Is AP3D1 p.Pro1053Arg (c.3158C>G) pathogenic?

AP3D1 p.Pro1053Arg (c.3158C>G) is classified Uncertain significance in AP3D1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-31). AlphaMissense: ambiguous (0.3807); Ultra-rare (popmax 0.0167%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AP3D1 p.Pro1053Arg (c.3158C>G)?

AP3D1 p.Pro1053Arg (c.3158C>G) is associated with Inborn genetic diseases (ClinVar).

How common is AP3D1 p.Pro1053Arg (c.3158C>G) in the general population?

AP3D1 p.Pro1053Arg (c.3158C>G) is ultra-rare (popmax 0.0167%, nfe) (gnomAD).

What do computational predictors say about AP3D1 p.Pro1053Arg (c.3158C>G)?

AlphaMissense predicts ambiguous (score 0.3807) — an in-silico prediction, not a clinical call.

AP3D1 p.Pro1053Arg

c.3158C>G · rs201595321 · VCV1426228

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3807 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3807	ambiguous
REVEL	0.576	indeterminate
SaProt	LLR -9.16	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 8,543 bp · p 0.28 · regional, not allelic
Overall
CADD	29.7	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 P991R vs ClinVar P1053R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% European (non-Finnish) · 196/1,176,504 alleles

Filtering AF 0.0147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.014%

Overall 0.013% 209/1,603,680 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0178%	5,633
European (non-Finnish)grpmax	0.0167%	6,003
Admixed American	0.00339%	29,527

Remaining individuals 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.Pro1053Arg
Coding: c.3158C>G
MANE Select: NM_001261826
dbSNP: rs201595321
Type: single nucleotide variant
Location: chr19:2110724 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.45 · 6 PDB

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.Pro1053Leu 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
AP3D1 p.Ala450Thr 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-pro1053arg (accessed [today's date]).

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