Is AP3D1 p.Arg117Cys (c.349C>T) pathogenic?

AP3D1 p.Arg117Cys (c.349C>T) is classified Uncertain significance in AP3D1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-29). AlphaMissense: likely pathogenic (0.9859); Very rare (popmax 0.00175%, amr); Associated with Hermansky-Pudlak syndrome 10.

What condition is associated with AP3D1 p.Arg117Cys (c.349C>T)?

AP3D1 p.Arg117Cys (c.349C>T) is associated with Hermansky-Pudlak syndrome 10 (ClinVar).

How common is AP3D1 p.Arg117Cys (c.349C>T) in the general population?

AP3D1 p.Arg117Cys (c.349C>T) is very rare (popmax 0.00175%, amr) (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.Arg117Cys (c.349C>T)?

AlphaMissense predicts likely pathogenic (score 0.9859) — an in-silico prediction, not a clinical call.

AP3D1 p.Arg117Cys

c.349C>T · rs754787367 · VCV1434996

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9859 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Hermansky-Pudlak syndrome 10

Computational evidence

Protein change
AlphaMissense	0.9859	likely pathogenic
REVEL	0.456	indeterminate
SaProt	LLR -13.80	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.94 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 28 kb · p 3.4e-09 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00175% Admixed American · 1/57,184 alleles

Filtering AF 0.000621% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000478%

Overall 0.00101% 16/1,589,232 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00175%	57,184
Remaining individualsnot grpmax-eligible	0.00163%	61,506
African / African-American	0.00135%	74,052
European (non-Finnish)	0.00111%	89,860

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.Arg117Cys
Coding: c.349C>T
MANE Select: NM_001261826
dbSNP: rs754787367
Type: single nucleotide variant
Location: chr19:2137016 (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

For Hermansky-Pudlak syndrome (Orphanet):

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

Similar variants

AP3D1 p.Arg117= 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.Ala455Thr 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-arg117cys (accessed [today's date]).

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