Is AP3D1 p.Ala455Thr (c.1363G>A) pathogenic?

AP3D1 p.Ala455Thr (c.1363G>A) is classified Uncertain significance in AP3D1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.2982); Rare (popmax 0.108%, nfe); Associated with Hermansky-Pudlak syndrome 10.

What condition is associated with AP3D1 p.Ala455Thr (c.1363G>A)?

AP3D1 p.Ala455Thr (c.1363G>A) is associated with Hermansky-Pudlak syndrome 10, thrombocytopenia (ClinVar).

How common is AP3D1 p.Ala455Thr (c.1363G>A) in the general population?

AP3D1 p.Ala455Thr (c.1363G>A) is rare (popmax 0.108%, nfe) (gnomAD).

How is Hermansky-Pudlak syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about AP3D1 p.Ala455Thr (c.1363G>A)?

AlphaMissense predicts likely benign (score 0.2982) — an in-silico prediction, not a clinical call.

AP3D1 p.Ala455Thr

c.1363G>A · rs200459002 · VCV988866

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2982 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.108%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hermansky-Pudlak syndrome 10

Computational evidence

Protein change
AlphaMissense	0.2982	likely benign
REVEL	0.29	benign-leaning
SaProt	LLR -10.45	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 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 4,612 bp · p 7.4e-05 · regional, not allelic
Overall
CADD	23.8	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 0.108% European (non-Finnish) · 1,275/1,179,992 alleles

Filtering AF 0.103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.101%

Overall 0.0889% 1,433/1,612,056 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.199%	502
European (non-Finnish)grpmax	0.108%	925
Finnishnot grpmax-eligible	0.0662%	1,511
Remaining individualsnot grpmax-eligible	0.0592%	1,689
African / African-American	0.02%	5,004
Admixed American	0.00833%	12,006
South Asian	0.0011%	91,088

Ashkenazi Jewish 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.Ala455Thr
Coding: c.1363G>A
MANE Select: NM_001261826
dbSNP: rs200459002
Type: single nucleotide variant
Location: chr19:2120980 (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

Hermansky-Pudlak syndrome 10 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thrombocytopenia

For Hermansky-Pudlak syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

AP3D1 p.Ala455= Likely benign ★ same residue
AP3D1 c.2001+6C>T Uncertain significance ★★ same condition
AP3D1 c.2601+6G>T Uncertain significance ★★ same condition
AP3D1 p.Ala1213Thr Uncertain significance ★★ ⚠ same condition
AP3D1 p.Arg117Cys Uncertain significance ★★ ⚠ same condition
AP3D1 p.Cys1165Gly Uncertain significance ★★ ⚠ same condition
AP3D1 p.Val1050Ile Uncertain significance ★★ ⚠ same condition
AP3D1 c.463-4G>A Benign/Likely benign ★★ 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-ala455thr (accessed [today's date]).

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