Is AP3D1 p.Pro697Leu (c.2090C>T) pathogenic?

AP3D1 p.Pro697Leu (c.2090C>T) is classified Uncertain significance in AP3D1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-18). AlphaMissense: likely benign (0.0883); Ultra-rare (popmax 0.0692%, sas); Associated with Inborn genetic diseases.

What condition is associated with AP3D1 p.Pro697Leu (c.2090C>T)?

AP3D1 p.Pro697Leu (c.2090C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AP3D1 p.Pro697Leu (c.2090C>T) in the general population?

AP3D1 p.Pro697Leu (c.2090C>T) is ultra-rare (popmax 0.0692%, sas) (gnomAD).

What do computational predictors say about AP3D1 p.Pro697Leu (c.2090C>T)?

AlphaMissense predicts likely benign (score 0.0883) — an in-silico prediction, not a clinical call.

AP3D1 p.Pro697Leu

c.2090C>T · rs140741000 · VCV1375601

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0883 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0692%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0883	likely benign
REVEL	0.346	indeterminate
SaProt	LLR -6.78	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.4, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 8,543 bp · p 0.28 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0692% South Asian · 63/91,082 alleles

Filtering AF 0.0554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0505%

Overall 0.0149% 240/1,612,826 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0692%	1,446
Middle Eastern	0.0495%	2,019
Remaining individualsnot grpmax-eligible	0.0144%	6,942
European (non-Finnish)	0.0136%	7,373
Admixed American	0.00333%	30,001
Finnishnot grpmax-eligible	0.00316%	31,606
African / African-American	0.00133%	75,038

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.Pro697Leu
Coding: c.2090C>T
MANE Select: NM_001261826
dbSNP: rs140741000
Type: single nucleotide variant
Location: chr19:2115597 (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.Pro697Thr Uncertain significance ★ ⚠ same residue
AP3D1 p.Pro697= Likely benign ★ 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-pro697leu (accessed [today's date]).

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