Is AP3D1 p.Gln474His (c.1422G>T) pathogenic?

AP3D1 p.Gln474His (c.1422G>T) is classified Uncertain significance in AP3D1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely benign (0.1731); Very rare (popmax 0.00891%, eas).

How common is AP3D1 p.Gln474His (c.1422G>T) in the general population?

AP3D1 p.Gln474His (c.1422G>T) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about AP3D1 p.Gln474His (c.1422G>T)?

AlphaMissense predicts likely benign (score 0.1731) — an in-silico prediction, not a clinical call.

AP3D1 p.Gln474His

c.1422G>T · rs372300803 · VCV1366899

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1731 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1731	likely benign
REVEL	0.139	moderately benign-leaning
SaProt	LLR -6.59	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 1	GERP -1.1, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 4,612 bp · p 7.4e-05 · regional, not allelic
Overall
CADD	17.97	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 0.00891% East Asian · 4/44,896 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000621% 10/1,611,576 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,224
South Asian	0.00659%	15,182

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.Gln474His
Coding: c.1422G>T
MANE Select: NM_001261826
dbSNP: rs372300803
Type: single nucleotide variant
Location: chr19:2120921 (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

Similar variants

AP3D1 p.Gln474Arg Uncertain significance ★★ ⚠ 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-gln474his (accessed [today's date]).

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