Is AP3D1 p.Arg692Trp (c.2074C>T) pathogenic?

AP3D1 p.Arg692Trp (c.2074C>T) is classified Uncertain significance in AP3D1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-20). AlphaMissense: likely benign (0.1535); Ultra-rare (popmax 0.0112%, eas).

How common is AP3D1 p.Arg692Trp (c.2074C>T) in the general population?

AP3D1 p.Arg692Trp (c.2074C>T) is ultra-rare (popmax 0.0112%, eas) (gnomAD).

What do computational predictors say about AP3D1 p.Arg692Trp (c.2074C>T)?

AlphaMissense predicts likely benign (score 0.1535) — an in-silico prediction, not a clinical call.

AP3D1 p.Arg692Trp

c.2074C>T · rs767508969 · VCV1370148

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1535 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0112%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1535	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -10.15	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -1.1, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 8,543 bp · p 0.28 · regional, not allelic
Overall
CADD	23.9	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 0.0112% East Asian · 5/44,816 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000993% 16/1,611,490 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0112%	8,963
Remaining individualsnot grpmax-eligible	0.00481%	20,795
Finnishnot grpmax-eligible	0.00159%	62,996
African / African-American	0.00134%	74,872
South Asian	0.0011%	91,054
European (non-Finnish)	0.000424%	235,781

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.Arg692Trp
Coding: c.2074C>T
MANE Select: NM_001261826
dbSNP: rs767508969
Type: single nucleotide variant
Location: chr19:2115613 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.45 · 6 PDB
Residue 692: the 'disordered' region

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

Similar variants

AP3D1 p.Arg692= Likely benign ★ 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
AP3D1 p.Ala1213Thr 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-arg692trp (accessed [today's date]).

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