln839Ter Pathogenic/Likely pathogenic ★★ same type
AP3B2 c.1110+3G>C Uncertain significance ★★ same type
AP3B2 c.1853-5C>A Uncertain significance ★★ same type
AP3B2 c.2834-3C>A Uncertain significance ★★ same type
AP3B2 p.Ala1076Pro 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/ap3b2-p-ser33phe (accessed [today's date]).

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