Is AP3D1 p.Glu663= (c.1989A>G) pathogenic?

AP3D1 p.Glu663= (c.1989A>G) is classified Benign in AP3D1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-01). Low-frequency (popmax 2.1%, afr).

How common is AP3D1 p.Glu663= (c.1989A>G) in the general population?

AP3D1 p.Glu663= (c.1989A>G) is low-frequency (popmax 2.1%, afr) (gnomAD).

AP3D1 p.Glu663=

c.1989A>G · rs73512353 · VCV721043

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.1%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.5	GERP -2.5, phastCons 0.027
Overall
CADD	3.326	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.1% African / African-American · 1,569/74,648 alleles

Filtering AF 2.02% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.98%

Overall 0.118% 1,884/1,596,152 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.1%	48
Middle Eastern	0.226%	443
Admixed American	0.183%	546
Remaining individualsnot grpmax-eligible	0.161%	622
European (non-Finnish)	0.00793%	12,603
South Asian	0.00452%	22,143

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: AP3D1
Protein: p.Glu663=
Coding: c.1989A>G
MANE Select: NM_001261826
dbSNP: rs73512353
Type: single nucleotide variant
Location: chr19:2116617 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.45 · 6 PDB
Residue 663: the 'disordered' region

Full AP3D1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP3D1 p.Glu663Lys Uncertain significance ★ ⚠ same residue
AP3D1 c.2001+6C>T Uncertain significance ★★ same type
AP3D1 c.2601+6G>T Uncertain significance ★★ same type
AP3D1 c.856+3G>A Uncertain significance ★★ same type
AP3D1 p.Ala1076Val Uncertain significance ★★ ⚠ same type
AP3D1 p.Ala1093Val Uncertain significance ★★ ⚠ same type
AP3D1 p.Ala1148Val Uncertain significance ★★ ⚠ same type
AP3D1 p.Ala1213Thr 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/ap3d1-p-glu663 (accessed [today's date]).

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