Is AP3B2 p.Ala1098Asp (c.3293C>A) pathogenic?

AP3B2 p.Ala1098Asp (c.3293C>A) is classified Uncertain significance in AP3B2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-05). AlphaMissense: ambiguous (0.3774); Rare (popmax 0.103%, amr); Associated with Inborn genetic diseases.

What condition is associated with AP3B2 p.Ala1098Asp (c.3293C>A)?

AP3B2 p.Ala1098Asp (c.3293C>A) is associated with Inborn genetic diseases, developmental and epileptic encephalopathy, 48 (ClinVar).

How common is AP3B2 p.Ala1098Asp (c.3293C>A) in the general population?

AP3B2 p.Ala1098Asp (c.3293C>A) is rare (popmax 0.103%, amr) (gnomAD).

What do computational predictors say about AP3B2 p.Ala1098Asp (c.3293C>A)?

AlphaMissense predicts ambiguous (score 0.3774) — an in-silico prediction, not a clinical call.

AP3B2 p.Ala1098Asp

c.3293C>A · rs188892600 · VCV1031454

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3774 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.103%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3774	ambiguous
REVEL	0.229	benign-leaning
SaProt	LLR -13.71	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 0.55, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 5,925 bp · p 0.51 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A1079D vs ClinVar A1098D) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.103% Admixed American · 62/60,026 alleles

Filtering AF 0.0826% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0752%

Overall 0.00527% 85/1,613,908 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.103%	968
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0144%	6,942
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,868
African / African-American	0.004%	25,015
European (non-Finnish)	0.000593%	168,554

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.Ala1098Asp
Coding: c.3293C>A
MANE Select: NM_001278512
dbSNP: rs188892600
Type: single nucleotide variant
Location: chr15:82659573 (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

Disease context

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

Also linked: developmental and epileptic encephalopathy, 48

Similar variants

AP3B2 p.Arg977Ter Pathogenic ★★ same condition
AP3B2 p.Gln839Ter Pathogenic/Likely pathogenic ★★ same condition
AP3B2 c.1110+3G>C Uncertain significance ★★ same condition
AP3B2 c.2834-3C>A Uncertain significance ★★ same condition
AP3B2 p.Ala1076Pro Uncertain significance ★★ ⚠ same condition
AP3B2 p.Ala4Val Uncertain significance ★★ ⚠ same condition
AP3B2 p.Ala546Pro Uncertain significance ★★ ⚠ same condition
AP3B2 p.Ala633Val 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/ap3b2-p-ala1098asp (accessed [today's date]).

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