Is AP3D1 p.Arg652His (c.1955G>A) pathogenic?

AP3D1 p.Arg652His (c.1955G>A) is classified Conflicting classifications of pathogenicity in AP3D1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-26). AlphaMissense: likely benign (0.0615); Ultra-rare (popmax 0.0135%, eas); Associated with Inborn genetic diseases.

What condition is associated with AP3D1 p.Arg652His (c.1955G>A)?

AP3D1 p.Arg652His (c.1955G>A) is associated with Inborn genetic diseases (ClinVar).

How common is AP3D1 p.Arg652His (c.1955G>A) in the general population?

AP3D1 p.Arg652His (c.1955G>A) is ultra-rare (popmax 0.0135%, eas) (gnomAD).

What do computational predictors say about AP3D1 p.Arg652His (c.1955G>A)?

AlphaMissense predicts likely benign (score 0.0615) — an in-silico prediction, not a clinical call.

AP3D1 p.Arg652His

c.1955G>A · rs764644332 · VCV1911068

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0615 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0135%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0615	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -7.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.78	GERP -2.9, phastCons 0.57
Regional constraint	o/e 1.04	unconstrained · MANE · 8,543 bp · p 0.28 · regional, not allelic
Overall
CADD	9.016	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 0.0135% East Asian · 6/44,528 alleles

Filtering AF 0.00583% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00396%

Overall 0.000873% 14/1,604,268 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0135%	7,421
Admixed American	0.00675%	14,805
African / African-American	0.00134%	74,736
South Asian	0.00112%	89,408
European (non-Finnish)	0.00017%	587,931

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.Arg652His
Coding: c.1955G>A
MANE Select: NM_001261826
dbSNP: rs764644332
Type: single nucleotide variant
Location: chr19:2116651 (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

Disease context

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

Similar variants

AP3D1 p.Arg652= Benign ★★ same residue
AP3D1 p.Arg652Cys Uncertain significance ★ ⚠ same residue
AP3D1 c.856+3G>A Uncertain significance ★★ same condition
AP3D1 p.Ala1076Val Uncertain significance ★★ ⚠ same condition
AP3D1 p.Ala247Val Uncertain significance ★★ ⚠ same condition
AP3D1 p.Ala285Ser Uncertain significance ★★ ⚠ same condition
AP3D1 p.Ala299Thr Uncertain significance ★★ ⚠ same condition
AP3D1 p.Ala438Thr 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/ap3d1-p-arg652his (accessed [today's date]).

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