Is AP3D1 p.Arg755Cys (c.2263C>T) pathogenic?

AP3D1 p.Arg755Cys (c.2263C>T) is classified Conflicting classifications of pathogenicity in AP3D1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-11). AlphaMissense: likely benign (0.109); Ultra-rare (popmax 0.0231%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AP3D1 p.Arg755Cys (c.2263C>T)?

AP3D1 p.Arg755Cys (c.2263C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AP3D1 p.Arg755Cys (c.2263C>T) in the general population?

AP3D1 p.Arg755Cys (c.2263C>T) is ultra-rare (popmax 0.0231%, nfe) (gnomAD).

What do computational predictors say about AP3D1 p.Arg755Cys (c.2263C>T)?

AlphaMissense predicts likely benign (score 0.109) — an in-silico prediction, not a clinical call.

AP3D1 p.Arg755Cys

c.2263C>T · rs200458511 · VCV1514952

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.109 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0231%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.109	likely benign
REVEL	0.411	indeterminate
SaProt	LLR -11.39	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 8,543 bp · p 0.28 · regional, not allelic
Overall
CADD	26.7	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 0.0231% European (non-Finnish) · 272/1,179,974 alleles

Filtering AF 0.0208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0199%

Overall 0.018% 291/1,612,652 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0231%	4,338
Remaining individualsnot grpmax-eligible	0.016%	6,249
African / African-American	0.00799%	12,511
East Asian	0.00223%	44,884
Admixed American	0.00167%	60,030
South Asian	0.0011%	91,088

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.Arg755Cys
Coding: c.2263C>T
MANE Select: NM_001261826
dbSNP: rs200458511
Type: single nucleotide variant
Location: chr19:2115305 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.45 · 6 PDB
Residue 755: 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.Arg755His Uncertain significance ★ ⚠ same residue
AP3D1 p.Arg755Pro 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-arg755cys (accessed [today's date]).

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