Is AP3D1 p.Arg652= (c.1956T>C) pathogenic?

AP3D1 p.Arg652= (c.1956T>C) is classified Benign in AP3D1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 22.5%, eas) — too common for a highly-penetrant pathogenic allele.

AP3D1 p.Arg652=

Q: How common is AP3D1 p.Arg652= (c.1956T>C) in the general population?

AP3D1 p.Arg652= (c.1956T>C) is common (popmax 22.5%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1956T>C · rs2074960 · VCV1169443

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 22.5%, eas) — too common for a highly-penetrant pathogenic allele

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 -10	GERP -3.1
Overall
CADD	0.021	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 22.5% East Asian · 9,978/44,442 alleles

Filtering AF 22.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 21.9%

Overall 20.6% 329,611/1,602,452 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	25.6%	4
East Asiangrpmax	22.5%	4
European (non-Finnish)	21%	5
Ashkenazi Jewishnot grpmax-eligible	20.8%	5
South Asian	20.5%	5
Remaining individualsnot grpmax-eligible	20.1%	5
Amishnot grpmax-eligible	17.2%	6
Middle Eastern	16.8%	6
African / African-American	14.6%	7
Admixed American	12.9%	8

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg652=
Coding: c.1956T>C
MANE Select: NM_001261826
dbSNP: rs2074960
Type: single nucleotide variant
Location: chr19:2116650 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.45 · 6 PDB
Residue 652: the 'disordered' region

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

Similar variants

AP3D1 p.Arg652Cys Uncertain significance ★ ⚠ same residue
AP3D1 p.Arg652His Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg652 (accessed [today's date]).

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